Time course and pattern of first relapse in stage I-II

G ITAL DERMATOL VENEREOL 2005;140:191-200
Time course and pattern of first relapse
in stage I-II primary cutaneous melanoma:
a multivariate analysis of disease-free survival in 3 174 patients
followed-up at the Turin Melanoma Centre from 1975 to 2004
M. G. BERNENGO 1, P. QUAGLINO 1, N. CAPPELLO 2, M. T. FIERRO 1, G. C. DOVEIL 1
G. MACRIPÒ 3, S. OSELLA-ABATE 1, A. PERONI 1, F. LISA 1, P. SAVOIA 1
Aim. Our aim is to define the trends in the hazard of overall
relapse and pattern of the first recurrence as functions of time
elapsed from diagnosis and to identify the parameters with
independent predictive value on the relapse risk in stage I-II
melanoma patients according to the revised AJCC classification.
Methods. A total of 3 174 stage I-II melanoma patients diagnosed
and prospectively followed-up since 1975 have been reviewed
as to disease course over time.
Results. A significant increase in the annual hazard of relapse was
found for each time interval from stage IA to IIB/IIC in the
first follow-up decade. The incidence of late metastases was significantly higher in patients with thicker melanoma than in
those with thinner melanoma. Distant relapses showed a low
(<1.5%), but constant annual incidence as first site of recurrence. The lower limb location showed a <1% interval incidence of visceral metastases as first site of relapse, irrespectively of the AJCC stage, compared to 4.7% for the other body
sites. Multivariate analysis of DFS showed that Breslow thickness, presence of ulceration and a primary location to foot carry an independent unfavourable prognostic significance.
Conclusion. The AJCC stage is associated with the incidence and
time course behaviour of the first relapse, the primary location
mainly to the pattern of the first relapse.
KEY WORDS: Disease-free survival - Melanoma follow-up Melanoma recurrence - Prognostic factors - Multivariate analysis.
S
everal studies have focused on the identification
of the prognostic factors predicting the outcome
of primary cutaneous melanoma patients and both the
Address reprint requests to: Prof. M. G. Bernengo, Department of Biomedical Sciences and Human Oncology, 1st Dermatologic Clinic, University of Turin, Via Cherasco 23, 10126, Torino, Italy.
E-mail: [email protected]
Vol. 140 - N. 3
11st Dermatologic Clinic
Department of Biomedical Sciences and Human Oncology
University of Turin, Turin, Italy
2Section of Medical Statistics, Department of Genetics
Biology and Medical Chemistry
University of Turin, Turin, Italy
3Section of Oncological Surgery
Department of Dermatology and Plastic Surgery
S. Giovanni Battista Hospital, Turin, Italy
clinical and histopathologic features with a major influence on survival have now been well established.1-6
Accordingly, it is well known that a disease recurrence occurs in 15% to 35% of patients. In about 2/3
of these cases, the metastatic spread develops primarily as loco-regional recurrence (satellite, in transit and
regional lymph node metastases), whereas the development of distant metastases consequent to an hematogeneous spreading occurs in 10% up to 25-30% of
patients.2-3
However, few papers are available in literature which
provide detailed data as to the metastatic pathway of
cutaneous melanoma, as well as on the time occurrence and pattern of first relapse.1, 5, 7 Moreover, the
parameters associated to a specific metastatic pathway have not yet been clearly defined and the relationship between the Breslow thickness and a higher
incidence of visceral metastases as first site of relapse
is still controversial.7-13
In this paper, 3 174 Italian melanoma patients, diagnosed and followed-up prospectively over a 29 year-
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TIME COURSE AND PATTERN OF FIRST RELAPSE IN STAGE I-II MELANOMA PATIENTS
TABLE I.—Demographic, clinical and pathologic features of the
patients’ cohort.
Parameters
Gender
— Male
— Female
Age (years)
— ≤53
— >53
Breslow thickness (mm)
— ≤1
— 1.01-2
— 2.01-4
— >4
Clark level
— II
— III
— IV
—V
Ulceration
— Present
— Absent
Primary site§
— Head/neck
— Upper limb
— Lower limb
— Anterior trunk
— Back
— Foot
Histotype d, §
— LMM
— SSM-RGP
— SSM-VGP
— ALM
— NCM
— NM
No.
(%)
Relapsesa
(%)
P
1 444 (45.5)
1 730 (54.4)
546 (37.8)
528 (30.5)
<0001b
1 598 (50.3)
1 576 (49.7)
516 (32.3
558 (35.4)
NSb
1 230 (38.8)
612 (19.3)
768 (24.2)
564 (17.8)
92 (7.5)
210 (34.3)
384 (50)
388 (68.8)
<0.001c
662 (20.9)
1682 (53)
680 (21.4)
150 (4.7)
54 (82.2)
562 (33.4)
358 (52.6)
100 (66.7)
<0.001c
934 (29.4)
2 240 (70.6)
592 (63.4)
482 (21.5)
<0.001b
368 (11.6)
366 (11.5)
896 (28.2)
464 (14.6)
814 (25.6)
266 (8.4)
114 (31)
112 (30.6)
276 (30.8)
154 (33.2)
272 (33.4)
146 (54.9)
<0.001c
210 (6.6)
1 684 (53.1)
400 (12.6)
212 (6.7)
86 (2.7)
582 (18.3)
48 (22.9)
308 (18.3)
208 (52)
116 (54.7)
46 (53.5)
348 (59.8)
<0.001c
a) The percentage of relapses has been calculated as the number of patients relapsed divided by the total number of patients with the same feature undergoing follow-up examinations; b) P value according to the χ2 test; c) P value according to the
linear trend test; §) Parameters identified by this symbol were put in order in this table
according to the incidence of relapses; d) Lentigo maligna melanoma (LMM); superficial spreading melanoma, radial growth phase (SSM-RGP); superficial spreading
melanoma, vertical growth phase (SSM-VGP); acral lentigginous melanoma (ALM);
non classified melanoma (NCM); nodular melanoma (NM).
period at a single institution, reclassified as stage I or
II according to the revised AJCC classification, have
been reviewed.
The objectives were to define: 1) the trends in the
hazard of overall relapse and pattern of the first recurrence; 2) the prognostic factors associated to a higher
relapse rate and higher incidence of distant metastases
as first site of relapse; 3) the prognostic factors with
independent predictive value on the disease-free survival.
192
Materials and methods
Patient population and follow-up
The clinical records of 4 182 melanoma patients,
the majority of whom were resident in Piedmont, diagnosed and prospectively followed-up at our Institution from 1975 to 2004 have been reviewed and reclassified according to the new AJCC staging system.3
Patients with incomplete histopathological data
(n=218), non cutaneous melanoma (n=114), cutaneous
in situ (n=215), unknown primary melanoma (n=74)
and multiple primary melanomas (n=183), were
excluded, as well as patients with clinical evidence of
recurrence synchronous to melanoma excision (n=96).
Finally, patients who had undergone elective nodal
dissection (n=33) and those with a positive sentinel
lymph node (SLN) biopsy (n=75) were not included.
The 3 174 patients that met inclusion criteria, with
stage IA to IIC, were classified accordingly: 1 716
patients (54.1%) were stage I (IA: 1 198; IB: 518) and
1 458 stage II (IIA: 512; IIB: 548; IIC: 398).
Follow-up physical examinations were performed
every 2 months for the first 2 years, every 3 months
from the 3rd to the 5th, every 6 months from the 6th to
the 10th and yearly thereafter 14, 15 for all patients irrespectively from Breslow thickness. Radiological procedures (chest X-rays in all patients; abdomen ultrasonography from 1976; brain, chest and abdomen
computed tomography scan from 1978) were done at
diagnosis and every 12 months during follow-up. A
complete restaging was carried out if the clinical picture became suspect. Lymph node dissection was usually performed only in the presence of a palpable
regional adenopathy until 1998; from then on, 274
patients with primary melanoma equal to or more than
1 mm, or thinner in the presence of ulceration and/or
regression and/or Clark level IV-V, underwent SLN
biopsy technique.
The first site of relapse was defined according to
the revised AJCC classification as stage III (regional
recurrences: satellites/in transit/nodal metastases), or
stage IV (distant soft tissue and/or visceral metastases).
Statistical analysis
The disease-free survival (DFS) was defined as the
time lapse from the definite surgery of the primary
melanoma to either the date of relapse or last follow-up
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
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BERNENGO
TABLE II.—Pattern of the first site of relapse according to the AJCC classification and primary melanoma location.
Relapses (%)a
Primary melanoma localisation
Relapses/patients at risk (%)a
Satellites/in transit/nodes
(Stage III)
Stage I
Head-neck, trunk, upper arm
N=652/2 012 (32.4%)
Thigh-leg N=276/896 (30.8%)
Foot N=146/266 (54.9%)
Total N=1 066/3,087 (34.5%)
Stage II
Soft tissue + viscera
(Stage IV)
Viscera
(Stage IV)
Total
Stage I
Stage II
Total
Stage I
Stage II
Total
9.9%
47.5%
26.5%
2.9%
9.7%
5.9%
1.9%
8.1%
4.7%
12.2%
19.7%
15%
52.6%
70.3%
51.9%
29.7%
53.4%
29.7%
1.2%
1.8%
2.7%
1.1%
1.1%
8.1%
1.2%
1.5%
4.8%
0.4%
0.5%
1.9%
0.5%
0.6%
6.1%
0.5%
0.6%
3.6%
a) According to the site of first relapse. The percentage of relapses has been calculated as the number of patients relapsed divided by the total number of patients with
the same feature undergoing follow-up examinations.
visit. A total of 210 out of 2 100 patients disease-free at
the last visit (10%) were lost to follow-up. The interval
between the first diagnosis and the last date known to be
disease-free was more than 10 years in 84 and between
5 and 10 years in 97 of these patients.
The hazard functions were used to evaluate the incidence of relapses (both overall and according to the site
of recurrence). The hazard of relapse was defined as the
probability per time unit that a patient, who is diseasefree at the beginning of the respective interval, will
relapse in that interval. It was computed as the number
of recurrences per time units in the respective interval,
divided by the number of disease-free patients entering the same time interval.11 The time intervals selected were yearly, up to 10 years from the surgery of primary melanoma, between the 10th and 15th and the
15th and 20th year. The hazard differences were analysed
using the Cochran test for linear trend.16
Multivariate DFS analyses were performed at first
diagnosis so as to evaluate the independent prognostic factors influencing the outcome of a patient disease-free at the beginning the follow-up. The parameters included in the multivariate analysis model
were gender, age, primary site, histotype, Breslow
thickness, Clark’s level and ulceration. The variables
age and Breslow thickness were continuous, the others categorical. The variable “histotype” was divided
into 2 groups, according to the relapse incidence (Table
I): in the first, were included the lentigo maligna
melanoma (LMM) and superficial spreading melanoma, radial growth phase (SSM-RGP) histotypes,
which shared a relapse rate less than 20%; in the second, the superficial spreading melanoma, vertical
growth phase (SSM-VGP), acral lentigginous melanoma (ALM), non classified melanoma (NCM) and
Vol. 140 - N. 3
nodular melanoma (NM) histotypes, with relapse incidences ranging from 47.3% up to 62%. The parameter “primary site” was evaluated according to 3 groups:
axial (head/neck, trunk), extremities (upper limb,
thigh/leg), and foot; this latter group was singled out
due to the significant higher relapse incidence found
in our patients’ cohort (54.2%) and on the basis of literature data, showing that the foot location is an independent prognostic unfavourable parameter in patients
with melanoma of the lower extremities. The relationship between DFS and prognostic factors was
determined by the Cox proportional hazard regression model, with a stepwise selection of the significant
variables.
Results
Relapse rate
The clinicopathologic features of the 3 174 patients
included in this study are summarized in Tables I and II,
together with the relapse incidence associated to each
prognostic factor. After a median follow-up of 10.2
years (range: 1-29 years), a relapse occurred in 1 074
patients (33.8%). A regional involvement occurred in the
majority of patients as first site of relapse (928 cases;
86.4%); according to the revised AJCC staging system,
102 were stage IIIA, 620 stage IIIB and 206 stage IIIC.
Only 146 patients (13.6%) developed distant localisations as first site of relapse. The 5- and 10-year DFS
were 67% and 62%, respectively (Figure 1). Significant DFS differences were observed according to the
AJCC stage (Figure 1; Table III).
As expected, a statistically significant higher relapse
rate was found to be associated with the male gender, higher Breslow thickness and deeper Clark lev-
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TIME COURSE AND PATTERN OF FIRST RELAPSE IN STAGE I-II MELANOMA PATIENTS
Global
100
90
90
80
80
70
70
60
%
%
60
50
40
30
30
20
20
10
10
0
5
10
15
A
20
Years
25
30
35
0
40
5
10
15
20
Years
25
30
35
40
Ulceration
90
80
80
70
70
60
%
60
%
0
100
90
50
50
40
40
30
30
Female
Male
20
10
0
IA
IB
IIA
IIB
IIC
B
Gender
100
C
50
40
0
AJCC stage
100
0
5
10
15
20
Years
25
30
35
Absent
Present
20
10
0
40
0
5
10
D
15
20
Years
25
30
35
40
Figure 1A-D.—Univariate analysis of DFS.
el, presence of ulceration and histology of SSM-VGP,
ALM, NM or NCM. According to the primary location, no difference in the relapse rate was found for
melanomas located on the head-neck, back, anterior
trunk, upper limb and thigh-leg; conversely, a primary location to the foot was associated to a statistically significant higher relapse rate (54.9%) with respect
to all the other sites (ranging from 30.6% up to 33.4%).
Actually, patients with a foot primary showed a different AJCC stage distribution, with a statistically
significant higher percentage of stage II vs stage I
with respect to all the other cutaneous locations
(P<0.001; Figure 2).
Time occurrence of the first relapse
The trend in the hazard of relapse was characterized by high values in the 1st year (16.6%), followed
194
by a progressive decrease down to 2.8% at the 5th year
and by a subsequent plateau, which was maintained up
to 20 years from primary melanoma surgery (Figure 3).
The decrease was statistically significant (P<0.001)
for stage IA only between the 1st and 2nd year after
melanoma excision (from 2.6% to 1.2%), for stage IB
and IIA from the 1st to the 4th year (from 9.6% to 4.9%
and from 26.5% to 8.1%, respectively) and for stage IIB
to the 5th year (from 43.3% to 8.5%). The annual
relapse incidence of stage IIC patients dropped to 4.2%
in the 8th year after high values in the first year (49%)
(Figure 4).
Significant differences were found in the time course
according to the pattern of first relapse (Figure 3).
Stage III recurrences showed higher relapse rates in
the first year, followed by a progressive annual
decrease, which was statistically significant until the
4th year, and finally by a plateau. On the other hand,
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TIME COURSE AND PATTERN OF FIRST RELAPSE IN STAGE I-II MELANOMA PATIENTS
Breslow thickness
100
90
80
80
70
70
60
%
%
60
50
40
20
10
0
5
10
15
E
20
Years
25
30
35
20
10
0
40
0
5
10
15
F
20
Years
25
30
35
40
30
35
40
Histologic subtype
100
90
90
80
80
70
70
60
%
60
%
II
III
IV
V
30
Primary site
100
50
40
<1
1.01-2
2.01-3
>4
30
50
50
40
40
30
30
20
20
10
10
0
Clark level
100
90
0
BERNENGO
0
5
10
15
G
Head-neck
Upper limb
20
Years
Back
Lower limb
25
30
35
0
40
0
5
10
H
Anterior trunk
Head-neck
AUM
NM
15
20
Years
UMM
SSM-VGP
25
NCM
SSM-RGP
Figure 1E-H.—Univariate analysis of DFS.
a low (less than 1.5%) but constant annual incidence
was found for distant relapses as first site of recurrence,
even after 10 years. When the pattern of first relapse
was compared within the same time interval, a significantly higher percentage of regional recurrences
was found up to the 7th year of follow-up. After which
time, there was no difference in the pattern of first
relapse.
Pattern of the first relapse
A different pattern in first relapse was seen to be
associated to the primary cutaneous location, rather
than the AJCC stage (Table II). The foot primary location was associated with a significantly higher inci-
Vol. 140 - N. 3
dence of regional recurrence as first site of relapse
(53.4%) compared to the other sites, whilst no differences in the incidence of regional relapses were
observed between the head-neck, trunk, upper arm
(26.5%) and thigh-leg primaries (29.7%).
Conversely, a statistically significant higher incidence of distant metastases as first relapse site was
found for the head-neck, trunk and upper arm locations (5.9%) compared to both thigh-leg (1.2%;
P<0.001) and foot (1.5%; P<0.001). This difference
was even more evident when considering only visceral locations (0.5-0.7% incidence for the thigh-legfoot primaries versus 4.5% for the other sites). Moreover, no difference in the incidence of distant (or visceral) metastases as first site of relapse was found
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TABLE III.—Univariate DFS analysis results.
TABLE IV.—DFS multivariate analysis.
% DFS (year)
Variable
5
10
15
20
94
77.1
55.1
39.2
21
92.5
70.5
50.1
34.5
14.3
89
65.9
47.9
32.2
14.3
86.5
65.9
39.3
32.2
10.7
IA vs IB, IB vs IIA,
IIB vs IIC: P<0.0001
IIA vs IIB: P=0.0002
63.9
70.3
59.1
66.9
66.6
51.1
63.1
49.3
<0.0001
70.8
63.8
65.9
60.8
61.8
58.9
58.4
58.9
NS
68.6
70.4
71.3
69.2
67.8
42.7
65.8
65.6
67.1
65.4
63.8
38.7
65.8
65.6
62.8
57.5
58.7
38.7
65.8
65.6
57.9
57.5
55.6
29
All vs foot P<0.0001
93.6
70.2
50.5
25.2
92
64
44.8
19.1
88.7
59.7
40.3
19.1
86.3
59.7
35.3
15.9
<0.0001
92.2
69.3
44.1
28.3
91.3
64.4
39.2
15.1
89.3
59.9
35.4
15.1
86.5
59.9
22.6
15.1
<0.0001
79
74.7
74.7
74.7
SSM-RGP
SSM-VGP
83.4
49
79.9
44.5
76.4
42.5
73.2
42.5
ALM
43.7
38.3
38.3
38.3
NCM
55.3
50.3
40.2
30.1
NM
Ulceration
Absent
Present
Global
37.3
32.6
28.7
25.9
80.6
33.7
67
76.8
29
62
72.5
27.4
59.9
69.3
25.9
57.1
AJCC stage
IA
IB
IIA
IIB
IIC
Gender
Male
Female
Age
≤53 years
>53 years
Primary site
Head-neck
Upper limb
Lower limb
Anterior trunk
Back
Foot
Breslow thickness
≤1 mm
1.01-2 mm
2.01-4 mm
>4 mm
Clark level
II
III
IV
V
Histotipe
LMM
Coefficient
Standard error
P value
Risk ratio
Breslow thickness
Ulcerationa
Foot primary locationb
0.5795
0.2827
0.0078
0.1248
0.0792
0.0029
0.00001
0.00045
0.00795
1.7851
1.3266
1.0078
a) The variable “ulceration” was coded as follows: absent=0, present=1. b) The variable “primary site” has been introduced in the multivariate analysis model divided into
3 separate dichotomised groups: axial (head/neck, trunk), extremities (upper limb,
thigh-leg), and foot.
Univariate and multivariate DFS analyses
NM vs: NCM P=
0.016, ALM P=0.04
others P<0.0001
LMM vs ALM, NCM
P<0.0001
SSM-VGP vs LMM,
SSM-RGP P<0.0001
SSM-RGP vs LMM,
ALM P<0.0001
<0.0001
between stage I and stage II for the thigh-leg (1.2% vs
1.1% and 0.4% vs 0.5%, respectively) and foot (1.8%
vs 1.1% and 0.5% vs 0.6%, respectively) locations.
On the other hand, the head-neck, trunk and upper
arm primaries showed a 3.3 fold higher relative risk of
developing an early distant relapse and a 4.2 fold higher risk of developing a first visceral relapse, in stage II
patients compared to stage I.
196
Variable
P value
Univariate DFS analysis results are summarized in
Figure 1 and Table III. An unfavourable disease outcome was associated not only with the AJCC stage
but also with male gender, high Breslow thickness and
Clark level, presence of ulceration, histotype of SSMVGP, ALM, NM, NCM, and primary location in the
foot.
Multivariate analysis showed that Breslow thickness, ulceration and primary location to the foot have
an independent adverse prognostic significance at the
time of melanoma excision.
Discussion
Limited data are available in literature about the
trends in the overall relapse hazard and the prognostic
factors associated to a specific metastatic pathway
(lymphatic vs haematic). To get more insights into this
crucial key-point for the development of clinicallybased follow-up guidelines, the evaluation of hazard
functions and multivariate DFS prognostic factors
analysis were used to analyse a cohort of 3 174 Italian
stage I to II melanoma patients diagnosed and followed-up prospectively with homogeneous criteria,
over a 30 year period, at a single institution.
The whole of our results allows to highlight some
critical issues, as follows.
The time occurrence of the first relapse is characterized by a high incidence in the first years, followed
by a plateau extending over a 10 year period after
melanoma excision. These figures support the clinical
need of prolonging follow-up visits even after this
time interval. The decrease in the incidence of relapses in the first years after melanoma excision is particularly evident in thick melanoma. On the other hand,
patients with thin melanoma (stage IA) maintain a low
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TIME COURSE AND PATTERN OF FIRST RELAPSE IN STAGE I-II MELANOMA PATIENTS
70
50
BERNENGO
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
0.0047 0.01 0.09 0.009 0.006 0.43
60
40
40
30
20
10
0
Head-neck
Back
Anterior
trunk
Stage I
Upper
limb
Thigh-leg
Foot
Hazard rate of relapse
% patients
50
30
20
Stage II
Figure 2.—Relationship between AJCC and primary site.
10
20
Hazard rate of relapse
0
0
15
1A
1
2
3
4
5
6
7
8
9 10 15 >20
Years after definite surgery of primary melanoma
1B
IIA
IIB
IIC
Figure 4.—Distribution of the hazard of overall relapse according to the
AJCC stage. The broken lines indicate the intervals during which the hazard decrease is statistically significant. The P values above the graphic
area (Cochran test for linear trend) indicate the hazard of relapse differences
according to the AJCC stage, for each time interval.
10
5
0
0
1
Total
2
3
4
5
6
7
8
9 10 15 >20
Years after definite surgery of primary melanoma
Visceral
Regional
Figure 3.—Distribution of the hazard of overall relapse and according to
the pattern of the first site of recurrence. The broken lines in the graph indicate the intervals during which the hazard decrease is statistically significant.
but almost constant relapse hazard, except for the first
year after melanoma excision. These findings are similar to those previously reported 1, 7, 11 and suggest that
there should not be a reduction in the frequency of
follow-up visits during time in this group of patients.
The hazard rate of relapse is associated to the AJCC
stage in as much as the incidence of recurrences in
each time interval increases significantly from stage IA
Vol. 140 - N. 3
to IIC up to 15 years from primary melanoma excision, even if the relapse rate differences tend to reduce
progressively to the same extent as does the disease-free
period. These figures are in agreement with the results
by Soong et al.,1 who assessed the prognostic significance of the Breslow thickness as the only independent
prognostic variable also in disease-free patients even
after more than 10 years from melanoma excision, and
by Gamel et al.17 who showed that low-and high-risk
melanoma patients share similar probabilities of cure
only after a 15 year follow-up. A consequence is that
the risk of developing late metastases (after more than 10
years from melanoma excision) is higher for patients
with a thick melanoma rather than a thin melanoma.
This is in contrast with previous data which either failed
to identify any parameter with predictive value 18, 19 or
suggested that late recurrences were more likely to
occur in patients with thin melanoma,20, 21 younger
patients, and/or females with melanoma located on
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TIME COURSE AND PATTERN OF FIRST RELAPSE IN STAGE I-II MELANOMA PATIENTS
the extremities.20 It is conceivable that these discrepancies may be attributable to the higher death rate in
thick melanomas during the first few years after primary excision, leading to a major incidence of low or
intermediate risk disease-free melanoma patients being
still alive after more than 10 years.
The time course of regional recurrences (which represent the most frequent first relapse site, accounting
for more than 80% of cases) differs from that of distant metastases as first site of relapse. In fact, the hazard rate of regional recurrences decreases over the first
4 years after melanoma excision, reaching thereafter
a plateau. On the other hand, a very low but constant
annual incidence was found for distant relapses as first
site of recurrence, even after 10 years. These figures
imply that it is not advisable to reduce the frequency
of radiological procedures over time. The hazard for
distant relapses was similar to, but not higher than,
that of regional from the 7th follow-up year. Therefore, the late occurrence of systemic relapses,2, 8, 9, 12
was not confirmed by our results.
The pattern of the first relapse (regional vs visceral)
is mainly associated to the primary site rather than to
the AJCC stage. Conflicting data are reported in literature as to which parameters have a predictive value for
the site of first relapse. Cohn-Cedermark et al.13 found
no association between Breslow thickness and a specific metastatic pathway, whereas a higher incidence
of distant first relapses was reported by Meier et al.9 for
patients with intermediate thickness melanoma and
by Martini et al.12 for patients with melanoma <1.5
mm; other authors suggested a higher risk of local
relapse for thick melanomas.22 Indeed, a higher incidence of early visceral relapses was reported in patients
with head and neck 12, 13 or with a trunk/upper limb
localisation.9 Some authors reported a significantly
lower incidence of first distant relapses in patients
with a lower limb primary 10 whereas others did not
confirm these findings.13 In our study, a primary location to either thigh-leg or foot is associated with an
extremely low (less than 1%) hazard rate of developing visceral metastases as first site of relapse, whilst a
statistically significant higher incidence of visceral
metastases as first site of relapse was found for patients
with melanoma located at the head-neck, trunk and
upper arm (4.7%). The relevance of the body site of the
primary was independent from the AJCC stage, in as
much as no difference in the incidence of distant metastases as first site of relapse was found between stage
198
I and stage II for patients with melanoma localized
on the thigh-leg or foot. These figures imply that radiological procedures in patients with a lower limb
melanoma should be aimed only to confirm the presence of regional adenopathies in clinically doubtful
cases or to evaluate the development of metastases in
the iliac basin not easily objectivable from a clinical
ground alone.
The variables with an independent unfavourable
prognostic relevance on DFS are high Breslow thickness, presence of ulceration, and, to a lesser extent, a
primary location on the foot. The poor prognosis of foot
primaries is therefore not only consequent to the high
Breslow thickness due to its frequent late diagnosis.23
Literature data on this issue are controversial, even if
prognostic studies often include the foot with the other lower limb locations (thigh and leg), which are associated to a better prognosis, thus hampering the assessment of the true independent prognostic relevance of
this body site.1, 2, 24, 25 The few case-control 26, 27 and
multivariate studies 28, 29 that analyse the foot as a separate entity, have shown that this primary location is an
independent adverse prognostic factor for DFS. It is to
underline that, according to our results, the poor prognosis of the foot is associated with a significant increase
in the percentage of regional rather than distant relapses as first site of recurrence. In fact, the risk of visceral involvement as first site of relapse is similar to that
observed for the thigh and leg locations associated to
a more favourable prognosis. This finding may shed
some light onto the biological factors that lead to such
an aggressive behaviour. In fact, it has been suggested that the repeated tissue compression in a weightbearing area could enhance the neoplastic spreading
through the lymphatic vessels and therefore increase
the incidence of regional recurrence.29 These data
clearly indicate that a different follow-up schedule
should be dedicated to patients with a foot primary.
The present analysis, performed on clinical data
collected over a 30-year period, can be potentially
biased by the modifications in both surgical management and radiological procedures that have taken place
over such a long time. Moreover, the revised AJCC
staging system 3 and the introduction of the SLN biopsy technique in the management of melanoma patients,
have brought significant changes to the clinical outcome figures compared to the 1997 version. Even so,
we feel that the results obtained in this study could be
of clinical relevance for the setting of adequate clini-
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TIME COURSE AND PATTERN OF FIRST RELAPSE IN STAGE I-II MELANOMA PATIENTS
cally-based follow-up guidelines. Furthermore, these
data represent homogeneous historical controls to use
as comparison with the long-term follow-up results
on representative cohorts of patients treated with the
SLN biopsy technique, not yet available in literature.
Riassunto
Epoca di comparsa e sede della prima recidiva nel melanoma stadio I-II: analisi multivariata della sopravvivenza
libera da malattia in 3 174 pazienti seguiti dal 1975 al 2004
presso il Centro Melanomi dell’Università di Torino
Obiettivo. Numerosi studi hanno valutato l’impatto di fattori clinico-patologici sul decorso clinico di pazienti affetti
da melanoma. È ben noto, inoltre, come una percentuale di
pazienti variabile tra il 15% ed il 35% sviluppa una recidiva di
malattia; in circa 2/3 dei casi, la prima sede di metastatizzazione
è a livello loco-regionale, mentre lesioni viscerali come prima
sede di progressione di malattia si verificano in una percentuale
di pazienti variabile dal 10% fino al 25-30%. Tuttavia, i fattori associati all’epoca di comparsa ed alla sede della prima recidiva non sono ancora completamente definiti, così come l’andamento del rischio di prima recidiva in funzione dell’intervallo intercorso dall’asportazione del melanoma.
Metodi. In questo lavoro è stata analizzata una casistica
di 3 174 pazienti affetti da melanoma cutaneo in stadio I (IA:
1 716; IB: 518) o II (IIA: 512; IIB: 548; IIC: 398) in base
alla recente classificazione proposta dall’American Joint
Committee on Cancer (AJCC), diagnosticati e seguiti prospetticamente presso il Centro Melanomi dell’Università di
Torino, dal 1975 al 2004. Gli obiettivi sono di definire: 1)
l’andamento del rischio di recidiva, sia complessivo sia in
base alla sede di prima recidiva, in funzione dell’intervallo di
tempo intercorso dall’asportazione; 2) i fattori prognostici
associati ad un maggior tasso di recidiva e ad una maggior incidenza di metastasi a distanza come primo sito di recidiva; 3)
i fattori prognostici con valore predittivo indipendente sulla
durata dell’intervallo libero da malattia. Tutti i pazienti sono
stati sottoposti a periodiche visite di follow-up clinico-strumentale, con criteri omogenei. Le visite cliniche di follow-up
sono state effettuate ogni 2 mesi per i primi 2 anni, ogni 3 mesi
dal 3° al 5° anno, ogni 6 mesi dal 6° al 10° anno e annualmente
in seguito per tutti i pazienti indipendentemente dallo spessore di Breslow. Accertamenti radiologici sono stati effettuate alla diagnosi e ogni 12 mesi durante il follow-up. La dissezione linfonodale è stata effettuata solo in presenza di adenopatia regionale palpabile fino al 1998; a partire da allora,
274 pazienti con melanoma primitivo di spessore maggiore
o uguale a 1 mm, o inferiore in presenza di ulcerazione e/o
regressione e/o IV-V livello di Clark, sono stati sottoposti a
biopsia linfonodale secondo la tecnica del linfonodo sentinella.
Risultati. Dopo un follow-up mediano di 10,2 anni (range: 1-29 anni), 1 074 pazienti hanno sviluppato una recidiva
di malattia (33,8%), la maggior parte dei quali a livello regio-
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BERNENGO
nale (928 casi, 86,4%). Solo 146 pazienti (13,6%) hanno sviluppato metastasi a distanza come prima sede di recidiva. La
percentuale di pazienti liberi da malattia a 5 anni è risultata
67%, a 10 anni 62%. L’incidenza annuale di recidive è stata
valutata in funzione dell’intervallo di tempo intercorso dall’asportazione del melanoma, come rapporto tra il numero di
pazienti recidivati in un anno ed il numero di pazienti in follow-up durante il medesimo intervallo di tempo. Globalmente, il rischio di recidiva presenta un andamento bifasico, caratterizzato da elevati valori nel primo anno (16,6%), seguiti da
un decremento progressivo fino al 2,8% al 5° anno e da un successivo plateau, che rimane costante fino a 20 anni dall’exeresi del primitivo. Analizzando tale andamento anche in funzione dello stadio AJCC, emerge come la riduzione del rischio
di recidiva sia soprattutto evidente per pazienti con melanoma
spesso; al contrario, pazienti con melanoma sottile (stadio
IA) mostrano una riduzione nell’incidenza di recidive solo
nel primo anno, ed in seguito mantengono valori costanti
anche oltre i 10 anni dall’asportazione del melanoma. Riteniamo pertanto che non vi siano indicazioni a ridurre la frequenza di visite di follow-up nel tempo, almeno in questo
gruppo di pazienti. Tuttavia, il rischio annuo di recidiva risulta costantemente associato allo stadio AJCC: ciò significa che
pazienti con melanoma spesso presentano un’incidenza di
recidive maggiore rispetto a quelli con melanoma sottile anche
oltre i 10 anni dalla prima diagnosi. Ciò significa che il rischio
di metastasi tardive è sempre maggiore per pazienti con melanoma spesso rispetto a pazienti con melanoma sottile, in contrasto con quanto riportato in letteratura. L’analisi dell’incidenza
di recidiva in funzione dell’epoca e sede di comparsa ha evidenziato come il rischio di prima recidiva a distanza (viscerale
e/o tessuti molli) sia basso (non superiore a 1,5% annuo), ma
costante nel tempo. Da un punto di vista clinico, pertanto,
non vi sono indicazioni a ridurre nel tempo la frequenza di indagini strumentali. La sede di prima recidiva è risultata associata alla sede del primitivo piuttosto che allo stadio AJCC. La
localizzazione primitiva al piede è risultata associata ad una
incidenza statisticamente superiore di prima recidiva regionale
(53,4%) in confronto alle altre sedi. Al contrario, un’incidenza statisticamente superiore di metastasi a distanza come primo sito di recidiva è stata documentata per melanomi localizzati
a livello della testa-collo, tronco e arti superiori (5,9%) nei
confronti di melanomi a livello della coscia-gamba (1,2%:
p<0,001) e del piede (1,5%; p<0,001); considerando solo le
localizzazioni viscerali, questa differenza diveniva ancora più
evidente (0,5-0,7% di incidenza per le localizzazioni primitive a coscia-gamba-piede vs 4,5% per gli altri siti). Inoltre,
nessuna differenza nell’incidenza di metastasi a distanza (o
viscerali) come prima sede di recidiva è stata trovata tra pazienti in stadio I e stadio II per melanomi localizzati a livello della coscia-gamba (1,2% vs 1,1% e 0,4% vs 0,5% rispettivamente) e del piede (1,8% vs 1,1% e 0,5% vs 0,6% rispettivamente). Questi risultati evidenziano come in pazienti con
melanoma localizzato all’arto inferiore (coscia-gamba e piede), l’esecuzione di indagini radiologiche debba essere mirata pressoché esclusivamente all’individuazione precoce di
adenopatie regionali profonde. L’analisi multivariata dell’in-
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TIME COURSE AND PATTERN OF FIRST RELAPSE IN STAGE I-II MELANOMA PATIENTS
tervallo libero da malattia ha evidenziato come fattori prognostici sfavorevoli un elevato spessore di Breslow, la presenza di ulcerazione ed una localizzazione del melanoma primitivo a livello del piede. Ci sembra pertanto opportuno sottoporre pazienti con melanoma localizzato al piede a visite
cliniche di follow-up più ravvicinate.
Conclusioni. Lo stadio AJCC è associato all’incidenza ed
all’epoca di comparsa della prima recidiva, mentre la sede
del melanoma primitivo determina maggiormente il pattern della prima recidiva. Riteniamo che i risultati del presente lavoro possano costituire la base per la stesura di linee-guida di follow-up clinico-radiologico basate su evidenze cliniche.
Parole chiave: Melanoma - Follow-up - Sopravvivenza libera da melanoma - Prognosi - Analis multivariata.
12.
13.
14.
15.
16.
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G ITAL DERMATOL VENEREOL 2005;140:201-10
Retrospective study of mycotic infections
of the feet due to dermatophytes and moulds
in Siena from 1993 to 2002
C. ROMANO, A. GHILARDI, L. MASSAI, E. MARITATI, M. FIMIANI
Aim. The aim of this paper is to evaluate the occurrence of
mycotic infections due to dermatophytes and moulds, diagnosed at the Mycology Unit of the Dermatology Department,
Siena, the only unit in Siena Province offering mycological
examination, from 1993 to 2002.
Methods. Five hundred and thirthy-nine patients with suspected mycotic infection underwent mycological examination.
Diagnosis was based on direct microscope observation and culture of pathological material on Sabouraud dextrose agar with
CAF and cycloheximide and on Sabouraud dextrose agar with
CAF only.
Results. Dermatophyte infections were found in 190 cases (112
males, 78 females, age 5-71 years, mean age 38) and mould
infections in 13 cases (9 males, 4 females, age 28-52 years, mean
age 37). With regard to dermatophyte infections, Trichophyton
rubrum was isolated in 71% of cases, Trichophyton mentagrophytes in 21% and Epidermophyton floccosum in 8%. The infections manifested as intertrigo in 87%, tinea pedis bullosa in
8%, “moccasin foot” in 4% and intertrigo plus bullae in 1%.
With regard to mould infections, Fusarium was isolated in 11
cases (Fusarium oxysporum in 10 cases and Fusarium solani
in 1). The clinical picture was interdigital intertrigo with areas
of whitish, macerated and eroded skin. Scytalidium hyalinum
was isolated in 2 cases. The clinical manifestations were “moccasin foot” in 1 case, plantar and interdigital desquamation in
the other.
Conclusion. Mycotic infections of the feet are usually caused by
dermatophytes, rarely (7%) by moulds. The most frequent site
is between toes IV and V. Predisposing factors are warm maceration, occlusion and, in mould infections, contact with soil.
When mycotic infections of the feet are suspected, it is advisable
Address reprint requests to: C. Romano, Via Monte Santo 3, 53100
Siena, Italy. E-mail: [email protected]
Vol. 140 - N. 3
Section of Dermatology,
Department of Clinical Medicine
and Immunological Science
University of Siena, Siena, Italy
to perform mycological examination with culture of pathological material not only on Sabouraud dextrose agar with CAF
and cycloheximide but also on Sabouraud dextrose agar with
CAF only. Long-standing monitoring of mould infections is
necessary because they are dangerous in immunodepressed
patients.
KEY WORDS: Mycosis - Feet - Tinea pedis - Dermatophytes Moulds.
M
ycotic infections of the feet are pratically widespread in developed countries at all latitudes
and are caused prevalently by dermatophytes such as
Trichophyton rubrum and Trichophyton mentagrophytes var. interdigitalis, less often Epidermophyton
floccosum. In certain geographical areas, as Poland
and USA, Trichophyton tonsurans and Trichophyton
violaceum have also been isolated.1, 2 It is known that
some peculiar environmental situations, as warm moist
climate, may favour the manifestation of dermatophytoses. About tinea pedis, maceration, excessive
sweating, rubber shoes, repeated trauma and poor personal hygiene are particularly considered predisposing
factors to the infection. For example, people practis-
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RETROSPECTIVE STUDY OF MYCOTIC INFECTIONS OF THE FEET DUE TO DERMATOPHYTES AND MOULDS IN SIENA
ing sports, such as swimming 3 and athletics,4 as well
as military personnel 5, 6 and coal miners 7, 8 are more
susceptible. It is no wonder that the infection can be
easily transmitted by the contact with infectious particles found in the environment like bathrooms, communal bathing places, swimming pools 9 and gymnasium floors. The most frequent form of tinea pedis is
interdigital, initially between toes IV and V. The least
frequent forms are vesico-bullous and “moccasin foot”.
Tinea pedis occurs prevalently in adults and is regarded as infrequent before puberty, but it may be misdiagnosed in children 10-12 where bullous form is more
frequent than in adults.13
Mycotic infections of the feet due to moulds, unlike
those due to dermatophytes, are rarely reported. They
are mainly due to Scytalidium and Fusarium. Infections
due to Scytalidium spp (dimidiatum and hyalinum)
have been described in residents of, or visitors to, tropical and subtropical countries,14 whereas autochthonous
cases are rare.15, 16 Scytalidium hyalinum has only been
isolated from human skin lesions, Scytalidium dimidiatum also from soil and plant litter. The clinical manifestations are indistinguishable from those of Trichophyton rubrum (desquamation and hyperkeratosis of the interdigital spaces and foot sole).4 Since
Fusarium is a soil saprophyte with world-wide distribution. Direct contact with soil, for example by going
barefoot, is a predisposing factor, as frequent wetting
of feet and excessive sweating are. Clinical manifestations are characterised by areas of moist white skin
between toes IV and V, often bilateral.17-19 Only one
case with a plantar infection due to Scopulariopsis
brevicaulis has been described until now.20 Mould
infections of the feet are constantly increasing everywhere 21, 22 but, while they can be limited to the skin in
immunocompetent patients, they may provoke deep
infections, sometimes fatal, in immunodepressed
patients.23, 24
We report a retrospective study of infections of the
feet diagnosed in Siena by mycological examination,
both with direct microscope and with coltural examination, between 1993 and 2002. The aim was to determine the occurrence of mycotic infections due to dermatophytes and moulds of the feet in Siena.
Methods
From March 1993 to March 2002, 539 cases of suspected mycotic infections of the feet underwent myco-
202
logical examination at the Mycology Laboratory, Dermatology Department, Siena University Hospital. They
included inpatients and outpatients. Diagnosis, performed by the same medical staff, was based on direct
microscope examination of pathological material
(flakes, blister roofs and liquid) after soaking in 30%
KOH and on culture of the same material on Sabouraud
dextrose agar with CAF and cycloheximide and on
Sabouraud dextrose agar with CAF only.
Dermatophytes were identified on the basis of macro
and microscopic characteristics of colonies according to the criteria of Rebell and Taplin.25 For moulds
we used the criteria of De Hoog.26 In particular, if a
mould grew in pure culture, its pathogenicity was
demonstrated by the same results when the pathological material was sown twice more at intervals of at
least 7 days.27 With their consent, histological examination of biopsy specimens was performed in 6/11
patients with Fusarium infection. Age, gender, occupation, habits, residence and any risk factors were
recorded for all patients. When mycological examination of material from the feet was positive and the
patient also had lesions in other parts of the body that
could be due to fungal infection, mycological examination was repeated with material from those lesions.
Results
In 539 cases of suspected fungal infection, 203 cases of mycotic infections of the feet were diagnosed
by mycological examination: 190 (93.6%) cases were
due to dermatophytes and 13 (6.4%) to moulds. In
cases with dermatophyte infections, direct microscope
observation and culture were positive in 176 (34%)
and 189 (36%) patients, respectively. The dermatophytes isolated were Trichophyton rubrum (71%), Trichophyton mentagrophytes interdigitale (21%) and
Epidermophyton floccosum (8%). The patients were
112 males (59%) and 78 females (41%) with a mean
age of 38 years (range 5 to 71 years). The clinical
manifestations were intertrigo in 165 cases (87%),
bullae in 16 (8%) and “moccasin foot” in 7 patients
(4%). Two patients (1%) had both intertrigo and bullae. Table I shows distribution according to age. Risk
factors and occupation are shown in Tables II and III.
We were only able to find predisposing factors in 60
cases (32%). Ninety-three percent of patients lived in
urban areas. In 16 patients (8%) tinea pedis was associated with onychomycosis, in 3 (1.6%) with tinea
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RETROSPECTIVE STUDY OF MYCOTIC INFECTIONS OF THE FEET DUE TO DERMATOPHYTES AND MOULDS IN SIENA
ROMANO
TABLE I.—Distribution in relation to age.
Age
Patients
Total
<20
21-30
31-40
41-50
51-60
>60
12
8
14
24
30
19
29
16
15
9
10
4
110
80
20 (11%)
38 (20%)
49 (25%)
45 (24%)
24 (13%)
14 (7%)
190
Males
Females
Total
TABLE II.—Predisposing factors.
Risk factors
No. cases
Swimming
Soccer
Gym
Rubber shoes
Excessive sweating
13 (7%)
7 (4%)
9 (5%)
18 (10%)
13 (7%)
TABLE III.—Occupation in 162 out 190 cases with dermatophytes.
No. cases
Males
Females
40 (25%)
70 (43%)
15 (9%)
7 (4%)
30 (19%)
20 (22%)
45 (50%)
7 (8%)
0 (0%)
18 (20%)
20 (28%)
25 (35%)
8 (11%)
7 (10%)
12 (17%)
162 (100%)
90 (100%)
72 (100%)
Figure 1.—Direct microscope examination of pathological material, after
soaking in 30% KOH added with Blue Parker ink: non dermatophytic
hyphae of large size and irregular diameter (250×).
Figure 2.—Macroscopic feature of culture of Fusarium oxysporum: pink
and cottony colonies.
Figure 3.—Microscopic examination: sickle-shaped thin-walled macroconidia typical of Fusarium.
cruris and in 2 (1%) with tinea manuum: also in these
cases, the same dermatophyte responsible of the infection of the feet was isolated.28, 29 The age range most
affected was 31-40 years. There were only 4 cases in
children under 10 years of age. The major predisposing factor was constant use of gym shoes (10%).
Students
Blue collar workers
White collar workers
Housewives
Unemployed
Total
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TABLE IV.—Agent isolated, details of patients, site of infection, therapy and follow-up.
Sex
Age
(years)
Origin
Site
Therapy
Follow-up
F. solani
M
34
Senegal
Bilateral interdigital spaces III and
IV
Apparent recovery, culture again
positive 7 months later
F. oxysporum
M
28
Senegal
Bilateral interdigital spaces II, III
and IV
F. oxysporum
F
32
Senegal
F. oxysporum
M
33
Senegal
Bilateral interdigital spaces III
and IV, lamellar desquamation
of sole, heel and dorsum of foot
Bilateral interdigital spaces III and
IV
F. oxysporum
M
29
Senegal
F. oxysporum
F
41
Italy
F. oxysporum
F
39
Italy
Bilateral interdigital spaces III and
IV
F. oxysporum
M
36
Italy
Bilateral interdigital spaces III and
IV
F. oxysporum
M
45
Italy
Bilateral interdigital spaces III and
IV
F. oxysporum
M
52
Italy
Bilateral interdigital spaces III and
IV
F. oxysporum
M
40
Italy
S. hyalinum
M
41
Italy
Bilateral interdigital spaces II, III
and IV, proximal onychomycosis of big toes
Moccasin foot
S. hyalinum
M
35
Italy
Bilateral plantar and interdigital
Systemic (250 mg) and
topical terbinafine ×
12 weeks
Systemic (250 mg) and
topical terbinafine ×
12 weeks
Itraconazole 200 mg ×
8 weeks, topical imidazole
Itraconazole 200 mg ×
6 weeks, topical imidazole
Itraconazole 200 mg ×
6 weeks, topical imidazole
Itraconazole 200 mg ×
6 weeks, topical imidazole
Itraconazole 200 mg ×
6 weeks, topical imidazole
Itraconazole 200 mg ×
6 weeks, topical imidazole
Itraconazole 200 mg ×
6 weeks, topical imidazole
Itraconazole 200 mg ×
6 weeks, topical imidazole
Itraconazole 200 mg ×
6 weeks, topical imidazole
Itraconazole 100mg × 4
weeks
Topical imidazole derivatives × 5 weeks
and itraconazole 100
mg × 4 weeks
Agent
Bilateral interdigital spaces III and
IV, proximal onychomycosis of
big toes
Bilateral interdigital spaces III and
IV
Figure 4.—Irregular and septate hyphae and spores in the stratum corneum (Gomori-Grocott 400×).
204
Clinical recovery, culture remained positive
Clinical and mycological recovery,
culture again positive 10 months
later
Clinical and mycological recovery,
culture again positive 9 months
later
Clinical and mycological recovery,
culture again positive 9 months
later
Clinical and mycological recovery,
culture again positive 6 months
later
Clinical and mycological recovery,
culture again positive 6 months
later
Clinical and mycological recovery,
culture again positive 4 months
later
Clinical and mycological recovery,
culture again positive 4 months
later
Clinical and mycological recovery
Clinical and mycological recovery,
culture again positive 6 months
later
Clinical and mycological recovery
Clinical and mycological recovery
Figure 5.—Macerated, whitish and eroded skin in a patient with intertrigo due to Fusarium oxysporum.
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RETROSPECTIVE STUDY OF MYCOTIC INFECTIONS OF THE FEET DUE TO DERMATOPHYTES AND MOULDS IN SIENA
With regard to occupation, blue collar workers were
the category most affected, constituting 37% of cases.
The most frequently associated dermatophytosis was
onychomycosis (8%).
In 13 cases of mould infection, direct microscope
examination was always positive, showing non dermatophytic hyphae of large (Figure 1) size and irregular diameter in cases due to Fusarium and hyaline
hyphae, more sinuous than those typical of dermatophytes, of variable size and in 1 of the 2 cases with
double-contoured appearance in the 2 cases with Scytalidium hyalinum.30 Similarly, culture on Sabou-raud
dextrose agar with CAF only, repeated at least three
times with multiple inoculations, always produced
pure cultures of the same mould.27 Fusarium oxysporum (Figures 2, 3) was isolated in 10 cases, Fusarium
solani in 1 case (Table IV shows clinical findings,
therapy and follow-up) and Scytalidium hyalinum in 2
cases.31
Histological examination of biopsy specimens of 6
patients with infection due to Fusarium revealed large
septate hyphae and spores in the stratum corneum
(PAS and Gomori-Grocott) (Figure 4). The clinical
picture was interdigital intertrigo in all cases. An
example of interdigital intertrigo due to Fusarium is
shown in Figure 5. Skin between toes IV and V was
always whitish, macerated and eroded. It was intensely painful in 7 and painless in 4 patients. Five were
farmers, 4 sometimes went barefoot and 2 reported
excessive sweating. The mean age of patients was 37
years. Seven patients had contact with soil. In all
patients with the infection of the feet, a topical and/or
systemic treatment was established, referring to the
current guidelines.32, 33 It is important to underline
that complete recovery was not achieved by 10/11
patients with Fusarium infection (both clinical and
micological): despite clinical improvement or recovery, culture remained always positive in 1 case (case
2 Table IV), and became negative but returned positive within 4-10 months in nine patients. Two patients
also had associated onychomycosis due to the same
mould.
In 1 case the clinical form of infections due to Scytalidium was “moccasin foot” with bilateral erythemato-squamous patches and hyperkeratosis, principally on the sole and sides of the foot, and less striking lesions in the interdigital spaces. In the other it
was bilateral interdigital and plantar desquamation.
The 2 patients had been to the Caribbean and often
went barefoot.31
Vol. 140 - N. 3
ROMANO
Discussion
Interdigital intertrigo emerges from our study as
the most frequent clinical form of tinea pedis (86%).
Trichophyton rubrum was the most frequent dermatophyte (71%). Imported dermatophytes, such
as Trichophyton violaceum and Trichophyton tonsurans, which have reappeared in Siena province
as agents of tinea capitis and tinea corporis,34, 35
were not found responsible for cases of tinea pedis
before 2002.
Our findings are in line with those of European 1 and
Italian studies conducted from the ’70s to the ’90s in
Rome, Milan and Florence 36-38 and in Cagliari in 2000.39
The latter study is different from our being the subjects
resident in rural areas. We were only able to find predisposing factors in 60 cases (32%). However, in a
recent Italian study, risk factors for superficial fungal
infections could be rarely determined.40 In our population, 20 patients (11%) used steroid cream of their own
initiative or because it was prescribed by the family
doctor, who had misdiagnosed the fungal infection as
eczema and in one case as psoriasis. This underlines
the importance of mycological examination, because
the clinical manifestations of dermatophytic tinea pedis
may not be easy to distinguish from other skin diseases
and from infections caused by other pathogens, such
as bacteria. Clinically, interdigital bacterial infections
usually have more macerated, weeping and painful
lesions than those due to dermatophytes, however an
intensely inflamed tinea pedis may simulate a bacterial cellulites.41
A clinical picture similar to that caused by bacterial disease, with intense maceration, is also typical of
interdigital infections due to Fusarium.17-19 In our population, 6.4% of foot infections were caused by moulds.
The criterion used to demonstrate their pathogenicity
was rigorous, consisting in repeated direct microscope
examination and culture.27 The pathological material
was sown on Sabouraud dextrose agar with chloramphenicol only, because cycloheximide inhibits mould
growth. Similarly on diagnostic procedures followed in
onychomycosis due to moulds,42 when the biopsy was
possible, the histological diagnosis confirmed the patogenical behaviour of the mould, showing its presence
in the stratum corneum 43 (Figure 4). One case of Fusarium infection was observed per year from 1996 to 2001
and 5 cases in 2002. Five cases were diagnosed in Senegalese patients, 6 in Italian patients. In 4 patients, the
infection was discovered by chance during a careful
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dermatological examination for other complaints
(urticaria, eczema, plantar warts). Only 1 patient
achieved clinical and mycological recovery. The others are subject to clinical and immunological followup. All are HIV-negative and immunocompetent, as
indicated by assay of immunoglobulins, complement
and lymphocyte subpopulations. We considered these
tests advisable because Fusarium spp may cause
invasive infections, sometimes fatal, in immunodepressed subjects, especially if neutropenic (<500 neutrophils/mm3) due to its distinct angioinvasion. Besides
oral and respiratory routes, a 3rd route of Fusarium
infection is cutaneous,23 as reported by Bodey et al. in
35 patients with blood malignancies who developed
disseminated Fusarium infection.44 Unsuccessful therapy in our series is in line with reports that cutaneous,
deep and disseminated Fusarium infection is often
relatively unresponsive to conventional systemic
antimycotics 24, 32 and it is still early to know the efficacy of new generation imidazoles.33, 45, 46 Moreover,
in vitro sensitivity may not always accurately predict
in vivo response.47
The 2 cases of infection due to Scytalidium were
presumably sporadic, as 1 was observed in 1997 and
the other in 1998, in 2 patients who had been to the
Caribbean where mould is endemic.31 As far as we
know, the mould has not been isolated in Siena or Italy
since then, whereas in other European countries, such
as France and the UK, 3% of foot infections are
ascribed to Scytalidium spp.48, 49 Lacroix recently proposed that cutaneous Scytalidium infection could be a
portal of entry for disseminated infection 48 in immunodepressed patients.50 If we exclude the 2 cases of intertrigo due to Fusarium observed in Milan,19 there have
been no other reports of foot infections due to moulds in
Italy, even if Fusarium is responsible for an increasing
number of cases of onychomycosis.21, 51-53 This suggests that the infection of the feet is underestimated for
two reasons:
1) if asymptomatic, the infection can be unobserved
and be discovered only by chance during meticulous
dermatological examination, as occurred in 4 of our
cases;
2) since mycology laboratories do not use medium
without cycloheximide on a routine basis and therefore
some moulds may not be diagnosed from cultures. On
the other hand, direct microscope examination does not
always allow us to identify non dermatophytic hyphae
without hesitation.
206
Conclusions
When mycotic infections of the feet are suspected,
we therefore recommend carrying out mycological
examination with culture of pathological material not
only on Sabouraud dextrose agar with CAF and cycloheximide but also on Sabouraud dextrose agar with
CAF alone. If therapy is unsuccessful when diagnosis
of tinea pedis was based on direct microscope examination only, mould infection should be suspected and
culture performed. In cases of repeated isolation of
Fusarium in pure culture, demonstrating its pathogenicity, and eventual confirmation by histological
examination, it is advisable to assess patient condition and perform follow-up to avoid dissemination
with possibly fatal outcome in the event of immune
depression. The increasing number of immunodepressed patients opens the prospect of a further increase
in mould infections. It is therefore important that hospitals have specialised mycology laboratories equipped
for the surveillance and control of these infections.
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45. Jensen TG, Gahrn-Hansen B, Arendrup M, Bruun B. Fusarium fungaemia in immunocompromised patients. Clin Microbiol Infect 2004;
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48. Lacroix C, Kac G, Dubertret L, Morel P, Derouin F, de Chauvin MF.
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50. Benne CA, Neeleman C, Bruin M, de Hoog GS, Fleer A. Disseminating
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51. Tosti A, Piraccini BM, Lorenzi S. Onychomycosis caused by nondermatophytic molds: clinical features and response to treatment of
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52. Godoy P, Nunes E, Silva V, Tomimori-Yamashita J, Zaror L, Fischman O. Onychomycosis caused by Fusarium solani and Fusarium
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Infezioni micotiche dei piedi da dermatofiti e muffe a Siena.
Studio retrospettivo dal 1993 al 2002
L
e micosi dei piedi sono infezioni, praticamente ubiquitarie,
causate prevalentemente da alcune specie di dermatofiti, quali Tricophyton rubrum e Tricophyton mentagrophytes
e, meno spesso, da Epidermophyton floccosum. In alcune
Vol. 140 - N. 3
aree geografiche, come la Polonia, la Spagna e gli Stati Uniti, possono essere in causa anche Tricophyton tonsurans e
Tricophyton violaceum 1, 2. È noto che alcune peculiari situazioni ambientali, come il clima caldo umido, possano favo-
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rire l’insorgenza di tutte le dermatofitosi. Nel caso della tinea
pedis, in particolare sono considerati fattori predisponenti
all’infezione, soprattutto la macerazione, l’eccessiva sudorazione, l’uso di scarpe di gomma, i traumi ripetuti e la scarsa igiene personale. Coloro che praticano sport quali nuoto 3
e atletica leggera 3, i militari 5, 6 e i minatori 7, 8 sono abitualmente esposti a più circostanze predisponenti e risultano perciò più suscettibili a questo tipo di patologia. Non
meraviglia perciò che l’infezione possa trasmettersi più facilmente attraverso il contatto con il materiale infetto presente in ambienti come bagni, piscine 9, palestre e docce pubbliche. La forma più comune di tinea pedis è quella che solitamente esordisce a livello del III-IV spazio interdigitale
con desquamazione. Meno frequenti sono la forma vescico-bollosa e il «piede a mocassino». L’infezione, tipica dell’età adulta, è infrequente nel periodo prepuberale 10-12, spesso non viene diagnosticata nei bambini, nei quali pare prevalere la forma bollosa 13.
Le infezioni micotiche dei piedi provocate da muffe, a
differenza di quelle da dermatofiti, sono descritte raramente. Scytalidium e Fusarium spp sono i più comuni agenti
causali. Le infezioni da Scytalidium spp. (dimidiatum e hyalinum) sono descritte in pazienti che hanno soggiornato in aree
tropicali e subtropicali o che vi risiedono 14, rari risultano
invece i casi autoctoni 15, 16. Scytalidium hyalinum è stato isolato esclusivamente da lesioni cutanee umane, Scytalidium
dimidiatum anche dal terreno e dalle piante in decomposizione. Il quadro clinico è indistinguibile da quello causato da
Trichophyton rubrum (desquamazione, ipercheratosi degli
spazi interdigitali e della pianta dei piedi) 4. Fusarium è un
saprofita del terreno diffuso a tutte le latitudini. Il contatto
diretto della cute col suolo, come l’abitudine di camminare
scalzi, ma anche l’eccessiva sudorazione o le frequenti abluzioni dei piedi costituiscono i principali fattori predisponesti a contrarre l’infezione. Essa si manifesta con macerazione della cute ad esordio interdigitale, spesso bilaterale 17-19.
A tutt’oggi la muffa Scopulariopsis brevicaulis è risultata
responsabile solo di un caso di infezione plantare 20. Le infezioni causate da alcune muffe sono ovunque in costante
aumento 21, 22 ma, mentre negli immunocompetenti restano
confinate alla cute, negli immunodepressi possono essere
causa di infezioni invasive, talora fatali 23, 24.
Riportiamo uno studio retrospettivo relativo alle infezioni micotiche dei piedi diagnosticate a Siena, mediante esame micologico, sia microscopico diretto che colturale, nel
decennio 1993-2002. Lo scopo del lavoro era quello di calcolare la frequenza delle forme causate da dermatofiti e da
muffe nella nostra città.
Materiali e metodi
Dal marzo 1993 al marzo 2002, sono stati sottoposti ad esame micologico, presso il Laboratorio di Micologia dell’Istituto di Dermatologia dell’Università di Siena, 539 pazienti sia con sospetta infezione micotica dei piedi ricoverati che
ambulatoriali. La diagnosi, formulata sempre dallo stesso
208
staff medico, si basava sull’esame microscopico diretto del
materiale patologico (squame, tetto e liquido di bolla), dopo
macerazione in idrossido di potassio (KOH) al 30% e su
quello colturale dopo semina su terreno di Sabouraud destrosio agar con cloramfenicolo (CAF) e cicloeximide e su
Sabouraud destrosio agar addizionato di solo CAF.
I dermatofiti venivano identificati sulla base delle caratteristiche macroscopiche e microscopiche delle colonie in
accordo con i criteri di Rebell e Taplin 25. Nel caso delle muffe abbiamo usato i criteri di De Hoog 26. In particolare, in
caso di crescita in coltura pura di una muffa, la sua patogenicità
veniva dimostrata quando due ulteriori semine di materiale
patologico, eseguite ad intervalli di 7 giorni, consentivano
di isolare sempre lo stesso micete in coltura pura 27. In 6
degli 11 pazienti con infezione da Fusarium spp, che avevano
acconsentito a sottoporsi a prelievo bioptico, si effettuava
l’esame istologico. Di tutti i pazienti venivano annotati età,
sesso, occupazione, residenza, abitudini e fattori di rischio.
Quando l’esame micologico risultava positivo ed il paziente presentava lesioni suggestive di dermatofitosi in altre parti del corpo, veniva eseguito l’esame micologico sul materiale
prelevato da tali sedi.
Risultati
Su 539 casi di sospetta infezione fungina venivano diagnosticati, mediante esame micologico, 203 casi di micosi dei
piedi: 190 (93,6%) erano causate da dermatofiti e 13 (6,4%)
da muffe. Nei casi di infezione dermatofitica, l’esame microscopico diretto era positivo in 176 (34%) pazienti e quello colturale in 189 (36%). I dermatofiti isolati erano Trichophyton
rubrum (71%) Trichophyton mentagrophytes interdigitale
(21%) e Epidermophyton floccosum (8%). I pazienti erano
112 di sesso maschile (59%) e 78 di sesso femminile (41%)
con una età media di 38 anni (range 5-71 anni). Le manifestazioni cliniche erano di tipo intertriginoso in 165 casi
(87%), bolloso in 16 (8%) e a «piede a mocassino» in 7
(4%). Due pazienti (1%) presentavano sia intertrigine che bolle. La Tabella I indica la distribuzione in accordo con l’età.
Le Tabelle II e III riportano i fattori di rischio e l’occupazione.
Sono stati rilevati fattori predisponenti solo in 60 casi (32%).
Il 93% dei pazienti proveniva da aree urbane. In 16 (8%) la
tinea pedis era associata ad onicomicosi, in 3 (1,6%) a tinea
cruris e in 2 (1%) a tinea manuum: anche in queste sedi
veniva isolato lo stesso dermatofita responsabile dell’infezione dei piedi 28, 29. Il range di età più colpito era compreso fra 31 e 40 anni. Si osservavano solo 4 casi in bambini al
di sotto dei 10 anni di età. Il fattore di rischio più spesso
riscontrato era l’uso di scarpe da ginnastica (10%).
Riguardo all’occupazione, lavoratori dediti a mansioni
prevalentemente manuali erano maggiormente affetti (37%).
La dermatofitosi più frequentemente associata alla tinea
pedis risultava l’onicomicosi (8%).
Nei 13 casi di infezione da muffe l’esame microscopico
diretto è risultato sempre positivo con presenza di ife non
dermatofitiche di grosse dimensioni e diametro irregolare
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
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RETROSPECTIVE STUDY OF MYCOTIC INFECTIONS OF THE FEET DUE TO DERMATOPHYTES AND MOULDS IN SIENA
nei casi da Fusarium (Figura 1) e di ife ialine, più sinuose di
quelle tipiche dei dermatofiti, di taglia variabile e, in uno dei
due casi, con doppio contorno, in quelle da Scytalidium hyalinum 30. Anche l’esame colturale su terreno di Sabouraud
destrosio agar con solo CAF, ripetuto per almeno 3 volte,
consentiva la crescita, in coltura pura, sempre della stessa
muffa 27. In 10 casi veniva isolato Fusarim oxysporum (Figure 2, 3) in uno Fusarium solani (la Tabella IV mostra aspetti clinici, terapia e follow up), in due Scytalidium hyalinum 31.
Nei 6 pazienti con infezione da Fusarium sottoposti a
biopsia, l’esame istologico rivelava, nello strato corneo, ife
settate di grosse dimensioni e spore alle colorazioni PAS e
Gomori-Grocott (Figura 4). Il quadro clinico era, in tutti i casi
di infezione da Fusarium, quello dell’intertrigine interdigitale (Figura 5). La cute del III-IV spazio interdigitale appariva sempre biancastra, macerata ed erosa. Sette pazienti
riferivano dolore, 4 non riferivano sintomi. Cinque soggetti erano agricoltori, 4 spesso camminavano scalzi e 2 riferivano eccessiva sudorazione. L’età media dei pazienti era 37
anni. Sette pazienti avevano contatti con il terreno. In tutti i
soggetti risultati affetti da infezione micotica dei piedi veniva instaurata opportuna terapia antimicotica sistemica e/o
topica, secondo le correnti linee guida 32, 33. È importante sottolineare che 10 degli 11 pazienti, con infezione da Fusarium,
non conseguivano la guarigione (sia clinica che micologica):
nonostante un miglioramento o un’apparente guarigione clinica, l’esame colturale risultava sempre positivo, anche
durante il trattamento, in un caso (caso 2, Tabella IV), mentre negli altri 9 si negativizzava per tornare positivo nell’arco di 4-10 mesi. Due pazienti inoltre presentavano anche
onicomicosi da Fusarium.
L’aspetto clinico nelle infezioni da Scytalidium era, in un
caso, quello del «piede a mocassino» con chiazze eritemato-squamose bilaterali ed ipercheratosi soprattutto alle piante e ai lati dei piedi e con lesioni meno evidenti negli spazi
interdigitali; nell’altro si apprezzava desquamazione plantare
ed interdigitale bilaterale. I due soggetti avevano soggiornato
ai Caraibi dove avevano camminato scalzi 31.
Discussione
Dal nostro studio emerge che la forma clinica più frequente di tinea pedis era l’intertrigine interdigitale (86%) e
il dermatofita più spesso isolato era Trichophyton rubrum
(71%). Dermatofiti di importazione quali Trichophyton violaceum e Trichophyton tonsurans, riscontrati a Siena quali
agenti di tinea capitis e corporis 34, 35, non sono stati isolati nelle infezioni dei piedi prima del 2002.
I nostri dati sono in accordo con quelli di studi europei 1
ed italiani effettuati dal ‘70 al ‘90 a Roma, Milano e Firenze 36-38 ed a Cagliari nel 2000 39. Quest’ultima indagine differisce dalla nostra per la provenienza dei pazienti da aree
rurali. Siamo stati in grado di individuare fattori predisponenti
solo in 60 casi (32%). D’altra parte, in un recente studio italiano, i fattori di rischio per le infezioni micotiche superficiali
sono stati rinvenuti raramente 40. Venti dei nostri pazienti
Vol. 140 - N. 3
ROMANO
(11%) avevano applicato creme corticosteroidee o perché
si erano automedicati o perché le stesse erano state consigliate
dal medico di medicina generale, che aveva confuso l’infezione micotica con eczema e, in un caso, con psoriasi. Questo sottolinea l’importanza dell’esame micologico, perché le
manifestazioni cliniche della tinea pedis da dermatofiti non
sono sempre distinguibili da altre patologie cutanee e da
infezioni causate da patogeni differenti, quali i batteri. Clinicamente le intertrigini batteriche possono presentarsi con
lesioni più macerate, gementi e dolorose rispetto a quelle
dermatofitiche, ma anche una tinea pedis con aspetto flogistico può a volte simulare una cellulite batterica 41.
Un aspetto simile a quello causato dalle patologie batteriche, con intensa macerazione, è tipico anche dell’infezione da Fusarium 17-19. Nel nostro studio il 6,4% delle infezioni
dei piedi erano causate da muffe. La loro patogenicità è stata dimostrata in modo rigoroso mediante ripetuti esami
microscopici diretti e colturali 27. Per quest’ultima indagine
si è eseguita la semina su terreno di Sabouraud destrosio
agar con solo CAF, in quanto la cicloeximide inibisce la crescita delle muffe. In analogia con le procedure diagnostiche
effettuate nelle onicomicosi da muffe 42, quando è stato possibile effettuare la biopsia, la diagnosi istologica ha confermato la patogenicità della muffa dimostrandone la localizzazione nello strato corneo 43 (Figura 4). È stato osservato un
caso all’anno di infezione da Fusarium dal 1996 al 2001 e 5
casi nel 2002. Cinque soggetti erano senegalesi, 6 italiani.
Inoltre in 4 pazienti, la scoperta dell’infezione è stata casuale, nel corso di una accurata visita dermatologica, dato che
il motivo del ricorso allo specialista era rappresentato da
un’altra patologia (orticaria, eczema, verruche plantari).
Solo un paziente ha conseguito la guarigione clinica e micologica. Gli altri sono stati controllati nel tempo, sia clinicamente che dal punto di vista immunologico. Tutti risultavano HIV-negativi ed immunocompetenti, come indicato dai
dosaggi di immunoglobuline, complemento e sottopopolazioni linfocitarie. Abbiamo ritenuto opportuno effettuare
queste indagini perché Fusarium spp. è responsabile, negli
immunodepressi, specie se neutropenici (<500 neutrofili/mm3) di infezioni invasive, talora fatali, legate al suo spiccato angiotropismo. Inoltre la porta di entrata può essere,
oltre all’apparato digerente e respiratorio, anche la cute 23
come riportato da Bodey et al. in 35 pazienti con tumori dell’apparato emopoietico che svilupparono una fusariosi disseminata 44. L’insuccesso terapeutico nella nostra casistica
è in linea con quanto osservato nelle infezioni da Fusarium
cutanee, profonde e disseminate, nelle quali non è insolita una
scarsa risposta agli antimicotici sistemici tradizionali 24, 32,
mentre è ancora prematura, anche per l’esiguo numero di
casi diagnosticati, una valutazione in merito all’efficacia
degli imidazolici di ultima generazione 33, 45, 46. D’altra parte alla sensibilità in vitro non corrisponde la stessa risposta
in vivo 47.
I nostri due casi di infezione da Scytalidium appaiono
sporadici perché osservati, uno nel ‘97 e l’altro nel ‘98, in 2
pazienti che avevano soggiornato in un area geografica come
quella caraibica, ove la muffa è endemica 31. In seguito essa
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RETROSPECTIVE STUDY OF MYCOTIC INFECTIONS OF THE FEET DUE TO DERMATOPHYTES AND MOULDS IN SIENA
non è stata più isolata a Siena né, a quanto ci risulta, in Italia, mentre in altri paesi europei, quali Francia e Inghilterra
il 3% delle infezioni dei piedi sono ascritte a Scytalidium
spp. 48, 49. Inoltre Lacroix ha di recente ipotizzato che anche
le scitalidiosi cutanee possano essere una porta di entrata
per infezioni disseminate 48 negli immunodepressi 50. Se si
eccettuano due casi di intertrigine da Fusarium osservati a
Milano 19 non ci risultano altre segnalazioni, in Italia, di
infezioni della cute dei piedi da muffe che, invece, sono
responsabili di un numero sempre crescente di onicomicosi 21, 51-53. Si può quindi ipotizzare che, ai piedi, le infezioni siano sottostimate per due motivi:
1) l’infezione, se asintomatica, può passare inosservata
agli occhi del paziente ed essere scoperta solo casualmente
nel corso di una visita dermatologica meticolosa, come si è
verificato in quattro dei nostri casi;
2) l’impiego, nei laboratori di micologia, di terreni privi
di cicloeximide non è routinario e pertanto una parte delle
muffe potrebbe sfuggire alla diagnosi colturale. D’altra parte l’esame microscopico diretto non sempre permette di identificare con sicurezza la presenza di ife non dermatofitiche.
Conclusioni
Alla luce di queste considerazioni ci sembra utile proporre, quando si sospetti un’infezione micotica dei piedi, l’esecuzione dell’esame colturale non solo su terreno di Sabouraud destrosio agar con CAF e cicloeximide ma anche su
Sabouraud destrosio agar con solo CAF. Se invece la diagnosi di tinea pedis è formulata sulla base del solo esame
microscopico diretto, qualora la terapia risultasse inefficace, bisogna sospettare un’infezione da muffe ed eseguire
l’esame colturale. Il ripetuto isolamento della muffa Fusarium in coltura pura, in modo da dimostrarne la patogenicità,
eventualmente confermata anche dall’esame istologico, rende consigliabile valutare le condizioni del paziente e controllarlo nel tempo per la possibilità che, in caso di immunodepressione, l’infezione si diffonda nell’organismo con
conseguenze anche fatali. Infine il crescente numero di
pazienti immunodepressi ci fa prevedere un incremento nel
futuro delle patologie da muffe. Pertanto un laboratorio di
micologia dotato di attrezzature idonee alla sorveglianza e
al contenimento di queste infezioni, può senz’altro risultare utile.
210
Riassunto
Obiettivo. Scopo del lavoro è stato quello di valutare la frequenza delle infezioni micotiche dei piedi da dermatofiti e da
muffe diagnosticate a Siena, dal 1993 al 2002, presso il laboratorio di Micologia della Clinica Dermatologica, l’unica
struttura attiva a Siena e provincia.
Metodi. Sono stati sottoposti ad esame micologico 539
pazienti con sospetta infezione micotica. La diagnosi si è
basata sull’esame microscopico diretto e su quello colturale del materiale patologico seminato su terreni di Sabouraud
destrosio agar con CAF e cicloeximide e Sabouraud destrosio agar con solo CAF.
Risultati. In 190 casi (112 di sesso maschile, 78 di sesso
femminile, di età compresa fra 5 e 71 anni, età media 38
anni) le infezioni erano di origine dermatofitica; in 13 casi
erano causate da muffe (9 maschi, 4 femmine, età 28-52,
età media 37 anni). Per quel che riguarda le infezioni dermatofitiche, Trichophyton rubrum è stato isolato nel 71%
dei casi, Trichophyton mentagrophytes interdigitale nel 21%
e Epidermophyton floccosum nell’8%. L’aspetto clinico dell’infezione era di tipo intertriginoso nel 87%, bolloso nel
8%, il «piede a mocassino» si apprezzava nel 4%; erano
associate intertrigine e bolle nell’1%. Nel caso delle muffe,
Fusarium è stato isolato in 11 casi (Fusarium oxysporum in
10, Fusarium solani in 1 caso); l’aspetto clinico era di intertrigine interdigitale con aree biancastre, macerate ed erose.
Scytalidium è stato identificato in 2 casi. Le manifestazioni
cliniche consistevano in un caso il «piede a mocassino»,
nell’altro in desquamazione plantare e interdigitale.
Conclusioni. Le infezioni micotiche dei piedi sono risultate prevalentemente causate da dermatofiti e raramente da
muffe (7%). Il sito più frequentemente interessato era il IIIIV spazio interdigitale. Fattori predisponenti erano la macerazione, l’occlusione e, nelle infezioni da muffe, il contatto
col suolo. Quando si sospetti una infezione micotica dei piedi è consigliabile eseguire l’esame micologico per confermare
la diagnosi, ricorrendo alla semina sia su terreni di Sabouraud
destrosio agar con CAF e cicloeximide, che su Sabouraud
destrosio agar con solo CAF. E’ infine suggerito un monitoraggio e un lungo follow-up delle infezioni da muffe perché potenzialmente pericolose nei pazienti immunodepressi.
PAROLE CHIAVE: Micosi - Piedi - Tinea pedis - Dermatofiti Muffe.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
Giugno 2005
G ITAL DERMATOL VENEREOL 2005;140:211-9
Stress reactivity in psoriatic patients
V. SCIUBBA, R. SODA, V. FALCOMATÀ, R. BOLDRINI, L. BIANCHI, S. CHIMENTI
Aim. This investigation aims at evaluating the correlation
between stressful life events, as those listed in the Social Readjustment Social Scale (SRRS), and the onset of the disease in
psoriatic patients, as well as investigating on the existence of specific personality traits.
Methods. A group of 33 patients affected by moderate-severe stable plaque psoriasis has been interviewed; all of them were
offered to fill in the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), so that 30 tests could be validated (15 men and
15 women).
Results. The MMPI-2 results exhibited different profiles between
the 2 genders: as to men, significant statistic differences were
to be found in scales displaying irritability and anger, while
women appeared to be affected by anxiety, depression and
somatization. As a result of these clinical interviews, a psychological support based on the cognitive therapy has also been
offered to 26 patients and 2 different types of patients have
been singled out: a first group reporting intolerance to adverse
environmental situations, a second group complaining for insufficient affective and social support.
Conclusion. Our data, collected by means of clinical interviews and
questionnaires, seem to confirm the correlation between the
somatic aspect of the disease and the protective function of the skin
against the outer world. These elements are fundamental to the
psychosomatic interpretation of this chronic-relapsing dermatosis,
which often poses a threat for the bodily self-image of each patient.
KEY WORDS: Psoriasis - Personality inventory - Stress, psychological.
Paper presented at the 78th National Congress of SIDEV. Rome, Italy,
June 25-28, 2003.
Accepted for publication January 11, 2005.
Address reprint requests to: Dr. L. Bianchi, Viale Oxford 81, 00133
Roma, Italy.
Vol. 140 - N. 3
Department of Dermatology
Tor Vergata University, Rome, Italy
I
t is well known how emotional stressful events are
frequently considered important factors in the onset
and exacerbation of psoriasis. This kind of disease is
characterized by a multi-factorial etiopathogenesis
where the immune system is involved.1-3 According
to these premises, a group of psoriatic patients has
been questioned on frequency and type of stressful
events, preceding the onset of the disease, as well as on
particular personality traits and psychopathological
disorders.
Materials and methods
The sample consisted of 33 patients aged 25-65
(median age 47 years), 17 women and 16 men, all
affected by severe stable plaque psoriasis. According
to their availability, they have been enrolled in psychological supporting interviews. After being visited
in outpatient’s services or hospitalized, patients have
been interviewed in order to evaluate whether the onset
of the disease had been preceded by stressful events or
not. Furthermore, on that occasion, they have been
asked to fill in the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) test.4 Subsequently, the
results of the MMPI-2 have been communicated and
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STRESS REACTIVITY IN PSORIATIC PATIENTS
TABLE I.—Stressful life events referred in the 2-month period preceding the onset of psoriasis.
Stressful event
Number
of patients
Mean value of
severity according
to SRRS
Death of close relatives
Accident or illness
Marriage
Altered health status of family’s members
Unstable economic situation
Conflicts with extended parents
End of school term
Change in life condition
Conflicts with the chief in charge at work
Change in working condition
Phobic episode during childhood
6
2
1
1
3
1
2
1
1
3
2
63
53
50
44
39
29
26
25
23
20
Unclassified
among the initial 33 patients, only 26 have undergone
further individual support interviews which varied
from 2 to a maximum of 9 sessions, in accordance
with the principle of the cognitive therapy. Dermatologists were responsible for the recruitment of patients,
while the psychologist was involved in studying carefully the psychological anamnesis, carrying out clinical interviews and interpreting the results of personality tests, which have been mathematically elaborated by a statistician. Both dermatologist and psychologist have been constantly working together by
exchanging information concerning their own competences about the diagnosis, the clinical history, the
pathogenesis of the disease and the psychological evaluation of each single patient, thus cooperating to the
final draft of the article.
The MMPI-2 test studies a series of variables through
numeric scales, which enable us to compare the scores
obtained with the average value of the total population.
Reference protocols applied to the Italian population
are those resulting from the MMPI-2 test, whose Italian translation and adaptation has been edited by
Pancheri P. and Sirigatti S.4 The aforementioned test
contains various scales, called “validity scales”, due to
certain present attitudes undermining the reliability
of the answers, thus making the test useless. Moreover, the scores provided by this test are divided into
10 clinical scales: Hypochondria, Depression, Hysteria, Psychopatic Deviate, Masculinity/Femininity,
Paranoia, Psychasthenia, Schizophrenia, Mania, Introversion, and 21 additional scales, always evaluating
personality traits, life style and interaction with the
outer world. The MMPI-2 test represents the revision
of the original MMPI test, which was elaborated in
212
the early ‘40s, containing only 10 clinical scales and
3 validity scales. It has been largely used and studied
at international level. A score which is higher or equal
to 65 is considered as a discriminating value between
clinical psychopathological groups and the remaining population. Life stressful events discovered during
clinical interviews have been classified according to the
Social Readjustment Rating Scale (SRRS): a list that
studies the impact of 43 events occurring with significant frequency, just before the onset of many somatic diseases. However, the SRRS does not include, for
instance, an event told by 2 patients, concerning a
“phobic episode during their childhood”, which seemed
to be definitely significant; the said event has been
added to the list as being a “spy-indicator” for a stressful life condition.
Results
According to data collected during the clinical interviews, 23 patients referred a stressful event, which
had occurred during or immediately before the onset
of the disease.
It has been shown that there is almost a 2-month
interval between the stressful event and the onset of the
disease.
As to the remaining 10 cases, it was not possible to
single out a similar event or the aforementioned interval seemed to be unclear. Number and types of the
analyzed events are showen in Table I.
Thirty protocols of the MMPI-2 test have been considered valid and divided into 2 subgroups: 15 men
and 15 women, mean age respectively 47 and 48 years
old. The average value of all scales has been calculated, thus highlighting the difference between its outcome and the average value regarding the total population. Therefore, the statistic Student’s t-test has been
used to a significance level of 0.05 with a bidirectional
hypothesis. Thus concluding that, according to some
scales, the difference between the average rate of subgroups and that of the total population does not seem
to be a fortuitous value. So, according to the aforementioned scales the 2 groups (patients and total population) do not correspond (Tables II, III).
The significant average values of the 2 subgroups
have resulted to be higher than those regarding the
total population, with the exception of the average rate
regarding the scale O-H in men, which instead is low-
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
Giugno 2005
STRESS REACTIVITY IN PSORIATIC PATIENTS
SCIUBBA
TABLE II.—Scales at the significative level of 0.05 in females.
L
Sample mean
Mean of reference
Student’s t test
6.00
5.06
2.487
Fb
5.33
3.18
2.343
Hs
D
HY
PT
ANX
FRS
DEP
HEA
WRK
TRT
13.53
7.99
3.354
28.33
22.75
2.902
29.3
24.1
2.571
21.3
14.8
2.650
13.00
7.11
4.333
11.60
6.76
4.353
12.93
8.90
2.349
13.80
7.95
4.040
14.13
9.82
2.557
10.67
6.77
2.971
er. Our data indicate that, except the scale O-H in men,
though it has to be considered alone, values obtained
from the sample are more close to those values considered as pathological. However, it is important to
point out that 43% of the valid test-protocols presented scores ≥ 65 T-values in 2 or more clinical scales. Furthermore, there is a possibility that strong denial and
protective mechanisms could reduce scores under the
alarm values. Scales reporting a significant difference
in women are as follows:
— Validity scale L: displaying the tendency for having an idealized self-image.
— Validity scale Fb: this is a severity rate for psychopathology and availability to discuss one’s own
problems.
— Clinical scale Hs (Hypochondria): it is mainly a
rate for somatization without involving the body
organs.
— Clinical scale Hy (Conversion Hysteria): a complex scale that indicates somatization, but also a request
for affection and inhibition of aggressiveness.
— Clinical scale D (Depression).
— Clinical scale Pt (Psychasthenia): scale that gives
an evaluation of anxiety and neurosis.
— Scale ANX (Anxiety): scale for generalized anxiety.
— Scale FRS (Fears): scale for phobias and fears.
— Scale HEA (Health concerns): scale for worries
about one’s health status.
— Scale WRK (Work interferences): scale for maladjustment at work.
— Scale TRT (Negative treatment indicators): scale
that helps defining an unfavourable prognosis concerning the results of a psychotherapeutic support/treatment.
As to the male subgroup, significant scales are
showed as follows:
— Clinical scale Hs (Hypochondria).
— Scale O-H (Overcontrolled hostility): scale that
indicates a rigid hyper-control of aggressiveness.
Vol. 140 - N. 3
TABLE III.—Scales at the significance level of 0.05 in males.
Sample mean
Mean of reference
Student’s t-test
Hs
O-H
ANG
TPA
FAM
7.53
5.24
2.439
13.27
15.03
-2.471
6.53
5.05
2.503
9.80
8.21
2.213
7.07
0.19
5.860
— Scale ANG (Anger): scale that gives an evaluation of problems regarding the control of rage.
— Scale TPA (Type A): scale that indicates a hostile, competitive and aggressive personality style, in
subjects concentrated on work.
— Scale FAM (Family problems): scale that gives
an evaluation of family’s conflicts experienced by the
subject.
All the data collected correspond to the constant
outcome, according to which women over 35 years
of age display a higher psychiatric morbidity rate compared to the male sample. Nine protocols of the female
subgroup present scores ≥ 65 T values in 2 or more clinical scales, against 4 corresponding scales of the male
subgroup.
Discussion and conclusions
The existing correlation between psychological
stress, discomfort situations and the onset of psoriasis
has been analyzed and documented since the ‘50s by
many authors.5-7 Further studies have particularly
developed in 2 directions: on one side clinicians have
tried to quantify and clarify the correlation between
stressful life events and the onset of the disease, on
the other side they have been investigating on the psychological discomfort status of patients and on their
personality traits.8, 9
The percentage rates of those cases displaying one
or more stressful events which preceded the onset of
the disease vary according to the studies conducted: 3244%,10, 11 46%,12 over 60%,1 80%,13 88.75%,14 90%.15
Usually, the present percentage rates have been
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SCIUBBA
STRESS REACTIVITY IN PSORIATIC PATIENTS
obtained by means of self-evaluation questionnaires
filled in by patients, or by clinical interviews; in some
studies, monitoring groups have been used. Seville
reported that the incubation period within stressful
events and the onset of the disease is usually limited to
1 month, apart from 2/3 of cases arising within 2 weeks.
He underlined the importance of investigating on the
events occurred in the said periods, so that they can be
taken into account and treated.12
Further surveys have focused on the possible correlation between stressful event, extent and severity of the
disease. In order to assess the stress rate suffered in a
certain period (mainly 1 year), one can use appropriate
scales, such as SRRS,16 by applying to each stressful life
event a certain score, thus calculating the corresponding total figures of the occurred events. In this way,
positive but modest correlations have been found,
r=0.28 in a study by Baughman et al.,17 and r=0.23 in
a prospective study by Gaston et al.18 However,
Baughman himself recognized that the stress rates
calculated by means of the said scales represent a
global quantitative datum, taking less into account
the quality of events and their significance related to
the history and personality of the subject. Furthermore, a 1-year period could be too long for precisely evaluating possible correlations between stress suffered and the onset of the disease. More than just
measuring stress, which can be experienced in a quite
long period of time such as 1 year, it might be significant to find out specific traumas, that might have
been acting as triggering events.
As to surveys focusing on determined personality
traits of psoriatic patients, it is necessary to assert that
few are the study samples reporting mean rates beyond
a normality interval, after psychological tests.19-21
Much more frequently, one can find statistically significant differences within psoriatic patients’ groups
and monitoring groups, also dermatological.13, 21-23
Griffiths et al.1 stated: “Even if, according mainly to
cross-studies, it might be early to define an association
with psoriasis and psychiatric conditions, research in
this field surely underline an increased prevalence of
anxiety and depression in psoriatic patients.
A common opinion by most of the authors, is that
there are no sufficient data in order to assess the existence of typical personality traits in psoriatic patients,
though in some studies consistently frequent psychopathological disorders have been found.14, 22
Many authors have used the MMPI test 4 which
214
helped individuating raisings in some clinical scales.
Goldsmith et al.23 found out higher rates in the scales
of Hysteria and Psychastenia, while Piret et al.24 by
comparing the protocols of 50 patients to the average
values of the total population, revealed raisings in the
scales of Paranoia, Psychasthenia, Schizophrenia,
Depression, Psychopatic Deviate and Social Introversion; the last scale has resulted significant only by
the male subgroup.
The present study analyzed the events occurred in the
2-month period preceding the onset of the disease and
enabled the identification of a stressful event for 70%
of cases; a quite high percentage rate which confirms
the significance of life events (Table I).
The MMPI-2 results indicate a major prevalence of
anxiety and depression in psoriatic patients only by
the female subgroup. Regarding this last subgroup,
additional scales FRS, HEA and WRK specify those
aspects that probably supply depressive and anxious
status. Always regarding the female subgroup the following scales, Pt, D, Hs and Hy refer to a framework
of neurosis, maladjustment, depression and somatization, which was probably developed after early affective lacks. It is interesting to notice that among the
indicators in scales Hs, Hy and D one can find the
need in attentions and affection as well as the incapability in expressing hostility in an open and direct
manner.
In men, the only significant clinical scale is that of
Hypochondria; with a high percentage rate, this scale
indicates somatization, hypochondriac concerns,
demand on attentions, unhappiness, negative approach
towards the others and indirect expression of hostility. The last indicator, together with what emerged from
additional scales, helps supposing that there are problems linked to the managing and expression of aggressiveness. As a matter of fact, scales ANG and O-H
both show irritability and difficulty in controlling rage;
these conditions are probably linked to strain situations, mostly due to work (scale TPA), or to difficult
family’s relationships (scale FAM).
However, psoriatic patients do not show having a
clearly more aggressive or impulsive behaviour compared to the total population, since scale Pd (Psychopathic Deviate) has no significant outcome.
In literature, the studies focusing on the evaluation
whether the probability of aggressive behaviours is
greater in psoriatic patients or not, produced opposing
results.21, 25
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STRESS REACTIVITY IN PSORIATIC PATIENTS
After determining that important denying mechanisms, mostly as regards aggressiveness, might take
place, discordances could be deriving from the fact
that too different appraisal instruments have been used
or from the differences in sample setting. Actually,
the results of the MMPI-2 regarding our sample, suggest that emotional reactivity is different in both genders: while in men aggressiveness shows to be present and manifest anyway, in women it is probably
much more controlled, thus prevailing anxious and
depressive status together with neurotic involvements.
Supporting clinical interviews conducted with 26
patients have confirmed both the frequency and the
importance of stressful life events as well as the incapability to cope with these episodes in a adequate manner. Often, it has been found out an inhibition in direct
and verbal expressions of one’s aggressiveness, which
being unable to find a solution itself, is followed by a
never ending status of irritability and intolerance (scale
ANG). More rarely, reaction-strategies to stress events
have been adopted, whose methodological inefficiency for the prefixed goals generates an even greater
sense of irritability. Besides a typology of patients
who perceive the outer world as a remarkable source
of stressful stimulus, clinical surveys have shown a
second typology of patients, who particularly experience the outer world, as incapable of giving them a
sufficient affective and social support. Hence, the reason for their depressive lived experiences.
In both cases, the relationship with the outer world
was problematic and the cutis, an organ which marks
the limits of ourselves by protecting us against external harmful agents, seemed to be irritated by this situation. As far as psoriasis is concerned, some of the
most significant structural data, the augmented proliferation of keratinocyte and the increased thickness
of the corneal stratum, could be conceived, in psychosomatic terms, as attempts by the cutis to enhance
its own defence and protective functions against the
outer world. The hypothesis of psoriasis, as a series of
symptoms triggered by a defence and hyper-protective
function of the organism, seems to agree with another datum emerging from the present study, that is the
typology of triggering events. Five in 23 singled out
events refer to the death of one’s parent and 1 to a very
serious disease, prelude to death always of a parent.
Since parents are by definition protective figures, it is
possible to presume that on their death a greater sense
of vulnerability could be achieved. On mourning, sub-
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SCIUBBA
jects are more susceptible to perceive the environment
as a possible source of discomfort, danger and threat.
Similar considerations about a paranoid modality
which would characterize the perception of the environment on behalf of psoriatic patients, have been
expressed in the study conducted by Barba et al.19 In
literature, some authors report frequent mourning
experiences as stressful events.3
It is necessary to remind that the present study is
mainly based on differences among average values of
the MMPI-2 test, compared to the total population
and not on values considered as psychopathological in
all patients. On the other hand, our attention was not
drawn to investigating on the presence and frequency
of psychopathological disorders, which are classifiable according to the criteria of the Diagnostic and
Statistical Manual of Mental Disorders – Fourth edition (DSM IV), but to individuating common modalities as to the perception of reality and reactive attitudes
towards it; in other words, our attention was mainly
drawn to cognitive processes, without forgetting how
much they are inextricably linked to emotional experiences.
The use, in a larger survey, of instruments able to
reveal components of manifested but most of all
repressed aggressiveness in psoriatic patients, as well
as the evaluation of the results coming from specificaimed psychotherapeutic treatments, could confirm
the outcomes and observations of our research.
References
1. Griffiths CEM, Richards HL. Psychological influences in psoriasis.
Clin Exp Dermatol 2001;26:338-42.
2. Naldi L, Peli L, Parazzini F, Carrel CF. Psoriasis study group of the
Italian group for epidemiological research in dermatology. Family
history of psoriasis, stressful life events, and recent infectious disease are factors for a first episode of acute guttate psoriasis: results of
a case-control study. J Am Acad Dermatol 2001;44:433-8.
3. Al’Abadie MS, Kent GG, Gawkrodger DJ. The relationship between
stress and the onset and exacerbation of psoriasis and skin conditions. Br J Dermatol 1994;130:199-203.
4. Butcher JN, Dahlstrom WG, Graham JR, Tellegen A, Kaemmer B.
Minnesota Multhiphasic Personality Inventory-2 (MMPI-2). Manual for administration and scoring. Minneapolis: University of Minnesota
Press;1989 (Italian translation edited by Pancheri P, Sirigatti S. Firenze: O.S. Organizzazioni Speciali editore; 1995).
5. Susskind W, McGuire RJ. The emotional factor in psoriasis. Scot
Med J 1959;4:503-7.
6. Wittkower E. Psychological aspects of psoriasis. Lancet 1946;41:
566-9.
7. Ingram JT. The significance and management of psoriasis. Br Med J
1954;2:823-8.
8. Engels DW. Psychosomatic illness review: IV. Dermatological disorders. Psychosomatics 1982; 23:1209-19.
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9. Panconesi E. Psychosomatic dermatology. In: Panconesi E, editor.
Stress and skin diseases: psychosomatic dermatology. Clinics in Dermatology 1984;2:95-179.
10. Farber EM, Bright RD, Nall ML. Psoriasis: a questionnaire survey of
2 144 patients. Arch Derm 1968;98:248-59.
11. Farber EM, Nall ML. The natural history of psoriasis in 5 600 patients.
Dermatologica 1974;148:1-18.
12. Seville RH. Stress and psoriasis: the importance of insight and empathy in prognosis. J Am Acad Derm 1989;1:97-100.
13. Fava GA, Perini GI, Santonastaso P, Fornasa CV. Life events and
psychological distress in dermatologic disorders: psoriasis, chronic
urticaria and fungal infections. Br J Med Psychol 1980;53:277-82.
14. Mazzetti M, Mozzetta A, Soavi GC, Andreoli E, Foglio Bonda PG,
Puddu P et al. Psoriasis, stress and psychiatry: psychodynamic characteristics of stressors. Acta Derm Venereol (Stockh) 1994;186(Suppl 74): 62-4.
15. Nyfors A, Lemholt K. Psoriasis in children: a short review and a survey of 245 cases. Br J Dermatol 1975;92:437-42.
16. Holmes TH, Rahe RH. The social readjustement rating scale. J Psychosom Res 1967;11:213-8.
17. Baughman R, Sobel R. Psoriasis, stress and strain. Arch Dermatol
1971;103:599-605.
18. Gaston L, Crombez JC, Lassonde M, Bernier-Buzzanga J, Hodgins S.
Psychological stress and psoriasis: experimental and prospective correlational studies. Acta Derm Venereol (Stockh) 1991;156 (Suppl
71):37-43.
19. Barba A, Trabucco G, Pasqualini A. Aspetti psicologici del paziente
psoriasico. G Ital Dermatol Venereol 1985;120:379-84.
20. Giordano N, Senesi M, Battisti E, Bonelli G, Magnani N, Nardini M
et al. Su alcuni aspetti della personalità in pazienti affetti da artropatia psoriasica. Minerva Med 1996;87:283-7.
21. Rubino IA, Sonnino A, Stefanato CM, Pezzarossa B, Ciani N. Separation-individuation, aggression and alexithymia in psoriasis. Acta
Derm Venereol (Stockh) 1989;146(Suppl): 87-90.
22. Rubino IA, Sonnino A, Pezzarossa B, Ciani N, Bassi R. Personality
disorders and psychiatric symptoms in psoriasis. Psychological Reports
1995;77:547-53.
23. Goldsmith LA, Fisher M, Wacks J. Psychological characteristics of psoriatics: implications for management. Arch Derm 1969;100:674-6
24. Piret JM, Hurel G, Bolgert M. Resultats du test Minnesota chez les psoriasiques. Note preliminaire. Bull Soc Fr Dermatol Syphiligr
1967;74:323-5.
25. Dooley G, Finlay AY. Personal construct systems of psoriatic patients.
Clin Exp Dermatol 1990;15:401-5.
La reattività allo stress nei pazienti affetti da psoriasi
È
noto come situazioni di stress emotivo frequentemente
si rivelano fattori importanti nell’insorgenza e nell’aggravamento della psoriasi, patologia ad eziopatogenesi multifattoriale in cui è implicato il sistema immunitario 1-3. In
base a queste premesse, in un gruppo di pazienti psoriasici
abbiamo indagato sulla frequenza e il tipo di eventi stressanti precedenti le prime manifestazioni della malattia come
pure sul possibile riscontro di particolari caratteristiche di personalità e disturbi psicopatologici.
Materiali e metodi
Hanno partecipato allo studio 33 pazienti, 17 donne e 16
uomini di età compresa tra 25 e 65 anni (età media di 47
anni) affetti da psoriasi volgare, arruolati in base alla loro
disponibilità a fruire di un servizio di consulenza psicologica. In occasione della visita ambulatoriale o del ricovero è stata effettuata un’intervista per accertare se l’esordio della
malattia fosse stato preceduto da eventi stressanti e, in quella occasione, è stato chiesto di compilare il test Minnesota
Multiphasic Personality Inventory-2 (MMPI-2) 4. La consulenza si è successivamente articolata nella comunicazione
dei risultati del test e, per 26 dei 33 pazienti iniziali, in ulteriori colloqui di sostegno individuali, variabili per numero da
un minimo di 2 a un massimo di 9, ispirati ai principi della
terapia cognitiva. Il reclutamento dei pazienti è avvenuto ad
opera dei dermatologi mentre lo psicologo ha curato l’approfondimento dell’anamnesi psicologica, effettuato i colloqui
e interpretato il test di personalità i cui risultati sono stati
216
elaborati matematicamente dallo statistico. Dermatologo e
psicologo sono stati costantemente in contatto per uno scambio di informazioni relative alle proprie competenze sulla
diagnosi, il decorso clinico, la patogenesi della malattia e
la valutazione psicologica dei singoli pazienti, collaborando
anche nella stesura dell’articolo.
Il test di personalità MMPI-2 misura una serie di variabili tramite delle scale numeriche che permettono di conoscere la posizione dei punteggi ottenuti rispetto alla media della popolazione generale. Le norme di riferimento per la
popolazione italiana sono quelle fornite dal test MMPI-2,
di cui Pancheri P. e Sirigatti S. hanno curato la traduzione e
l’adattamento italiano 4. Il test contiene alcune scale dette di
validità perché valutano la presenza di atteggiamenti che,
pregiudicando l’affidabilità delle risposte, rendono il test
inutilizzabile; esso dà inoltre punteggi su 10 scale cliniche
denominate: Ipocondria, Depressione, Isteria, Deviazione
psicopatica, Mascolinità/Femminilità, Paranoia, Psicastenia, Schizofrenia, Mania, Introversione e su 21 scale aggiuntive che valutano sempre la personalità, lo stile di vita, l’interazione con l’ambiente. L’MMPI-2 costituisce la revisione dell’MMPI originale, elaborato nei primi anni ‘40, che contiene solo le 10 scale cliniche e 3 scale di validità e che è stato ampiamente utilizzato e studiato in campo internazionale. Un punteggio maggiore o uguale a 65 è assunto come
valore che discrimina tra gruppi clinici psicopatologici e
resto della popolazione.
Gli eventi stressanti riscontrati in base all’intervista, sono
stati classificati in base alla Social Readjustement Rating
Scale (SRRS), che è una lista che valuta l’impatto di 43
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eventi che appaiono con significativa frequenza prima dell’inizio di molte malattie somatiche. La SRRS, tuttavia, non
prevede un evento del tipo “episodio fobico nell’infanzia” che,
comunque, era apparso decisamente significativo nel racconto di 2 pazienti; si è ritenuto pertanto di poterlo aggiungere alla lista considerandolo evento-spia di una condizione
esistenziale stressante.
Risultati
Secondo i dati ricavati dalle interviste, per 23 pazienti è stato possibile individuare un evento stressante che si è verificato in concomitanza o in un periodo immediatamente precedente le prime manifestazioni di malattia; l’intervallo preso in considerazione tra evento stressante e insorgenza dei sintomi risulta al massimo di 2 mesi. Per i restanti 10 casi non
è chiaramente individuabile un evento di tal genere o l’intervallo temporale risulta più incerto. Il numero e la tipologia degli eventi riscontrati sono illustrati nella Tabella I.
Sono stati ricavati 30 protocolli validi del test MMPI-2 suddivisi in 2 sottocampioni di 15 maschi e 15 femmine di età
media rispettivamente di 47 e 48 anni.
Sono state calcolate le medie delle scale ed è stata valutata
la differenza di tali medie da quelle della popolazione generale. A tal fine è stato utilizzato l’indicatore statistico t di
Student a un livello di significatività dello 0,05 con ipotesi
bidirezionale. Ciò ha permesso di concludere che per alcune scale la differenza della media dei sottocampioni dalla
media della popolazione generale è non casuale e che pertanto
rispetto alle predette scale le due popolazioni (dei pazienti e
della popolazione generale) non coincidono (Tabelle II, III).
Le medie significativamente diverse dei sottocampioni sono
risultate superiori a quelle della popolazione generale, tranne quella della scala O-H nei maschi che risulta invece inferiore. Ciò indica che, fatta eccezione per la scala O-H, che
comunque merita considerazioni a parte, i valori forniti dal
campione si avvicinano maggiormente a quelli considerati
patologici. A questo proposito è da rilevare che il 43% dei protocolli validi del test ha presentato valori >65 punti T in 2 o
più scale cliniche e, inoltre, è nota la possibilità che forti
meccanismi di negazione e difesa abbassino i punteggi al
di sotto dei valori di allarme.
Le scale risultate significativamente diverse sono state,
per le donne:
— La scala di validità L: dà una misura della tendenza a
presentare un’ immagine di sè idealizzata.
— La scala di validità Fb: è un indice di gravità della psicopatologia e della disponibilità a discutere dei propri problemi.
— La scala clinica Hs (Ipocondria): è principalmente un
indice della somatizzazione senza base organica.
— La scala clinica Hy (Isteria): scala complessa che indica somatizzazione, ma anche tra l’altro, bisogno di affetto e
inibizione dell’aggressività.
— La scala clinica D (Depressione).
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— La scala clinica Pt (Psicastenia): dà una misura dell’ansia e del nevroticismo.
— La scala ANX dell’ansia generalizzata.
— La scala FRS delle fobie e paure.
— La scala HEA delle preoccupazioni per la propria salute.
— La scala WRK del disadattamento sul lavoro.
— La scala TRT: dà una misura della prognosi sfavorevole
relativa ai risultati di un trattamento psicoterapeutico.
Per il sottocampione degli uomini sono invece risultate
significative soltanto:
— La scala clinica Hs (Ipocondria).
— La scala O-H: indica un ipercontrollo rigido dell’aggressività.
— La scala ANG: dà una misura dei problemi nel controllo
della rabbia.
— La scala TPA: rileva uno stile di personalità ostile,
competitivo e aggressivo di soggetti centrati sul lavoro.
— La scala FAM: dà una misura dei contrasti familiari
percepiti dal soggetto.
I risultati si accordano con il dato costante secondo cui,
sopra i 35 anni, la morbilità psichiatrica femminile è superiore a quella maschile. Nove protocolli del sottocampione
femminile presentano punteggi al di sopra di 65 punti T in 2
o più scale cliniche, contro 4 corrispondenti del sottocampione
maschile.
Discussione e conclusioni
L’esistenza di un nesso tra stati di stress o disagio psicologici e manifestazioni cliniche della psoriasi è stata osservata e documentata sin dagli anni ‘50 da vari Autori 5-7. Studi successivi si sono dispiegati per lo più in 2 direzioni: da
una parte hanno cercato di quantificare e chiarire la relazione tra eventi stressanti e manifestazioni cliniche, dall’altra
hanno indagato sullo stato di disagio psicologico dei pazienti e sulle loro caratteristiche di personalità 8, 9.
Le percentuali dei casi in cui è stato possibile individuare
uno o più eventi stressanti in un periodo precedente l’insorgenza
della malattia variano secondo gli studi: 32-44% 10, 11, 46% 12,
oltre il 60% 1, 80% 13, 88,75% 14, 90% 15.
Tali percentuali sono ottenute di solito con questionari di
autovalutazione compilati dai pazienti o con interviste; alcuni studi hanno utilizzato gruppi di controllo. Seville 12 inoltre riporta che il periodo di incubazione tra il verificarsi della condizione di stress e la manifestazione della sintomatologia è di solito limitato a 1 mese, con 2/3 dei casi che si
manifestano entro 2 settimane, e sottolinea l’importanza di
indagare sugli eventi che si siano verificati in questi periodi,
in modo che possano essere presi in considerazione e trattati.
Altri studi hanno indagato se vi sia correlazione tra stress
ed estensione e gravità della malattia. Come misura dello
stress subìto in un determinato periodo (di solito 1 anno), si
utilizzano apposite scale, come la SRRS 16, che attribuisco-
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no a ogni evento esistenziale stressante un punteggio e si
calcola il totale corrispondente agli eventi occorsi. Sono state trovate così delle correlazioni positive, ma modeste: r=0,28,
in uno studio di Baughman et al. 17, e r=0,23 in uno studio
prospettico di Gaston et al. 18. Come viene riconosciuto però
dallo stesso Baughman, la misura dello stress calcolata con
le predette scale è un dato quantitativo globale che tiene
poco conto della qualità degli eventi e del loro significato in
relazione alla storia e alla personalità del soggetto; inoltre,
il periodo di 1 anno può essere un periodo troppo lungo per
valutare correttamente l’esistenza di correlazioni tra stress
subìto e manifestazioni di malattia. Più di una misura generica dello stress, sperimentato in un arco di tempo piuttosto
lungo come può essere 1 anno, potrebbe essere importante
l’individuare specifici traumi che possano aver agito come
eventi scatenanti.
Per quanto riguarda le indagini sull’esistenza di determinate caratteristiche di personalità dei malati di psoriasi occorre dire che sono pochi gli studi che riportano, per campioni
di pazienti, valori medi ai test psicologici al di fuori di un
intervallo di normalità 19-21. Molto più frequente è il riscontro di differenze statisticamente significative tra gruppi di
pazienti psoriasici e gruppi di controllo, anche dermatologici 13, 21-23. Griffiths et al. 4 dichiarano: «Anche se sembra
prematuro, sulla base degli studi prevalentemente trasversali,
stabilire legami tra psoriasi e condizioni psichiatriche, le
ricerche certamente sottolineano l’aumentata prevalenza di
ansia e depressione nei pazienti psoriasici». La maggior parte degli Autori non ritiene che ci siano dati sufficienti per
affermare l’esistenza di caratteristiche di personalità tipiche
dei malati di psoriasi, anche se in alcuni studi è stata trovata una notevole frequenza di disturbi psicopatologici 14, 22.
Il test MMPI 4 è stato utilizzato da vari autori e in genere
ha fatto riscontrare elevazioni in alcune scale cliniche. Goldsmith et al. 23 riscontrarono rispetto ai controlli, valori più alti
nelle scale Isteria e Psicastenia, Piret et al. 24, comparando
i protocolli di 50 pazienti con i valori medi della popolazione generale, rilevarono elevazioni nelle scale Paranoia, Psicastenia, Schizofrenia, Depressione, Deviazione Psicopatica e Introversione sociale; quest’ultima scala è risultata significativa solo nel sottocampione maschile.
Nel presente studio l’analisi degli avvenimenti di rilievo
occorsi nei 2 mesi precedenti le prime manifestazioni di
malattia ha portato a individuare almeno un evento stressante nel 70% dei casi, in una percentuale perciò abbastanza elevata e che conferma l’importanza degli eventi esistenziali (Tabella I).
I risultati del MMPI-2 indicano una maggiore prevalenza
di ansia e depressione nei pazienti psoriasici solo nel sottocampione femminile. Relativamente ad esso, le scale aggiuntive FRS, HEA e WRK specificano degli aspetti che probabilmente alimentano quegli stessi stati ansiosi e depressivi.
Le scale Pt, D, Hs e Hy, sempre nel sottocampione femminile. rimandano a un quadro di nevroticismo, disadattamento, depressione e somatizzazione, costruitosi probabilmente su precoci carenze affettive. E’ interessante notare che tra
i descrittori delle scale Hs, Hy e D si ritrovano sia il bisogno
218
di attenzione e di affetto sia l’incapacità a esprimere l’ostilità in maniera aperta e diretta.
Negli uomini, l’unica scala clinica significativa è quella dell’Ipocondria, che, per punteggi elevati, indica somatizzazione, preoccupazioni ipocondriache, richiesta di attenzione, infelicità, atteggiamento critico verso gli altri ed espressione di ostilità in maniera indiretta. Quest’ultimo descrittore,
assieme a quanto emerge dalle scale aggiuntive, fa supporre che esistano problemi legati alla gestione e all’espressione dell’aggressività. Infatti, le scale ANG e O-H depongono
ambedue per irritabilità e difficoltà nel controllo della rabbia, condizioni presumibilmente legate a stati di tensione
dovuti soprattutto al lavoro (scala TPA) o a difficoltà nelle
relazioni familiari (scala FAM). Tuttavia, i pazienti psoriasici non avrebbero tendenzialmente un comportamento palesemente più aggressivo o impulsivo della popolazione generale poiché la scala Pd (Deviazione Psicopatica) non risulta
significativa.
In letteratura, gli studi che hanno cercato di verificare se
la probabilità di comportamenti aggressivi sia maggiore nei
pazienti psoriasici, hanno fornito risultati contrastanti 21, 25.
Oltre a valutare la possibilità che intervengano, soprattutto
per l’aggressività, importanti meccanismi di negazione, le
discordanze potrebbero derivare dal fatto che siano stati usati strumenti di valutazione troppo diversi o da differenze nella composizione del campione. In effetti, i risultati al test
MMPI-2 del nostro campione suggeriscono che la reattività
emotiva sia diversa nei 2 sessi: mentre negli uomini l’aggressività appare comunque presente e manifesta, nelle donne è probabilmente più controllata e prevalgono stati ansiosi e depressivi con implicazioni nevrotiche.
I colloqui di sostegno effettuati con 26 pazienti hanno
confermato sia la frequenza e l’importanza di condizioni
ambientali stressanti, sia spesso l’incapacità a farvi fronte con
comportamenti adeguati. Ciò che spesso si è riscontrato è
un’inibizione nelle manifestazioni verbali e dirette della propria aggressività la quale, non giungendo in tal modo a risolversi, lascia come residuo uno stato perenne di irritabilità e
insofferenza (scala ANG); più raramente vengono adottate
strategie di reazione allo stress metodologicamente inefficaci
per gli scopi da raggiungere, derivandone così uno stato di
irritazione ancora maggiore. Oltre a un tipo di pazienti che
percepiscono l’ambiente come notevole fonte di stimoli
stressogeni, è apparsa dai colloqui una seconda tipologia di
pazienti che vivono l’ambiente soprattutto come incapace
di fornire loro un sufficiente sostegno affettivo o sociale e ciò
renderebbe ragione dei vissuti depressivi.
In ambedue i casi la relazione con l’ambiente è problematica e la cute, intesa come organo che ci delimita e nello stesso tempo ci protegge dagli agenti nocivi esterni, sembra risentirne. Alcuni dei dati strutturali più significativi
della psoriasi, l’aumentata proliferazione del cheratinocita
e l’incremento dello spessore dello strato corneo, potrebbero
essere anche letti, in chiave psicosomatica, come tentativi
della cute di incrementare le proprie funzioni di difesa e
protezione nei confronti dell’ambiente esterno. L’ipotesi
della psoriasi come manifestazione di difesa e iperprote-
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
Giugno 2005
STRESS REACTIVITY IN PSORIATIC PATIENTS
zione dell’organismo è in accordo con un altro dato emerso nel presente studio, relativo alla tipologia degli eventi
scatenanti. Su 23 eventi individuati, 5 sono relativi alla morte di un genitore e 1 a una malattia molto grave, preludio di
decesso, sempre di un genitore. Poiché i genitori sono per
definizione figure protettive, è possibile ipotizzare che alla
loro perdita conseguano sentimenti di maggiore vulnerabilità. In occasione del lutto si renderebbe più acuta, nei soggetti predisposti, la percezione dell’ambiente come possibile
fonte di disagio, pericolo, minaccia. Considerazioni simili
su una modalità paranoidea che caratterizzerebbe la percezione dell’ambiente da parte dei pazienti psoriasici sono
espresse nello studio di Barba et al. 19. Il frequente riscontro di lutti tra gli eventi stressanti è riportato da alcuni Autori in letteratura 3.
Occorre ricordare che il presente studio si basa principalmente su differenze di valori medi delle scale dell’MMPI-2 rispetto alla popolazione generale e non di valori considerati psicopatologici per tutti i pazienti. D’altra parte, non
ci si è interessati di indagare se nei pazienti fossero riscontrabili e, con quale frequenza, disturbi psicopatologici classificabili secondo i criteri del Diagnostic and Statistical
Manual of Mental Disorders – 4th Ed. (DSM IV), quanto
piuttosto di vedere se fossero individuabili delle modalità
comuni relative alla percezione della realtà ed agli atteggiamenti reattivi verso di essa; in altre parole ci si è interessati
soprattutto ai processi cognitivi, senza dimenticare quanto essi
siano inestricabilmente legati alle esperienze emotive.
L’utilizzo, su di una più ampia casistica, di strumenti in grado di rivelare le componenti di aggressività manifesta, ma
soprattutto repressa, nei pazienti psoriasici e la valutazione
dei risultati di trattamenti psicoterapeutici mirati verso obiettivi specifici, potrebbero confermare i risultati e le osservazioni della nostra indagine.
Vol. 140 - N. 3
SCIUBBA
Riassunto
Obiettivo. Valutare la presenza di un’associazione tra
eventi stressanti, quali quelli elencati dalla Social Readjustement Rating Scale, ed esordio della malattia in pazienti
affetti da psoriasi volgare di moderata-severa gravità e indagare sull’esistenza di tratti comuni di personalità.
Metodi. Sono stati intervistati un gruppo di 33 pazienti
affetti da psoriasi volgare di moderata-severa gravità. Tutti
i pazienti hanno completato il test di personalità Minnesota
Multiphasic Personality Inventory-2 (MMPI-2), fornendo
30 protocolli interpretabili (15 uomini e 15 donne), i cui
punteggi sono stati confrontati con quelli della popolazione
generale.
Risultati. I risultati di questo confronto mostrano diversi
profili per i 2 sessi: negli uomini le differenze statisticamente significative sono relative soprattutto a scale che indicano irritabilità e difficoltà a controllare sentimenti di rabbia,
nelle donne l’aggressività appare maggiormente di tipo introversivo e predominano indicatori di ansia, depressione e
somatizzazione. È stato anche fornito un sostegno psicologico a 26 pazienti, ispirato ai principi della terapia cognitiva; i colloqui hanno evidenziato 2 tipologie di pazienti: l’una in cui prevalgono sentimenti di insofferenza verso condizioni avverse ambientali, l’altra in cui è centrale la percezione di un insufficiente sostegno affettivo e sociale.
Conclusioni. L’analisi congiunta dei dati ricavati dalle
interviste, dai test e dai colloqui sembra convalidare la correlazione tra componente somatica della malattia e funzione protettiva della cute nei confronti dell’ambiente esterno,
elementi alla base dell’interpretazione psicosomatica di questa dermatosi a carattere cronico-recidivante spesso fortemente lesiva dell’immagine corporea del paziente.
PAROLE CHIAVE: Psoriasi, diagnosi - Stress - Psoriasi, psicologia.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
219
G ITAL DERMATOL VENEREOL 2005;140:221-7
Photodynamic therapy with topical δ-aminolaevulinic acid
for the treatment of plantar warts
E. PROCACCINI 1, G. FABBROCINI 2, M. LO PRESTI 2, V. BATTIMIELLO 2, M. DELFINO 2, G. MONFRECOLA 1
Aim. Treatments currently employed for plantar warts (PW) are
often painful and poorly effective. This study evaluates the
effect of photodynamic therapy (PDT) with topical δ-aminolaevulic acid (ALA) on PW.
Methods. Before treatment, the superficial hyperkeratotic layer of warts was removed by the application, for 7 days, of an
ointment containing 10% urea and 10% salicylic acid. Then,
after gentle curettage, a cream containig 20% ALA was applied
under occlusive dressing for 3 h on 30 patients with 84 warts,
while 30 patients with 62 warts (controls) received only base
cream. Both groups were irradiated using a visible light lamp
(range 400-700 nm, peaking at 630 nm). The light dose was 50
J/cm2 each session. Patients were followed-up for 12 months.
During the treatment some patients referred mild burning sensation or a slight pain. The absorption of ALA in warts was
investigated and demonstrated by in vivo fluorescence spectroscopy.
Results. Two months after the last irradiative session, 84.5% of
the ALA-PDT treated lesions and 22.5% of controls had
resolved.
Conclusion. The results of this study suggest that topical ALAPDT can be considered as alternative treatment for PW.
KEY WORDS: δ-aminolaevulinic acid - Photodinamic therapy Warts.
P
hotodynamic therapy (PDT) is based on the administration of a photosensitiser and its activation with
specific wavelenghts. This activation produces cell
damage and leads the target tissue to destruction.
Dougherty et al.1 first reported the clinical use of
Address reprint requests to: Dr. G. Monfrecola, Dipartimento di Patologia Sistematica, Sezione di Dermatologia, Via S. Pansini 5, 80131 Napoli. E-mail: [email protected] .
Vol. 140 - N. 3
1Unit of Dermatology
ASL Napoli 1, Naples, Italy
2Unit of Dermatology
Department of Systematic Pathology
Federico II University of Naples, Naples, Italy
PDT with systemic photosensitisers as porphyrins or
related substances. Prolonged photosensitivity was
the most important adverse side-effect of this therapeutic approach. Kennedy et al.2 first suggested the
topical employment of δ-aminolaevulinic acid (ALA)
after showing its skill in penetrating through damaged
epidermidis. From a dermatological point of view,
topical ALA-PDT with visible light irradiation has
been successfully used for the treatment of nonmelanoma skin cancer and of premalignant conditions.3
Warts are benign skin papillomas caused by an epidermotropic DNA virus called human papilloma virus
(HPV). This kind of lesions are very common and can
affect several sites including face, hands, feet and genitalia. Warts are usually asymptomatic, with the exception of plantar warts (PW). These are frequently associated with pain, because of the pressure exerted by the
body weight on the hyperkeratotic lesions. The therapeutic approach to warts is often frustrating because the
available treatments are not always effective in eradicating the HPV infection, especially when the lesion
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PHOTODYNAMIC THERAPY WITH TOPICAL δ-AMINOLAEVULINIC ACID FOR THE TREATMENT OF PLANTAR WARTS
PROCACCINI
is situated in plantar site. In fact, this kind of lesions
trend to become deeper giving frequent relapses.
PDT’s ability to inactivate virus and bacteria is
already known 4, 5 and has been demonstrated in former studies about herpes virus as well.6 Topical use of
PDT has already been tested for the treatment of anal
condilomatosis.7 The aim of this study was to evaluate
the potential of ALA-PDT in the treatment of PW.
Materials and methods
not matched respect to age, sex, duration and site of
lesion. The keratolitic ointment was applied in both
group and it was kept in place with a sticking-plaster
for 7 consecutive days before the PDT session. On the
8th day the keratotic material of each wart was removed
with gentle curettage and the 20% ALA emulsion or
base cream was applied with an occlusive dressing
for 3 h. This was followed by the irradiative one (50
J/cm2) with visible light. Patients underwent a PDT
sessions for two a weeks. A 3rd session was performed
15 days after the 2nd one.
Patients
Evaluation of therapeutic efficacy
After giving their consent, 60 patients, 34 males
(55%) and 26 females (45%), with average age 31±7.8
years (18-40 years), that have been suffering from PW
for more or less a year were enrolled in the study.
Some of them were affected from recalcitrant and multiple lesions making a total of 146 warts. No subject had
undergone surgical excision or cauterization and all
patients received no treatment for a 2 month period
before the study. All patients were seen at the Department of Dermatology of the University of Naples and
were all resident in Campania.
The lesions were photographed and measured at the
beginning and at the end of the treatment. The efficacy evaluation was performed by measuring the median diameter of warts. Patients were followed-up at 1,
3, 6 and 12 months.
Chemicals
ALA was purchased from Sigma-Aldrich (Milan,
Italy). A concentration of 20% was prepared in a base
cream (Eucerin). Keratolitic ointment was composed
of 10% urea and 10% salicylic acid in petrolatum was
used.
With a type-1 error of 5% a type-2 error of 10%,
an expected cure rate of 20% in placebo group and a
difference in cure rate of 30% we obtained that 57
warts were necessary for each treatment arm.
Since our experimental data were normally distributed, we used parametric tests for small samples at P
0.001 significance level for the statistical evaluation.
To compare the therapeutic effectiveness of the 2 treatments, a Student’s t-test was used (Biomedical date
package BMDP IBM, versione 1993).
High sensitivity spectroscopy: experimental apparatus and procedures
Irradiation source
Irradiation source was a tungsten lamp with a soectrum emission ranging from 400 to 700 nm, peaking
at 630 nm3. Total light dose administered was 50 J/cm2,
measured with a power meter (Ophir, Optronics LTD,
Wilmington, MA, USA).
Therapeutics procedures
Patients were assigned randomly to 2 groups (the
choice was done considering the hospital identification
number) and the study was inducted in double-blind.
Group A,3 composed of 30 patients with 84 PW,
received ALA-PDT. On the other hand, group B, composed of 30 patients with 62 PW, received placeboPDT, i.e. base cream without ALA. The 2 groups were
222
Statistics
High sensitivity spectroscopy was used to evaluate the
fluorescence an investigation done to get an index of the
absorption of ALA. The excitation source for the spectroscopic measurement was a N pulsed laser PTI 2300
(γemiss=337.1 nm, energy=1/1.5 mJ/pulse, pulse duration=500 ps, highest repetition rate=20 Hz) which
pumped a PTI PL201 dye laser. The dye cuvette contained a 5×10-4 M solution of [2-(4’-Biphenylyl)-6phenylbenzoxazole] (PBBO) in ethanol, wich, on excitation at 337 nm, emits a sharp band of between 391 and
411 nm. The laser beam was focused through standard
optics and with the help of a micro-metric rotator mounted on the head of a fibre bundle (fiber diameter = 200
µm). The latter delivered the excitation radiation from
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PHOTODYNAMIC THERAPY WITH TOPICAL δ-AMINOLAEVULINIC ACID FOR THE TREATMENT OF PLANTAR WARTS
PROCACCINI
the laser to the surface of the tissue under investiga- TABLE I.—Characteristics of warts in the 2 groups at the beginning.
tion. The distal ends of the excitation fibre-bundle were
ALA-PDT
Placebo
arranged in a probe wich also contained the heads of the
Average size at the beginning
75
70
fluorescence fibres. The latter collect the fluorescence
(range - mm2)
(15-124)
(27-119)
radiation emitted by the tissue and deliver it to the
Average life (months-range)
12
12
entrance slit of the spectrograph (Chromex 500 IS/SM,
(8-14)
(9-13)
focal length 0.5 m, plane grating ruled at 300 lines/mm)
through micro-metric translators and rotators. Measurements were performed in the dark and the probe was TABLE II.—Results obtained in the two groups.
positioned, as far as it was possible, in light contact
After ession After ession After ession
with and perpendicular to the tissue. Details of this
Lesions
Healings
1
2
3
fibre-optic system have been reported elsewhere.8 The
84
71 (84.5%) 34 (47.9%) 26 (36.6%) 11 (15.5%)
fluorescence spectrum was formed on a CCD matrix PDT
—
6 (42.8%) 8 (57.7%)
detector (OMA SPEC 4000, EG&C Princeton Applied Placebo 62 14 (22.5%)
Research) with 512×512 pixels (19×19 µm2), whose
spectral response is in the range of 400-950 nm. The
CCD detector (cooled with circulating water and a
Peltier cooler) was connected via an optical fibre link Healed with placebo a statistically significant difference
to the DRAM of a control board, installed in the PC between these 2 groups was shown by Student t-test
that controlled the spectra acquisition. The arrange- (P<0.001). Thirty-four out of 71 PW healed after one
ment of the fibres in the fibre-bundle system allowed the PDT treatment (47.9%); 26 (36.6%) required 3 2 treatspectra of the fluorescence radiation collected at different ments one only 11 (15.5%) required sessions. The perpoints along the vertical dimension of the probe to be centage of remissions was greater than the expected
recorded on different rows of CCD matrix. In order to number of spontaneous remissions (20-30%). In the
maximize the signal-to-noise ratio a unique spactrum placebo-PDT group, 6 (42.8%) occurred after 1 treatment,
was obteined by averaging all the CCD matrix rows. In 2 (15.4%) after 2 sessions and 5 (38.5%) after 3 treataddition, because the CCD camera shutter was kept ments.
During the irradiation some patients experienced a
open during each acquisition 1 800 spectra were recorded and averaged to provide a unique space and time mild burning sensation or a slight pain, but local anaesaveraged spectrum. Each acquisition lasted 3 min. The thesia was never requested and no treatment had to be
repetition rate of the laser pulses was set at 10 Hz the interrupted because of pain. Twenty-four h after each
exposition time at 1 s. The final fluorescence spectrum treatments in the ALA PDT group a moderate swelling
was obteined by subtracting a background spectrum and a mild erythema of the irradiated area occurred.
from the fluorescence time and space averaged specIn this study we performed in vivo spectroscopic
trum. The background spectrum was obtained in the measurements on 3 patients with 5 PW treated with
same way by keeping the probe in air. Electronic noise ALA PDT. To support the PDT efficacy, we moniwas reduced by keeping the detector at a temperature of tored the protoporphirin IX (PpIX) fluorescence in 2
–70˚C during all the measurements.
spectral intervals: 460-580 and 600-720 nm in which
The fluorescence spectra measurements were per- the main emission band of this compound is located
formed by 2 indipendent and blinded observers.
after excitation by 337 nm irradiation. In the ALA
treated area as well as in surrounding non-ALA treated tissue we observed a narrow emission peak locatResults
ed at ~635 nm.
In our study we obtained a significant reduction of
ALA treated PW compared to placebo-PDT. The characteristics of warts at the beginning of the treatment are
Discussion and conclusions
reported in Table I. Table II shows results obtained in the
Traditional approaches to the treatments of PW,
ALA treated PW group, 71/84 lesions (84.5%) completely healed compared to PW (14/62 lesions; 22.5%). such as electrosurgery and cryotherapy, associated or
Vol. 140 - N. 3
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223
PROCACCINI
PHOTODYNAMIC THERAPY WITH TOPICAL δ-AMINOLAEVULINIC ACID FOR THE TREATMENT OF PLANTAR WARTS
not with the topical administration of keratolytic ointments, are not always effective. Furthermore they can
be related with a several number of relapses, because
of the persistance of the infection by HPV after the
treatment. Patients suffering from frequent relapses
often get tired with a painfull and expansive therapies.
Our results, in agreement with Stender et al.,9, 10 suggest that ALA-PDT can be an alternative treatment
for recalcitrant hand and foot warts. The percentage of
remission was significantly (P<0.05) higher in the
ALA-PDT arm compared with the placebo-PDT.
ALA is a small, soluble molecule that is not a dye per
se, but it is metabolised into PpIX in the haem biosynthetic pathway.
Unlike other photosensitisers, such as porphirins
and their related compounds, ALA’s ability to penetrate
through an alterated epidermidis has been demonstrated. For this reason it can be used in the treatment
of dermatologic diseases such as actinic keraratoses,
Bowen’s disease and psoriasis.11-13 Smetana et al.14
studied the possibility of treating viral infections with
5-ALA PDT and concluded that it be effective. Actually cells infected by HPV accumulate PpIX after the
addition of ALA in vitro, and a drastic reduction of
their virus titer can be demonstrated after exposure to
red light.
The mechanism of ALA completely understood.
Many findings suggest that it could be attributed to
the following actions:
1) The activation of PpIX, produces cytotoxic singlet oxygen and other free radicals,3 nucleic acid,
enzymes and cellular membranes are rapidly attacked
causing the release of a wide variety of highly reactive
pathophysiological products, such as prostaglandins,
thromboxanes and leukotrienes. Activation of complement systems and infiltration of immunologically
active blood cells into the damaged warts enhance the
damaging effect of these aggressive intermediates and
ultimately initiate area necrosis.
2) Cellular necrosis mainly caused by the vascular
occlusion and nutritional deprivation of the cell, with
a direct virucidal effect.
Clinical studies concerning the topical application
of ALA in the PDT of dermathological pathologies
are often accompained by fluorescence emission measurements with the aim of assessing the depth penetration and concentration of PpIX in normal and pathological tissues in order to determine a possible selec-
224
tivity of the photosensitiser’s formation and to optimise
the concentration of topical application of ALA and
light dosimetry for PDT (irradiance and total light
dose).
It is well estabilished that hyperkeratotic regions
prevent the up-take of ALA,15 but we are confident
that the dekeratinization treatment of warts made them
more permeable to ALA and acted as a selective mechanism for its uptake in the lesions only. These findings support the observation that the stratum corneum
rapresents the main obstacle preventing the uptake of
ALA into the skin and that hyperkeratotic areas inhibit ALA’s penetration into the skin.15, 16 Previous unsuccessfull results obtained by Kennedy et al.15 concerning the photosensitisation of verrucae by mean of the
topical application of ALA can probably be explained
with the lack of any attempt to foster ALA penetration
into the lesions.
References
1. Dougherty TJ. Photodynamic therapy: new approaches. Semin Surg
Oncol 1989;5:6-16.
2. Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with
endogenous protoporphyrin IX, basic principles and present clinical
experience. J Photochem Photobiol 1990;6:143-8.
3. Svanberg K, Anderson T, Killander D, Wang U, Stenram S, Andersson-Engels R et al. Photodynamic therapy of non-melanoma malignant tumors of the skin using topical δ-aminolaevulinic acid sensitization and laser irradiation. Br J Dermatol 1994;130:743-51.
4. Rosenblum LA, Hoskwith B, Kramer SD. Photodynamic action of
methylene blueon polliomyelitis virus. Proc Soc Exp Biol Med
1937;37:877-81.
5. Schultz EW, Krueger AP. Inactivation of staphylococcus bacteriophage by methylene blue. Proc Soc Exp Biol Med 1930;26:100-1.
6. Friedrich EG. Relief for herpes vulvitis. Obstet Gynecol 1973;41:
74-7.
7. Frank RGJ, Bos JD. Photodynamic therapy for condylomataacuminata
with local application of 5 aminolevulinic acid. Genitourin Med
1996;72:70-1.
8. Colasanti A, Colasanti P, Fabbrocini G, Liuzzi R, Quarto M, Riccio
P et al. Non-invasive spectroscopic analysis of dermatological lesions
excited with N2 laser. SPIE Ser Opt Biopsies Europto 1995;2627:
77-89.
9. Stender IM, Na R, Fogh H,Gluud C, Wulf HC. Photodynamic therapy with 5-aminolaevulinic acid or placebo for recalcitrant foot and hand
warts: randomized double- blind trial. Lancet 2000;355:963-6.
10. Stender JM, Lock-Andersen J, Wulf HC. Recalcitrant hand and foot
warts successful treated with photodynamic therapy with topical 5aminolaevulinic acid: a pilot study. Clin Exp Dermatol 1999;24:
154-9.
11. Calzavara-Pinton PG. Ripetitive photodynamic therapy with δ-aminolaevulinic acid as an appropriate approach to the routine treatment
of superficial non-melanoma skin tumors. J Photochem Photobiol
1995;29:53-7.
12. Kaufmann R, Boehncke WH, Sterry W. Treatment of psoriasis by
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
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topical photodynamic therapy with polichromatic light. Lancet
1994;343:801.
13. Collins P, Robinson DJ, Stringer MR. The variable response of plaque
psoriasis after a single treatment with topical δ-aminolaevulinic acid
photodynamic. Br J Dermatol 1997;137:743-9.
14. Smetana Z, Malik Z, Orenstein A, Mendelson E, Ben Hur E. Treatment
of viral infections with 5-aminolaevulinic acid and light. Lasers Surg
PROCACCINI
Med 1997;21:351-8.
15. Kennedy JC, Pottier RH. Endogenous protoporphyrin IX, a clinically useful photosensitizer por photodynamic therapy. J Photochem
Photobiol 1992;14:275-92.
16. Golf BA, Bachor R, Kollias N, Hasan T. Effects of photodynamic therapy with topical application of 5-aminolaevulinic acid on normal skin of
hairless guinea pig. J Photochem Photobiol 1992;15:239-51.
Terapia fotodinamica con acido δ-aminolevulinico
per il trattamento di verruche plantari
L
a terapia fotodinamica (photodynamic therapy, PDT) si
basa sull’impiego di un fotosensibilizzante e sulla successiva irradiazione con lunghezze d’onda idonee a essere
assorbite dal fotosensibilizzante stesso, la cui attivazione
provoca la distruzione del tessuto bersaglio. L’utilizzazione
clinica della PDT è stata riferita per la prima volta da Dougherty et al.1 mediante l’impiego di un fotosensibilizzante
sistemico. Tale metodica è tuttavia gravata dall’inconveniente di rendere il paziente fotosensibile per alcune settimane. Kennedy et al.2 hanno suggerito per primi l’uso topico dell’acido δ-aminolevulinico (ALA), dopo averne dimostrato la capacità di penetrare attraverso l’epidermide danneggiata. La PDT con ALA topico e luce visibile ha trovato
indicazione, in campo dermatologico, nel trattamento delle
neoplasie cutanee non melanocitiche e delle precancerosi 3.
Le verruche sono papillomi cutanei benigni, causati da un
virus epidermotropo a DNA, noto come virus del papilloma
umano (human papilloma virus, HPV). Le lesioni possono
localizzarsi in varie sedi, come il viso, le mani, i piedi e i genitali; esse sono per lo più asintomatiche, con l’eccezione delle verruche plantari, dolorose a causa della pressione esercitata dal peso corporeo sulle lesioni ipercheratosiche. Il trattamento delle verruche spesso risulta complesso, specie nelle
lesioni plantari, che tendono ad approfondirsi nella cute con
frequenti recidive, quando non si ottiene la completa eradicazione del virus. La capacità della PDT di inattivare virus e
batteriofagi, d’altra parte, è nota da tempo 4, 5. Essa è stata
dimostrata anche nei confronti del virus erpetico 6. In un precedente studio, la PDT topica è stata impiegata nel trattamento
di pazienti con condilomatosi ano-genitale 7. Lo scopo di questo studio è stata la valutazione dell’impiego della PDT topica mediante ALA nel trattamento delle verruche plantari.
Materiali e metodi
Pazienti
Previo consenso informato, sono stati esaminati 60 pazienti, 34 di sesso maschile (55%) e 26 di sesso femminile (45%),
Vol. 140 - N. 3
con età media di 31±7,8 anni (range 18-40), affetti da circa
1 anno da verruche plantari resistenti ad altre terapie convenzionali, alcuni con lesioni multiple, per un totale di 146
verruche plantari sottoposte a trattamento. In nessun caso
era stata praticata escissione chirurgica o elettrochirurgia,
né era stato effettuato alcun tipo di trattamento nei 2 mesi precedenti allo studio.
Farmaci
È stato utilizzato come farmaco fotosensibilizzante ALA,
acquistato presso la Sigma-Aldrich di Milano - Italia incorporato al 20% in crema base.
Come unguento cheratolitico è stato utilizzato un prodotto aggiungendo urea al 10% e acido salicilico al 10% in
vaselina.
Sorgente irradiativa
Per l’irradiazione è stata adoperata una lampada al tungsteno con spettro di emissione tra 400 e 700 nm, picco a 630
nm. La dose irradiativa utilizzata è stata di di 50 J/cm2 a 10
cm di distanza dalla lampada misurata con radiometro Ophir,
modello DGX 10A (Ophir Optronics LTD, Wilmington,
MA, USA).
Procedure terapeutiche
Lo studio è stato effettuato in doppio cieco, assegnando
i pazienti a 2 gruppi con modalità random, basata sul numero della tessera sanitaria. Il primo gruppo era formato da 30
pazienti con 84 verruche plantari, trattati con PDT topica.
Il secondo gruppo, composto da 30 pazienti con un totale
di 62 verruche plantari, è stato, invece, utilizzato come
controllo e trattato con placebo-PDT, cioè crema base priva di ALA. I 2 gruppi non sono stati uniformati per età,
sesso, durata e sede delle lesioni. In entrambi i gruppi, prima della terapia, è stato applicato l’unguento cheratolitico,
tenuto in sede con cerotto adesivo, per 7 giorni consecutivi. L’8° giorno, dopo eliminazione del materiale cheratosico da ogni verruca, è stata eseguita la PDT mediante
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PROCACCINI
PHOTODYNAMIC THERAPY WITH TOPICAL δ-AMINOLAEVULINIC ACID FOR THE TREATMENT OF PLANTAR WARTS
applicazione in occlusiva di ALA in una base, del solo placebo per 3 h, seguita da irradiazione con luce visibile al
dosaggio di 50 J/cm2. Sono state praticate 2 sedute a distanza di 1 settimana, e, in caso di persistenza delle lesioni,
una 3° seduta, 15 giorni dopo la 2°.
Valutazione dell’effetto terapeutico
Le lesioni sono state fotografate prima dell’inizio e alla fine
del trattamento. I controlli clinici sono stati eseguiti contestualmente alla terapia. Il follow-up dei pazienti è stato praticato a 1, 3, 6 e 12 mesi.
Dati statistici
Con un errore di tipo 1 del 5%, e un errore di tipo 2 del
10%, un indice terapeutico atteso del 20% nel gruppo placebo
e una differenza di indice terapeutico del 30%, abbiamo ottenuto che per ciascun braccio del trattamento erano necessarie 57 verruche. Poiché i dati sperimentali risultavano normalmente distribuiti, per la valutazione statistica, sono stati adoperati test parametrici per campioni limitati con livello di significatività p=0,001. Per confrontare l’efficacia terapeutica dei 2 diversi trattamenti è stato impiegato il t-test di
Student (Biomedical date package BMDP IBM, versione
1993).
Spettroscopia ad alta sensibilità: apparato sperimentale e
procedure
È stato utilizzato uno spettroscopio ad elevata sensibilità per
la valutazione della fluorescenza come indice di assorbimento del farmaco. Come sorgente di eccitazione per le misure spettroscopiche è stato usato un laser N pulsato PTI 2300
(γemiss=337,1 nm, energia=1-1,5 mJ/impulso, durata d’impulso=500 ps, massima velocità di ripetizione=20 Hz) che
pompava un dye laser PTI PL 201. La cuvette conteneva [2(4’-Biphenylyl)-6-phenylbenzoxazole] (PBBO) 5×10-4 M in
etanolo, che, con eccitazione a 337 nm, emette una sottile
banda tra 391 e 411 nm. Il raggio laser è stato focalizzato
attraverso ottiche standard, con l’ausilio di un rotore micrometrico montato sulla testa del fascio di fibre (diametro
fibre=200 µm) utilizzato per portare la radiazione laser di
eccitazione sul tessuto da esaminare. L’estremità distale
del fascio di fibre è stata disposta in una sonda che conteneva anche le teste delle fibre utilizzate per raccogliere la
fluorescenza dai tessuti e convogliarla alla finestra d’ingresso dello spettrografo (Chromes 500 IS/SM lung. Focale 0,5 m, griglia regolata a 300 linee/mm) attraverso trasduttori e rotatori micrometrici. Le misurazioni sono state
effettuate al buio, posizionando la sonda, per quanto possibile, perpendicolare e in leggero contatto con il tessuto.
Questo sistema di fibre ottiche è stato descritto dettagliatamente in altra sede 8.
La lettura dello spettro di fluorescenza è stata effettuata
con sensore CCD (OMA SPEC 4000 EG&C Princeton
Applied Research) dotato di 512×512 pixels (19×19 µm2).
Il sensore è stato connesso mediante fibra ottica al DRAM
226
di una scheda installata nel computer impiegato per controllare l’acquisizione spettrale. Grazie alla disposizione in
fascio delle fibre, è stato possibile rilevare lo spettro della
radiazione fluorescente in differenti punti lungo l’asse verticale della sonda, registrandolo su linee diverse del sensore CCD. Per ottimizzare il rapporto segnale-disturbo, è stato elaborato uno spettro unico, ricavato dalla media delle
righe del sensore CCD. Inoltre, tenendo aperto l’otturatore
durante ogni acquisizione, sono state registrate 1 800 rilevazioni spettrali, di cui è stata calcolata la media, al fine di
ricavare un unico spettro medio nei parametri spazio-temporali. Per ogni singola acquisizione sono stati impiegati 3
min, con velocità di ripetizione dell’impulso laser regolata
a 10 Hz e tempo di esposizione di 1 s. Lo spettro di fluorescenza definitivo è stato calcolato sottraendo dallo spettro
medio un valore di fondo, ottenuto esponendo, con le stesse modalità, la sonda all’aria. Il rumore di fondo elettronico è stato ridotto tenendo il sensore a -70 °C durante le
misurazioni. Le rilevazioni sono state effettuate, in cieco, da
2 osservatori indipendenti.
Risultati
Nel nostro studio si è ottenuta una remissione statisticamente significativa delle verruche plantari trattate con la
PDT, rispetto al gruppo placebo. Le caratteristiche iniziali
delle verruche assegnate ai 2 gruppi sono riassunte in Tabella I. Come si evince dalla Tabella II, nel gruppo trattato con
ALA si è verificata guarigione completa in 71/84 lesioni
(84,5%), mentre, nel gruppo placebo il rapporto è stato
14/62 (22,5%). Il t-test di Student ha evidenziato la significatività statistica della differenza tra i 2 gruppi (P<0,001).
Nel gruppo PDT 34 verruche (47,9%) sono guarite dopo
un solo trattamento, 26 (36,6%) dopo 2 trattamenti, mentre
solo per 11 lesioni (15,5%) è stato necessaria una terza
applicazione. La percentuale di verruche guarite risulta
superiore a quella attesa di guarigioni spontanee (20-30%).
Per quanto riguarda, invece, le verruche guarite nel gruppo
placebo, 6 (42,8%) sono regredite dopo 2 trattamenti e 8
(57,2%) dopo 3 sedute. I pazienti trattati con PDT hanno riferito, durante l’irradiazione, sensazione di bruciore, o lieve
dolore, ma in nessun caso è stata necessaria anestesia, né
sospensione del trattamento. In questi pazienti, 24 h dopo l’irradiazione, si osservava modesto edema ed eritema della
sede trattata. In questo studio abbiamo effettuato misurazioni
spettroscopiche in vivo su 3 pazienti con 5 verruche plantari,
dopo la prima applicazione di ALA topico. Al fine di sostenere i risultati della PDT, che mostravano elevata fotosensibilizazione delle verruche dopo curettage e applicazione
topica di ALA, è stata monitorata la fluorescenza indotta
dalla protoporfirina IX (PpIX) nei 2 intervalli spettrali: 460580 nm e 600-720 nm in cui si colloca la principale banda
di emissione del composto dopo eccitazione con luce a 337
nm. Nel raffronto tra le aree trattate e i tessuti sani circostanti,
abbiamo riscontrato, per entrambi, l’emissione di una sottile banda con picco a 635 nm.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
Giugno 2005
PHOTODYNAMIC THERAPY WITH TOPICAL δ-AMINOLAEVULINIC ACID FOR THE TREATMENT OF PLANTAR WARTS
Discussione e conclusioni
I trattamenti tradizionali per le verruche plantari, quali
crioterapia ed elettrochirurgia, associati o meno ad applicazione topica di soluzioni lattico-saliciliche, possono risultare insoddisfacenti, con risultati incostanti, poiché non assicurano la completa eradicazione del virus. Le recidive, infatti, non sono rare, e i pazienti soffrono, in tal caso, nel doversi sottoporre a numerosi cicli di terapia, spesso dolorosa e,
a lungo andare, onerosa dal punto di vista economico. I nostri
risultati indicano che la PDT con ALA può essere un valido
trattamento per le verruche plantari, in accordo con i dati di
Stender et al. 9, 10 che hanno trattato efficacemente con ALAPDT verruche recalcitranti dei piedi e delle mani. Il numero di verruche guarite risultava significativamente più elevato
nel gruppo trattato con ALA – PDT rispetto al gruppo placebo-PDT (P<0,05).
L’ALA è una piccola molecola solubile, che penetra attraverso l’epidermide alterata e viene rapidamente metabolizzata in PpIX. La sua efficacia è stata dimostrata in pazienti
con carcinoma basocellulare, cheratosi attinica, malattia di
Bowen e psoriasi 11-13. Lo studio di Smetana et al. 14 ha evidenziato l’efficacia di ALA-PDT nella terapia di alcune infezioni virali, dimostrando l’accumulo di porfirina IX nelle
cellule infettate da HPV, dopo aggiunta di ALA in vitro, e la
drastica riduzione del titolo virale dopo successiva PDT con
luce rossa.
Il meccanismo dell’effetto virucida di ALA-PDT non è
ancora del tutto chiarito. Molti dati suggeriscono che entrino in gioco i seguenti fattori:
1) l’attivazione di PpIX, produce ossigeno singoletto,
citotossico, e altri radicali liberi, generati da una reazione con
trasferimento di energia. Il conseguente rapido danneggiamento strutturale di acidi nucleici, degli enzimi e soprattutto delle membrane cellulari porta al rilascio di svariati composti altamente reattivi, quali: prostaglandine, trombossani
e leucotrieni. L’attivazione del complemento e l’infiltrazione delle verruca danneggiata da parte di cellule ematiche
immunologicamente attive contribuiscono ad accentuare
l’effetto tossico dei mediatori, dando, infine, inizio alla necrosi dell’area interessata.
2) La necrosi cellulare vieni determinata principalmente
dall’occlusione vascolare e dalla deprivazione nutritiva delle cellule.
Gli studi clinici sull’applicazione topica della PDT in svariate patologie dermatologiche sono spesso accompagnati
dalla misurazione della fluorescenza emessa, al fine di valutare la profondità di penetrazione e la concentrazione di
PpIX nei tessuti sani e patologici, per evidernziarne una
eventuale selettività della formazione di PpIX, e per deter-
Vol. 140 - N. 3
PROCACCINI
minare sia la concentrazione ottimale di farmaco, che la
dose della luce necessaria.
È stato quindi accertato che le verruche, caratterizzate da
mancata ipercheratosi impediscono l’assorbimento di ALA.
Tuttavia noi siamo propensi a credere che un trattamento
cheratolitico preventivo possa renderle permeabili ad ALA,
agendo come meccanismo selettivo per l’assorbimento del
composto nelle verruche. I nostri dati confermano l’osservazione secondo cui lo strato corneo rappresenta il principale ostacolo alla penetrazione di ALA 15, 16. I risultati deludenti
ottenuti in passato da Kennedy et al. 15, nel tentativo di fotosensibilizzare le verruche mediante applicazione topica di
ALA, possono verosimilmente essere attribuiti alla mancanza di sforzi per favorire la penetrazione della sostanza
nelle lesioni.
Riassunto
Obiettivo. Le metodiche comunemente impiegate per il
trattamento delle verruche plantari (elettrochirurgia, crioterapia) sono spesso dolorose e non sempre efficaci. In questo
studio è stato valutato l’effetto della terapia fotodinamica
(photodynamic therapy, PDT) con acido δ-aminolevulinico
(ALA) per uso topico nel trattamento delle verruche plantari.
Metodi. Il trattamento è stato effettuato rimuovendo inizialmente lo strato superficiale, ipercheratosico, delle verruche, mediante applicazione per 7 giorni di unguento a base di
urea 10% e acido salicilico 10%. Successivamente, dopo leggero curettage, è stato applicato ALA al 20% in crema, con
medicazione occlusiva per 3 h. Lo studio è stato condotto in
30 pazienti con 84 lesioni, mentre, per altri 30 pazienti, con
62 verruche (controlli), è stato utilizzato unicamente il veicolo.
Tutte le verruche sono state poi irradiate, con una lampada a
luce visibile (emissione tra 400 e 700 nm con picco a 630
nm) con una dose pari a 50 J/cm2 per seduta. La terapia è
stata effettuata 1 volta alla settimane per 2 o 3 settmane. È stato effettuato un follow-up di 1 anno. Durante il trattamento,
alcuni pazienti lamentavano sensazione di bruciore e/o dolore. L’assorbimento dell’ALA nelle verruche è stato verificato in vivo, mediante spettroscopia di fluorescenza.
Risultati. I risultati ottenuti dimostrano la risoluzione delle verruche, a 2 mesi dall’ultimo trattamento nel 84,5% delle lesioni nel gruppo PDT e nel 22,5% dei controlli.
Conclusioni. I risultati di questo studio suggeriscono che
la PTD con ALA topico può costituire una valida alternativa nel trattamento delle verruche plantari, nelle condizioni
descritte, che permettono un’adeguata penetrazione del farmaco.
PAROLE CHIAVE: Acido δ-aminolevulinico - Terapia fotodinamica – Verruche.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
227
G ITAL DERMATOL VENEREOL 2005;140:229-36
Skin reactivity in relation to the menstrual cycle
D. BONAMONTE 1, C. FOTI 1, R. IEVA 1, E. DI NARO 2, G. LOVERRO 2, G. ANGELINI 1
Aim. Some literature studies have reported that hormonal fluctuations during the menstrual cycle may have some effect, to a
more or less marked degree, both on some skin physiological
parameters and on the clinical expression of contact irritation.
The aim of the present study is to assess the influence of female
sex hormones on contact irritation and on some physiological skin
parameters (evaporimetric, corneometric, sebometric values).
Methods. We studied a selected group of 15 women aged between
20 and 45 years (mean age: 28.9) with a regular menstrual
cycle and a control group of 15 women aged between 54 and 60
years (mean age: 56.8), who had been in menopause for at least
1 year. In both study groups contact irritation was assessed by
patch tests with sodium lauryl sulfate (SLS) at scaled aqueous
dilutions from 0.1% to 1%, while the other physiological parameters were studied by means of evaporimetry, sebometry and
corneometry.
Results. In the first group of women the response to the patch
tests with SLS varied during the different phases of the menstrual cycle: in the premenstrual-progestinic period there was
more marked reactivity of the skin to irritant stimuli than during the ovulatory period. The evaporimetric, sebometric and
corneometric measurements also yielded generally higher values during the menstrual period than during the ovulatory
period. Comparison between the 2 groups showed that skin
reactivity in menopausal women is comparable to that in fertile women during the menstrual period. This is probably a
consequence of the hormonal situation, characterized by low
estrogen levels during the menstrual phase and in the
menopause. The results obtained with evaporimetry, sebometry and corneometry demonstrated statistically significant dif-
Address reprint requests to: Dott. D. Bonamonte, Clinica Dermatologica,
Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy.
E-mail: [email protected]
Vol. 140 - N. 3
1Section of Dermatology
Department of Internal Medicine
Immunology and Infectious Diseases
University of Bari, Bari, Italy
2Third Unit of Obstetrics and Gynecology
University of Bari, Bari, Italy
ferences in the 2 periods of the menstrual cycle, the values
being higher during the menstrual phase.
Conclusion. The results of our study seem to demonstrate that
the female sex hormones play an important role in cutaneous
physiopathological mechanisms.
KEY WORDS: Cutaneous reactivity - Menstrual cycle - Female – Hormones - Contact irritation - TEWL - Corneometry - Sebometry.
A
s well as affecting some dermatological complaints (herpes simplex, acne vulgaris, chronic
urticaria, polymorphous erythema, atopic dermatitis),1-8 the menstrual cycle seems to have some effect,
of a variable entity, on various physiological and physiopathological skin parameters.
In 1941 Halter,9 and then in 1968 Bjørnberg 10 reported significantly increased skin reactivity to irritant
stimuli just before and during the menstrual period.
Later, Agner et al.9-14 observed that skin testing with
sodium lauryl sulfate (SLS) yielded a significantly
more intense response during the first day of menstruation than in the follicular phase.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
229
BONAMONTE
SKIN REACTIVITY IN RELATION TO THE MENSTRUAL CYCLE
The greater skin irritability observed in the premenstrual and menstrual phases is probably caused at least
in part by the reduced efficacy of the skin barrier in this
period. It is known that the main functions of the skin
barrier are exerted by the lipids in the stratum corneum,
which are prevalently polar, unlike those in sebum, and
can swell in the presence of water. Some studies aiming
to assess cyclical variations in the production of sebum
in the different phases of the menstrual cycle have yielded conflicting results.12-15 Periodic sebometric measurements carried out by Burton et al.13 in 10 fertile
women with a regular menstrual cycle demonstrated
reduced sebaceous production during the ovulatory
phase, when estrogen production is at its height. Instead,
the role of the physiological levels of progesterone on
sebaceous secretion seems to be controversial:12, 16-19
it does not therefore seem justifiable to attribute the
activity of the sebaceous glands during the second half
of the menstrual cycle to hormonal fluctuations.
One possible method for measuring the efficacy of the
skin barrier is by gauging transepidermal water loss
(TEWL). With this method, some authors 11, 20 have
failed to demonstrate significant variations in the 2 periods of the menstrual cycle, whereas other authors 21
have reported significantly higher values of TEWL in
the premenstrual phase than in the periovulatory phase.
This evidence suggests that the skin barrier may be
less efficacious in the premenstrual phase.
The skin moisture level appears to undergo variations
during the menstrual cycle as well.22 By stimulating
hormonal receptors in the derma, estrogens may trigger an increase in the content of hyaluronic acid and
hence in the ability to retain water.23 Moreover, a close
correlation has been demonstrated between increased
synthesis of hyaluronic acid and the number of dermal
estrogen receptors.24
The present study assesses the role of the menstrual cycle on contact irritation and some physiological
skin parameters.
Materials and methods
A total of 30 women was enrolled in this study, subdivided into 2 groups: 15 women aged between 20
and 45 years (mean age: 28.9) with a regular menstrual cycle lasting between 25 and 30 days and a control group consisting of 15 women aged between 54
and 60 years (mean age: 56.8) who had been in
menopause for at least 1 year.
230
A careful history was elicited, including the age of
menarche, the duration of the menstrual cycle and its
degree of regularity, as well as any pregnancies or
spontaneous or voluntary abortions. In the menopausal
women any disturbances caused by the climacterium
were also enquired into. Women in treatment with oral
contraceptives or other drugs affecting the endocrinesexual sphere were excluded from the study.
In the group of fertile women contact irritability
was assessed by patch tests with scaled dilutions of
SLS performed during both the progestinic and the
ovulatory phases. Other physiological skin parameters were studied in the same phases. Ultrasound examination of the uterus and the ovaries was conducted
using a sonograph (Aloka 5000; Aloka Co, Ltd, Tokyo,
Japan) equipped with a 5-MHz vaginal probe. Both
ovaries were examined and endometrium thickness
was measured. Ovulation was confirmed by ultrasound. The progestinic phase was identified during
the period between the 21st and 23rd day of the menstrual cycle.
In the menopausal women the patch tests and assessments of the physiological skin parameters were performed only once.
Patch tests
Both groups of women underwent patch tests with
a series of 4 scaled aqueous dilutions of SLS (1%,
0.625%, 0.25%, 0.1%), in quantities of 20 µL, while
distilled water was used as a control. The tests were performed according to the standard method using Finn
Chambers®‚ (Epitest Ltd Oy, Finland) and Scampor®‚
tapes (Nargesplaster A/S, Norway).
The patch tests were applied high on the back and a
reading was made at 30 min from removal of the apparatus, 48 h after their application.
Measurement of some physiological parameters
The degree of skin hydration was assessed by corneometry of the volar surface of the forearm using the
CM 825® Corneometer (Courage + Khazaka, Cologne,
Germany).
The sebometric values were measured on the T zone
of the forehead using the SM 810® Sebumeter
(Courage + Khazaka, Cologne, Germany).
The amount of skin evaporation of water was determined by calculating the TEWL. This investigation
was conducted in an air-conditioned room at a tem-
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
Giugno 2005
SKIN REACTIVITY IN RELATION TO THE MENSTRUAL CYCLE
TABLE I.—Minimum irritant concentration (MIC) induced by sodium
lauryl sulfate (SLS) in the ovulatory and premestrual phases in
women with a regular menstrual cycle.
Patient N.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
SLS MIC (%)
ovulatory
SLS MIC (%)
premenstrual
0.25
0.25
0.25
0.625
0.625
0.625
1
1
1
1
1
1
1
1
1
0.25
0.25
0.25
0.25
0.25
0.625
0.625
0.625
0.625
0.625
0.625
0.625
1
0.625
1
perature of 20 °C, 60% relative humidity and in semidarkness, using the TEWA meter TM 210® (Courage
+ Khazaka, Cologne, Germany). The measurement
was made high on the back, and the mean value of
continuous measurements made over a period of 2
min was calculated.
Statistical analysis
For statistical analysis, the reactions to the patch
tests were classified as follows:
0.5=hardly perceptible erythema;
1=slight erythema;
2=modest erythema with possible slight edema of the
edge;
3=modest erythema and widespread edema;
4=intense erythema and edema;
5=erythema and blisters.
For each subject studied and in both phases of the
menstrual cycle the minimum irritant concentration
(MIC) was calculated from the results of the patch
tests with SLS.
Comparison of the values observed for the variables
under study in the 2 menstrual periods (MIC, TEWL,
corneometry, sebometry) was made with the Wilcoxon test for paired samples.
Comparison between the physiological values
obtained in the fertile women and in the menopausal
women was made with the Wilcoxon test for independent samples.
Vol. 140 - N. 3
BONAMONTE
TABLE II.—Physiological skin parameters measured in the ovulatory and premenstrual phases in women with a regular menstrual
cycle.
TEWL
Patient
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Corneometry
Sebometry
Ovulatory
Premenstrual
Ovulatory
Premenstrual
Ovulatory
Premenstrual
8.5
9.5
9.4
12.4
19.6
12.3
10.1
14.3
9.9
9.4
12.9
7.5
11.2
8.6
10.6
10.7
11.0
11.2
14.4
21.7
14.7
11.7
15.7
11.5
12.3
14.6
9.4
10.3
11.0
13.3
35
31
31
30
31
35
31
38
28
34
32
28
40
33
46
38
34
34
31
33
37
33
39
37
44
36
30
36
49
36
60
112
122
117
118
92
134
180
180
120
134
140
169
180
175
87
135
132
136
146
115
136
169
199
224
140
154
136
180
169
Results
This study on skin irritability according to the phase
of the menstrual cycle yielded significantly lower MIC
values induced by SLS during the premenstrual phase
than in the ovulatory phase (Wilcoxon test, P=0.05)
(Table I). In none of the women in the fertile group was
a response obtained to the lowest concentration of
SLS (0.1%). In the same group of subjects the evaporimetric measurements showed that baseline TEWL
in the premenstrual phase is significantly higher than
in the ovulatory phase (Wilcoxon test, P<0.01) (Table
II). Higher corneometry values were obtained in the
premenstrual than in the ovulatory phase (Wilcoxon
test, P<0.01) (Table II). Finally, sebaceous production
was significantly higher during the progestinic phase
than during the ovulatory phase (Wilcoxon test,
P<0.01) (Table II).
Comparison of values for the variables under study
obtained in the 2 groups (Tables III, IV) demonstrated that there was no statistically significant difference
between the MIC values of SLS obtained in the fertile
women in the premenstrual phase and those in the
menopausal women (Wilcoxon test, P>0.05) (Tables
I, III). Conversely, a significant difference was found
between the MIC values obtained in the ovulatory
phase and those obtained in the menopausal women
(Wilcoxon test, P=0.05) (Tables I, III).
No significant variations emerged as regards TEWL
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
231
BONAMONTE
SKIN REACTIVITY IN RELATION TO THE MENSTRUAL CYCLE
TABLE III.—Minimum irritant concentration (MIC) of sodium lauryl
sulfate (SLS) obtained in menopausal women.
Patient N.
SLS MIC %
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
0.25
0.25
0.25
0.25
0.25
0.625
0.625
0.625
0.625
0.625
0.625
0.625
1,625
1,625
1,625
TABLE IV.—Physiological skin parameters in menopausal women.
Patient N.
TEWL
Corneometry
Sebometry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
12.6
13.3
10.0
11.3
15.5
8.3
11.8
8.0
6.8
11.9
6.5
11.8
12.8
11.6
11.9
32
31
24
39
35
26
32
31
39
29
38
40
24
41
40
198
90
15
161
124
7
127
42
118
40
110
31
16
16
78
(Wilcoxon test, P>0.05) (Tables II, IV), and neither
did the corneometric measurements (Wilcoxon test,
P>0.05) (Tables II, IV), nor the sebometric measurements (Wilcoxon test, P>0.05) show any significant differences in the 2 groups (Tables II, IV).
Discussion and conclusions
The menstrual cycle seems to have some effect,
albeit to a variable degree, on physiological skin parameters. The skin would appear to be more susceptible
to irritant stimuli during the premenstrual phase, as
demonstrated by studies reporting a more intense
response to patch tests with SLS during this phase
than during the follicular phase.4 Our findings con-
232
firm this report, because we also obtained a significantly more intense reaction during the premenstrual
phase.
The greater skin irritability during the premenstrual and menstrual phases could be due to the decreased
efficacy of the skin barrier. In fact, our data also show
higher TEWL during the premenstrual period. However, the data in the literature are not concordant on this
point.4, 13, 14
The sex hormones also seem to exert an important
role in determining the degree of skin moisture. The
corneometric measurements we made in the fertile
group of subjects yielded higher values in the premenstrual phase than during ovulation. Bearing in
mind that lower corneometric values correspond to
greater hydration, it seems that the optimal moisturization state is present during the follicular phase. As
the blood concentration of estrogens is highest during ovulation, stimulation of the hormonal receptors
present on the fibroblasts presumably triggers an
increase in hyaluronic acid production, thus enhancing
water retention in the derma.16 This is confirmed by the
correlation demonstrated in some studies between
increased hyaluronic acid production induced by estradiol and a higher number of dermal receptors for the
same hormone.17
Nor is sebaceous production constant throughout
the menstrual cycle. Our study demonstrated higher
values in the progestinic phase than in the ovulatory
phase. On this parameter the sex hormones would
appear to play an important, albeit not determinant,
role in regulating the sebaceous glands, estrogen having an inhibitory effect on sebaceous production and
progesterone a stimulating effect. Nonetheless, the
role of the latter hormone has not yet been fully clarified.5, 12
The following conclusions can thus be drawn from
the present study.
1) Skin irritability, as assessed by SLS, is more pronounced during the premenstrual phase than the follicular phase.
2) The skin response to irritant stimuli is comparable in menopausal women and in fertile women in the
premenstrual phase, probably because both in
menopause and in the progestinic-premenstrual phase
there is a low estrogen count.
3) TEWL is higher during the premenstrual period
than during the periovulatory phase. In fact, the higher blood concentration of estrogens seems to trigger an
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
Giugno 2005
SKIN REACTIVITY IN RELATION TO THE MENSTRUAL CYCLE
increase in hyaluronic acid in the derma, which
enhances water retention. This conclusion is confirmed
by the lower corneometric values observed during
ovulation.
References
1. Farah FS, Shbaklu Z. Autoimmune progesterone urticaria. J Allergy
Clin Immunol 1971;48:257-61.
2. Wojnarowska F, Greaves MW, Peachy RDG, Drury PL, Bessere GM.
Progesterone-induced erythema multiforme. J Roy Soc Med 1985;78:
407-8.
3. Brunsting LA. Atopic dermatitis (disseminated neurodermatitis) of
young adults. Arch Dermatol 1936;34:935.
4. Pirila V. On Besnier’s prurigo in Finland. Acta Derm Venereol (Stockh)
1950;30:114-32.
5. Hellerstrom S, Lidman H. Studies of Besnier’s prurigo (atopic dermatitis). Acta Derm Venereol (Stockh) 1956;36:11-22.
6. Garell DC. Atopic dermatitis in females during adolescence. Am J Dis
Child 1964;107:350-5.
7. Raika G. Factors influencing atopic dermatitis. In: Raika G, editor.
Atopic dermatitis. London: WB Saunders; 1975.p.135.
8. Kemmett D, Tidman MJ. The influence of the menstrual cycle and
pregnancy on atopic dermatitis. Br J Dermatol 1991;125:59-61.
9. Halter K. Zur Pathogenese des Ekzems. Arch Derm Syph
1941;181:593.
10. Bjørnberg A. Skin reactions to primary irritants in patients with hand
eczema. Göteborg: Isacson; 1968.
11. Agner T, Damm P, Skouby SO. Menstrual cycle and skin reactivity.
J Am Acad Dermatol 1991;24:566-70.
12. Strauss JS, Kligman AM. The effect of androgens and estrogens on
human sebaceous glands. J Invest Dermatol 1962;39:139-55.
13. Burton JL, Cartlidge M, Shuster S. Variations in sebum excretion
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during the menstrual cycle. Acta Derm Venereol (Stockh) 1973;53:
81-4.
Hodgson-Jones IS, MacKenna RMB, Wheatley VR. The study of
human sebaceous activity. Acta Derm Venereol Suppl (Stockh)
1952;32:155-61.
Kalz F, Scott A. Cutaneous changes during the menstrual cycle. Arch
Dermatol (Chicago) 1956;74:493-503.
Haskin D, Lasher N, Rothman S. Some effects of ACTH, cortisone,
progesterone and testosterone on sebaceous glands in the white rat. J
Invest Dermatol 1953;20:207-12.
Lasher N, Lorinez AL, Rothman S. Hormonal effects on sebaceous
glands in the white rat. II. The effect of pituitary adrenal axis. J Invest
Dermatol 1954;22:25-31.
Smith JG Jr. The aged human sebaceous gland; the effects of hormone administration and a comparison with adolescent gland function.
Arch Dermatol 1959;80:663-71.
Jarret A. The effects of progesterone and testosterone on surface
sebum and acne vulgaris. Br J Dermatol 1959;71:102-16.
Agner T. Non invasive measuring methods for the investigation of
irritant patch test reactions. A study of patients with hand eczema,
atop ic dermatitis and controls. Acta Derm Venereol Suppl (Stockh)
1992;173:1-26.
Harvell J, Hussona-Saeed I, Maibach HI. Changes in transepidermal
water loss and cutaneous blood flow during the menstrual cycle. Contact Dermatitis 1992;27:294-301.
Berardesca E, Gabba P, Farinelli N, Borroni G, Rabbiosi G. Skin
extensibility time in women.Change in relation to sex hormones. Acta
Derm Venereol (Stockh) 1989;69:431-3.
Bentley JP, Brenner RM, Linstedt AD, West NB, Carlisle KS, Rokosova BC et al. Increased hyaluronate and collagen biosynthesis and
fibroblast estrogen receptors in macaque sex skin. J Invest Dermatol
1986;87:668-73.
Uzuka M, Nakajima K, Ohta S, Mori Y. The mechanism of estrogen
induced increase in hyaluronic acid biosynthesis, with special reference to estrogen receptor in the mouse skin. Biochim Biophys Acta
1980;627:199-206.
Reattività cutanea in relazione al ciclo mestruale
I
l ciclo mestruale, oltre che alcune affezioni dermatologiche (herpes simplex, acne volgare, orticaria cronica, eritema
polimorfo, dermatite atopica) 1-8, sembra influenzare in
maniera più o meno importante anche diversi parametri fisiologici e fisiopatologici cutanei.
Già Halter nel 1941 9 e Bjørnberg nel 1968 10 hanno riportato una significativa aumentata risposta della reattività cutanea a stimoli irritativi prima e durante la mestruazione. In
seguito, Agner et al. 11 hanno osservato che la risposta cutanea allo stimolo irritativo mediante sodio lauril solfato (SLS)
è significativamente più intensa nel primo giorno di mestruazione rispetto alla fase follicolare.
La maggiore irritabilità cutanea osservabile in fase premestruale e mestruale è verosimilmente determinata, almeno in parte, dalla minore efficacia della barriera epidermica
in tale periodo. È noto che le principali funzioni di barriera
cutanea sono svolte dai lipidi dello strato corneo, i quali, a differenza di quelli del sebo, sono in prevalenza polari con
Vol. 140 - N. 3
capacità di rigonfiarsi in presenza di acqua. Alcuni lavori, finalizzati a studiare le variazioni cicliche nella produzione di sebo
nelle diverse fasi del ciclo mestruale, hanno portato a risultati contraddittori 12-15. Burton et al.13, attraverso misurazioni sebometriche periodiche sulla fronte di 10 donne in
età fertile e con ciclo mestruale regolare, hanno rilevato una
ridotta produzione di sebo durante la fase ovulatoria, periodo in cui la produzione di estrogeni è massima. Controverso sembra essere, invece, il ruolo dei livelli fisiologici del progesterone sulla secrezione sebacea 12, 16-19: l’attività delle
ghiandole sebacee durante la seconda metà del ciclo mestruale difficilmente quindi potrebbe essere attribuita a variazioni ormonali.
Un metodo idoneo a misurare l’efficacia della funzione di
barriera epidermica è quello della perdita transepidermica di
acqua (transepidermal water loss, TEWL). Utilizzando questa metodica, alcuni Autori 11, 20 non hanno evidenziato variazioni statisticamente significative fra i 2 periodi del ciclo
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
233
BONAMONTE
SKIN REACTIVITY IN RELATION TO THE MENSTRUAL CYCLE
mestruale, mentre da altri studi 21 emerge che la TEWL in fase
premestruale mostra valori significativamente più alti rispetto a quelli ottenuti in fase periovulatoria. Quest’ultima evidenza suggerisce che in fase premestruale vi sarebbe una
minore efficienza della funzione di barriera.
Anche il livello di idratazione cutanea subirebbe variazioni durante il ciclo mestruale 22. Gli estrogeni, infatti, attraverso la stimolazione di recettori ormonali nel derma, provocherebbero un aumento nel contenuto di acido ialuronico
con conseguente capacità di trattenere acqua 23. È stata, inoltre, dimostrata una stretta correlazione tra l’aumentata sintesi di acido ialuronico e il numero dei recettori dermici per
gli estrogeni 24.
Nel presente studio è stato valutato il ruolo del ciclo
mestruale sull’irritazione da contatto e su alcuni parametri
fisiologici cutanei.
Materiali e metodi
Per questo studio sono state arruolate 30 donne, suddivise in 2 gruppi: un primo gruppo di 15 donne di età tra 20 e
45 anni (età media: 28,9) e con ciclo mestruale regolare,
compreso tra 25 e 32 giorni, e un secondo gruppo di controllo
di 15 donne di età compresa tra 54 e 60 anni (età media:
56,8) in menopausa da almeno 1 anno.
In tutti i casi si è proceduto a un’accurata anamnesi circa
l’età del menarca, la durata del ciclo mestruale e la sua regolarità, le eventuali gravidanze o gli aborti spontanei o provocati. Nelle donne in menopausa si è anche indagato su
eventuali disturbi legati al climaterio. Le donne in trattamento con contraccettivi orali o altri farmaci che interferiscono con la sfera endocrino-sessuale non sono state comprese nello studio.
Nel gruppo di donne in età fertile l’irritabilità da contatto è stata valutata mediante patch test con diluizioni scalari
di SLS eseguiti in fase progestinica e in fase ovulatoria. Nelle stesse fasi sono stati anche studiati alcuni parametri fisiologici cutanei. Tutte le pazienti sono state sottoposte a esame ecografico transvaginale per valutare la morfologia dell’utero e delle ovaie e la corrispondenza dello spessore endometriale e della attività ovarica con la fase del ciclo mestruale. L’esame ecografico è stato eseguito utilizzando un ecografo (Aloka 5000; Aloka Co, Ltd, Tokyo, Japan) equipaggiato con sonda vaginale da 5-MHz. La fase progestinica è
stata identificata nel periodo compreso fra il 21° e 23° giorno del ciclo mestruale.
Nelle donne in menopausa i patch test e la determinazione dei parametri fisiologici cutanei sono stati eseguiti una sola
volta.
acqua distillata come controllo. I test sono stati eseguiti
secondo la metodica standard utilizzando Finn Chambers®‚
(Epitest Ldt Oy, Finlandia) e cerotti Scampor®‚ (Nargesplaster A/S, Norvegia).
I patch test sono stati applicati sulla parte alta del dorso;
la lettura è stata eseguita dopo 30 min dalla rimozione dell’apparato testante a distanza di 48 h dall’applicazione.
Misurazione di alcuni parametri fisiologici
Lo stato di idratazione cutanea è stato valutato mediante
corneometria sulla superficie volare dell’avambraccio con
l’impiego del Corneometer CM 825® (Courage + Khazaka,
Köln, Germany).
Sulla zona T della fronte sono stati misurati i valori della
sebometria mediante Sebumeter SM 810® (Courage + Khazaka, Köln, Germany).
L’entità di evaporazione cutanea di acqua è stata determinata attraverso il calcolo della TEWL. Per questa indagine, effettuata in stanza climatizzata con 20 °C di temperatura,
60% di umidità relativa e in condizioni di semi-oscurità, è stato impiegato il TEWA meter TM 210® (Courage + Khazaka, Köln, Germany). La misurazione è stata eseguita sulla parte alta del dorso, calcolando il valore medio di misurazioni continue nello spazio di 2 min.
Elaborazione statistica
Ai fini dell’analisi statistica, alle reazioni ai patch test è stato attribuito il seguente valore numerico:
0,5=eritema appena percettibile;
1=eritema debole;
2=eritema modesto con possibile scarso edema del margine;
3=eritema modesto con edema diffuso;
4=eritema e edema intensi;
5=eritema e bolle.
Per ogni soggetto in esame e in entrambe le fasi del ciclo
mestruale dai risultati dei patch test con SLS è stata ricavata la concentrazione minima irritante (minimum irritant concentration, MIC).
Il confronto tra i valori osservati nelle 2 fasi mestruali
relativi alle variabili in studio (MIC, TEWL, corneometria,
sebometria) è stato effettuato mediante il test di Wilcoxon per
campioni appaiati.
Il confronto fra i valori dei parametri fisiologici nelle donne in età fertile con quelli nelle donne in menopausa è stato
valutato mediante il test di Wilcoxon per campioni indipendenti.
Risultati
Patch test
A entrambi i gruppi di donne sono stati praticati patch
test con una serie di 4 diluizioni scalari di SLS in acqua (1%,
0,625%, 0,25%, 0,1%), in quantità di 20 mL ciascuna, e con
234
I risultati dello studio relativi all’influenza del ciclo
mestruale sull’irritabilità cutanea possono essere riassunti
come segue.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
Giugno 2005
SKIN REACTIVITY IN RELATION TO THE MENSTRUAL CYCLE
I valori della MIC indotta dal SLS durante la fase premestruale sono significativamente più bassi rispetto a quelli
ottenuti in fase ovulatoria (test di Wilcoxon, P=0,05) (Tabella I). In nessuna delle donne comprese in questo gruppo si è
ottenuta risposta alla concentrazione più bassa del SLS
(0,1%). Nello stesso gruppo di soggetti le misurazioni evaporimetriche hanno dimostrato che la TEWL basale durante la fase premestruale è significativamente maggiore rispetto a quella in fase ovulatoria (test di Wilcoxon, P<0,01)
(Tabella II). Per quanto riguarda la corneometria, si sono
ottenuti valori più alti durante la fase premestruale rispetto
alla fase ovulatoria (test di Wilcoxon, P<0,01) (Tabella II).
Dalle rilevazioni sebometriche nei 2 periodi del ciclo mestruale, si evince che la produzione di sebo è significativamente
maggiore durante la fase progestinica rispetto a quella ovulatoria (test di Wilcoxon, P<0,01) (Tabella II).
Dal confronto delle variabili in esame fra il gruppo delle
donne in età fertile e quello delle donne in menopausa (Tabelle III, IV) emerge quanto segue.
Non vi è differenza statisticamente rilevante tra i valori della MIC da SLS in fase premestruale e quelli in donne in
menopausa (test di Wilcoxon, P>0,05) (Tabelle I, III). Al
contrario, è emersa una differenza significativa tra la stessa
MIC in fase ovulatoria e quella nelle donne in menopausa (test
di Wilcoxon, P=0,05) (Tabelle I, III).
Nel caso della TEWL, non vi sono variazioni significative fra i 2 gruppi di soggetti in studio (test di Wilcoxon,
P>0,05) (Tabelle II, IV). Tra i 2 stessi gruppi di soggetti non
sono neanche emerse differenze significative sia per quel
che riguarda la valutazione corneometrica (test di Wilcoxon,
P>0,05) (Tabelle II, IV) che quella sebometrica (test di Wilcoxon, P>0,05) (Tabelle II, IV).
Discussione e conclusioni
Il ciclo mestruale sembra influenzare, in misura più o
meno determinante, alcuni parametri fisiologici cutanei. Al
riguardo, infatti, sembra che vi sia una maggiore irritabilità
cutanea nella fase premestruale, come dimostrato da alcuni
studi dai quali emerge una più intensa risposta al patch test
con SLS durante la stessa fase del ciclo rispetto alla fase
follicolare 4. Anche i nostri studi confermano questo dato: la
risposta ai patch test con SLS osservata durante la fase premestruale è risultata, infatti, significativamente più elevata
rispetto a quella in fase ovulatoria.
La maggiore irritabilità cutanea in fase premestruale e
mestruale potrebbe essere determinata dalla minore efficacia della barriera epidermica. Come confermato dai nostri
dati, infatti, anche la TEWL appare più elevata nel periodo
premestruale. Tuttavia, al riguardo i dati in letteratura non
sono concordi 4, 13, 14.
Gli ormoni sessuali svolgerebbero un ruolo importante
anche nell’influenzare il livello di idratazione cutanea. Dalle misurazioni corneometriche emergono, infatti, valori più
elevati in fase premestruale rispetto all’ovulazione; dal
momento che a bassi valori corneometrici corrispondono
Vol. 140 - N. 3
BONAMONTE
valori più alti di idratazione, sembrerebbe che durante la
fase follicolare vi sia uno stato di idratazione ottimale. Gli
estrogeni, la cui concentrazione ematica è massima durante
l’ovulazione, attraverso lo stimolo dei recettori ormonali
presenti sui fibroblasti, provocherebbero un aumento nella
produzione di acido ialuronico in grado di trattenere acqua
nel derma 16. A conferma di ciò, alcuni studi dimostrano
una correlazione tra l’incremento di acido ialuronico indotto dall’estradiolo e il numero dei recettori dermici per lo
stesso ormone 17.
Anche la produzione di sebo non è costante durante il
ciclo mestruale. Dal nostro studio sono emersi valori più
elevati in fase progestinica rispetto a quelli in fase ovulatoria. A questo riguardo, sembra che gli ormoni sessuali svolgano un ruolo importante, sebbene non determinante, nella
regolazione delle ghiandole sebacee: in particolare, gli estrogeni svolgerebbero un’azione inibitrice sulla produzione di
sebo, mentre il progesterone avrebbe un effetto stimolatorio;
tuttavia, il ruolo di quest’ultimo ormone non è ancora definitivamente chiaro 5, 12.
Dai risultati del presente studio si possono trarre le seguenti conclusioni:
1) L’irritabilità cutanea, valutata mediante SLS, durante la
fase premestruale è maggiore rispetto a quella in fase follicolare.
2) La risposta cutanea allo stesso stimolo irritativo nelle
donne in menopausa è sovrapponibile a quella delle donne
in età fertile in fase premestruale, verosimilmente per il fatto che sia la menopausa che la fase progestinico-premestruale sono caratterizzate dalla carenza di estrogeni.
3) L’evaporazione transepidermica di acqua durante il
periodo premestruale è più elevata rispetto a quella in fase
periovulatoria. In quest’ultimo periodo, infatti, gli estrogeni, a massima concentrazione ematica, provocano un incremento nel derma di acido ialuronico, che, trattenendo acqua,
ne riduce l’evaporazione. Questo dato è confermato dai più
bassi valori corneometrici osservabili durante l’ovulazione.
Riassunto
Obiettivo. In base ad alcuni dati della letteratura, le variazioni ormonali durante il ciclo mestruale influenzerebbero,
in maniera più o meno importante, sia alcuni parametri fisiologici cutanei, sia l’espressione clinica dell’irritazione da
contatto. Lo scopo di questo lavoro era valutare l’influenza
degli ormoni sessuali femminili sull’irritabilità da contatto
cutanea e su alcuni parametri fisiologici (evaporimetria, corneometria, sebometria).
Metodi. Sono stati selezionati un gruppo di 15 donne di età
compresa tra 20 e 45 anni (età media: 28,9) con ciclo mestruale regolare e un gruppo di controllo costituito da 15 donne di
età compresa tra 54 e 60 anni (età media: 56,8) e in menopausa da almeno 1 anno. In entrambi i gruppi in studio l’irritazione da contatto è stata valutata mediante patch test con
sodio lauril solfato (SLS) a diluizioni scalari dallo 0,1%
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235
BONAMONTE
SKIN REACTIVITY IN RELATION TO THE MENSTRUAL CYCLE
all’1% in acqua, mentre gli altri parametri fisiologici cutanei sono stati valutati mediante evaporimetria, sebometria e
corneometria.
Risultati. Nel primo gruppo di donne la risposta ai patch
test con SLS variava nelle diverse fasi del ciclo mestruale: nel
periodo progestinico-premestruale si riscontrava, infatti, una
più marcata reattività della cute allo stimolo irritativo rispetto a quanto osservato nel periodo ovulatorio. Anche le misurazioni evaporimetriche, sebometriche e corneometriche
hanno rilevato valori generalmente più elevati durante la
fase mestruale rispetto a quella ovulatoria. Dal confronto
fra i 2 gruppi in studio è emerso che la reattività cutanea in
menopausa è sovrapponibile a quella in età fertile durante il
236
periodo mestruale. Ciò come verosimile conseguenza della
situazione ormonale, che, in fase mestruale e in menopausa,
è caratterizzata da carenza di estrogeni. Dai risultati ottenuti mediante evaporimetria, sebometria e corneometria sono
emerse differenze statisticamente significative tra i 2 periodi del ciclo mestruale, con valori più elevati durante la fase
mestruale.
Conclusioni. Dai risultati del presente studio sembra che
gli ormoni sessuali femminili giochino un ruolo importante
nei meccanismi fisiopatologici cutanei.
Parole chiave: Reattività cutanea - Ciclo mestruale - Ormoni femminili - Irritazione da contatto - TEWL - Corneometria - Sebometria.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
Giugno 2005
REVIEWS
G ITAL DERMATOL VENEREOL 2005;140:237-47
Oral medications for psoriasis
J. C. CATHER 1, 2
Several oral medications have been used to treat psoriasis. Systemic medications are indicated for the treatment of psoriasis
refractory to topical medications, associated with a decreased
quality of life, or moderate to severe in nature (large body surface area involved >10%, erythrodermic, or pustular). Additionally, psoriatic arthritis requires systemic therapy. Only the
tumor necrosis factor antagonists prevent the progression of
joint disease and therefore a shift in the treatment paradigm
from traditional oral medications to newer biologic agents
(etanercept, infliximab, or adalimumab) for this indication is
in practice. This article will review the more commonly used traditional oral medications used for the treatment of psoriasis
with emphasis on appropriate patient selection, monitoring,
and combination therapies.
KEY WORDS: Psoriasis, diagnosis - Psoriasis, drug therapy - Treatment, outcome.
T
he use of traditional systemic medications for psoriasis has evolved greatly over the past 30 years.
Continuous disease control oftentimes requires frequent dosage adjustments, rotations to alternate medications, and combination therapy.1 Combination and
rotational therapies may reduce the cumulative toxicity of each individual therapy while maintaining quality of life and disease control.2 Therapies must be individualized and appropriate for the severity and extent
of lesions, as well as, take into consideration the medical history and lifestyle of the patient.3 Several other
Address reprint requests to: J. C. Cather, MD, Texas Dermatology Associates, 5310 Harvest Hill Rd., Suite 260, Dallas, Texas 75230, USA.
E-mail: [email protected]
Vol. 140 - N. 3
1Texas Dermatology Research Institute,
2Clinic Baylor University Medical Center,
Dallas, TX, USA
Dallas, TX, USA
comprehensive reviews on systemic psoriasis therapy may be of interest.4-6 The first line oral systemic
agents include methotrexate (MTX), cyclosporine
(Cy), and acitretin while the second line agents include
6-thioguanine, hydrea, and sulfasalazine (Table I).
Oral agents rationale
Psoriasis is an immune-mediated disease in which
T-lymphocytes and pro-inflammatory cytokines are
central in the pathogenesis. The commonly used systemic medications have mechanisms of action which
modulate T-lymphocytes or their cytokines. As the
pathogenesis of psoriasis is unraveling on a molecular
basis, therapies are being developed from living cell
cultures (biologic agents) to target one particular step
in the psoriasis cascade.7 Biologics are considered
safer for long term continuous use compared to our
traditional systemics.
Patient selection
In general, patients with psoriasis tend to have a
higher incidence of obesity, diabetes, hypertension,
and depression. Therefore a careful review of past
medical history and current medications is warranted
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
237
CATHER
ORAL MEDICATIONS FOR PSORIASIS
TABLE I.—Systemic medications for psoriasis.
Medication
Methotrexate
Cyclosporine
Retinoids
Hydroxyurea
CellCept
6-Thioguanine
Sulfasalazine
Description
Original formulation:
—2.5 mg pills and 25 mg/cc solution (per os, s.c.,
i.m.)
— Time released pills: Trexall® 5, 7.5, 10, and 15
mg
Micronized (more predictable absorption): Neoral®
or Gengraf®
— Capsules: 25 mg and 100 mg
— Suspension 100 mg/ml
USP modified (not micronized): SandImmune®
— Capsules: 25 mg and 100 mg
— Suspension 100 mg/ml
Acitretin (Soriatane®): 10 mg and 25 mg
Isotretinoin (Accutane®, Soret® Amnesteen®)
500 mg
250 and 500 mg
40 mg
500 mg
and will help individualize therapy (Table II). For
example, Cy exacerbates hypertension and hyperlipidemia; retinoids exacerbate hyperlipidemia, and diabetics may be predisposed to liver toxicity from MTX.
Additionally, retinoids can be considered first line
therapy in patients with a history of a systemic malignancy, invasive melanoma, multiple skin cancers, or
chronic viral infections (human immunodeficiency
virus, HIV or hepatitis C) given the cutaneous chemoprevention and minimal immunosuppression associated
with their use.4, 8
The affect an agent has on fertility must be discussed
at length. Cy is the least concerning from a family planning prospective (pregnancy category C). Both women
and men have fertility changes on MTX. Women must
avoid pregnancy while on therapy and for a minimum
of one ovulatory cycle before considering conception
TABLE II.—Systemic medications for psoriasis.
Medication
Methotrexate
Cyclosporine
Soriatane
Hydroxyrea
6-Thioguanine
Mycophenolate
Mofetil
238
Contraindications
Notes
Absolute contraindications:
— Women who are pregnant, actively trying to conceive,
— or breastfeeding
— Men trying to father children
— Trimethoprim-sulfamethoxazole antibiotics
Relative contraindications:
— Chronic infections
— Noncompliance
— Hepatic, bone marrow or renal disease
— Excessive alcohol intake
— Active peptic ulcers
— Concomitant nephrotoxic agents
Absolute contraindications:
— Hepatitis C and HIV
— Uncontrolled hypertension
— Renal dysfunction
— Underlying active malignancy
Relative contraindications:
— Chronic infections
— Noncompliance
— Breastfeeding
— Patients requiring live attenuated or live vaccines
Absolute contraindications:
Women who are pregnant or who desire pregnancy within
— 3 years
Acceptable for all forms of disease
Rapid flare stopper
OK for women trying to conceive
Absolute contraindications:
— Myelosuppression
Women desiring conception or lactation
Absolute contraindications:
Myelosuppression
Women desiring conception or lactation
Absolute contraindications:
Active infections
Palmoplantar disease
Most rapid medication to control erythrodermic or
— pustular disease
Palmoplantar disease
Acceptable for: hepatitis C, HIV
No significant presence in semen
Acceptable for: hepatitis C, HIV
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(pregnancy category X).9 Additionally, since oligospermia and sperm abnormalities have been reported, men
should ensure adequate contraception until they have
been off MTX for 3 months.10, 11 While men do not
have any fertility issues with acitretin, women who are
pregnant or who desire conception within 3 years of the
last dose of acitretin (pregnancy category X) should
be excluded from acitretin therapy - consider instead
isotretinoin (pregnancy category X but shorter halflife). Hydrea is pregnancy category D; however, the
risk benefit ratio does not support its use for psoriasis
in women trying to conceive.
Initiation of systemic therapy
Prior to initiating any systemic therapy it is important to document the extent of disease (cutaneous,
nail, joint involvement) and its impact on quality of
life. The majority of traditional medications have
known end organ toxicities, as well as a number of
possible drug-drug interactions that require evaluation.
Baseline laboratory studies usually include: complete
blood count with platelets (CBC), comprehensive
metabolic panel (electrolytes, blood urea nitrogen,
BUN), serum creatinine (Cr), liver transaminases
(AST, ALT, GGT), albumin, and alkaline phosphatase,
cholesterol, triglycerides, serum pregnancy test
(HCG), and urinalysis. Additionally, given the
immunosuppressive nature of these agents, evaluation for underlying latent infections such as HIV,
hepatitis B and C, and tuberculosis (tuberculin skin
test) is warranted. Finally, investigation into history of
ultraviolet exposure and resultant skin cancers, prior
immunosuppressants, and general health maintenance
issues regarding history of cervical dysplasia, abnormal mammograms, and results of regular screening
tests (if applicable) for prostate and colon cancer are
important prior to the administration of any immunosuppressant (Table III).
The first line systemics: MTX, Cy, and acitretin
TABLE III.—Initiation and monitoring therapy.
Initiation of therapy
MTX
CyA
Sor
Hyd
TG
CC
SSZ
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CMP
CBC
Chol
Tg
HCG
Mg
UA
Liver biopsy*
Blood pressure
Skin exam
?
X
twice
X
X
X
X
Follow-up
— MTX: CMP q 4-8 weeks, CBC 7 days after test dose, 2 weeks after 1st
full dose, 4 weeks after 1st full dose, and then every 4-6 weeks thereafter;
HCG every 4-6 weeks if pregnancy possible; Chol and Tg every 4-6
weeks; liver biopsies after 1-1.5 g and then every 1 g thereafter
— CyA: CBC and CMP and Mg q 4-8 weeks, UA every 6-8 weeks, blood
pressure daily then increase to weekly if stable blood pressure and
labs, glofil yearly
— Sor: CBC, CMP, Tg, Chol after 2-3 weeks and then every 4-6 weeks if
stable. HCG monthly if pregnancy possible.
— Hyd: CBC and CMP after 3-4 weeks and then CBC every 3-4 weeks
until target dose reached. HCG, CMP and CBC every 6-8 weeks.
— TG: CBC and CMP every 3-4 weeks until target dose reached. HCG,
CBC and CMP q 6-8 weeks.
— CC: CBC weekly first 3 weeks and then every 2 weeks the second
month and then CBC and CMP q 4 weeks until target dose reached
then q 6-8 weeks
— SSZ: CBC and CMP every 3 weeks during dose escalation. CMP and
CBC every 3 months thereafter
CMP: electrolytes + liver function tests (AST, ALT, albumin, total bilirubin) +
serum creatinine + blood urea nitrogen. CBC: complete blood count. Chol: cholesterol. Tg: Triglycerides. HCG: serum pregnancy. Mg: Magnesium. UA: urinalysis.
Glofil: glomerular filtration rate. Skin exams: full skin examination for skin cancer
surveillance.
*A baseline liver biopsy is recommended at or near start of therapy for patients
with hepatic risk factors. Thereafter, biopsies should be done every 1-1.5 g with
normal LFTs and absence of risk factors. Liver biopsies may not be warranted for
the elderly or those with limited life expectancy, patients with a bleeding diathesis,
cardiac instability, or acute illness.
(US) by the Federal Drug Administration (FDA) for the
treatment of psoriasis. This cytotoxic agent targets
proliferating lesional psoriasis T-lymphocytes over
keratinocytes.14 MTX is eliminated primarily
unchanged via the kidneys and has a half-life of approximately 5-10 h.
MTX
Clinical usage
It was in 1951 that Gubner reported aminopterin
improved the cutaneous and rheumatologic symptoms
of psoriasis.12 Shortly thereafter, a less toxic and more
effective compound, MTX 13 was discovered. In 1971,
20 years later, MTX was approved in the United States
MTX has been used for all forms of psoriasis as
well as psoriatic arthritis. MTX levels increase with certain nonsteroidal anti-inflammatory agents (salicylate, naproxen, ibuprofen).15, 16 However, no change in
levels is seen with piroxicam (Feldene®), flurbipro-
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fen (Ansaid®), ketoprofen (Orudis®), celecoxib (Celebrex®), rofecoxib (Vioxx®), and meloxicam (Mobic®).17
Initiation of therapy
A test dose of 5 mg is given followed by a CBC 7
days later to assess for possible MTX idiosyncratic
reactions and myelosuppression. If baseline and test
dose CBCs are stable, then a full dose (usually 10 to
15 mg per week, mg/wk) is given. Two weeks after
the first full dose repeat labs are obtained. Pending
clinical response, the dosage may be slowly increased
by 2.5 mg every 3-4 weeks up to a maximum of 30
mg/wk. If significant improvement is not seen within
12 weeks, alternative treatments should be considered.
For elderly patients or patients with known renal
dysfunction, dosing should be started more conservatively (7.5 or 10 mg/wk) to reduce the likelihood of
toxicity. Renal function determination during therapy is of primary importance to avoid excessive myelosuppression from reduced renal clearance. Of note,
with increasing age creatinine clearance is a more
appropriate measure of renal function.
Laboratory monitoring
Initially, laboratories are obtained every other week
and then every 4-6 weeks - the exact frequency of laboratories is determined by dose, renal function, and
laboratory history (Table III). Additionally, full skin
examinations are performed every 6 months for skin
cancer surveillance. Routine laboratories including
liver function tests may miss liver toxicity induced by
MTX.18 Therefore, the American Academy of Dermatology (AAD) recommends periodic liver biopsies.13 In the absence of known hepatic disease risk
factors including: persistent elevated liver function
tests (LFTs), excessive alcohol consumption, history
of hepatitis B or C, family history of inheritable liver
disease, history of exposure to hepatotoxic drugs or
chemicals, and less important factors such as diabetes
and obesity the first biopsy should occur after a total
cumulative dose of 1-1.5 g. For patients with hepatic
risk factors, a baseline biopsy should be obtained as
soon as therapeutic usefulness has been documented
in a patient (i.e. 2-3 months into therapy). Biopsies
should be done at least 2 weeks after the last dose of
MTX. Continuation of therapy is appropriate as long
as hepatic fibrosis is absent or mild; however, with
240
increasing fibrosis, therapy must be abandoned. The
AAD liver biopsy recommendations differ from those
of the American College of Rheumatology where routine liver biopsies are not recommended 19 which suggests that there may be inherent differences in MTXinduced liver toxicity in psoriasis patients compared to
rheumatoid arthritis (RA) patients. Psoriasis patients
have been described with MTX-induced cirrohosis
requiring liver transplantation.20
In the UK, serum type 3 procollagen aminopeptide
is under study as a marker for patients with liver fibrosis resulting from MTX 21 and could potentially replace
secondary and subsequent liver biopsies if serial aminoterminal propeptide of type III procollagen levels are
normal. This test is unreliable in patients with psoriatic
arthritis and varies with the type of assay performed.22
Adverse effects
CLINICAL
Gastrointestinal (nausea, vomiting) symptoms,
fatigue, headaches, and hair loss are the most common patient complaints. Patients may experience less
nausea if MTX is taken in 2-3 divided doses or if higher doses of folic acid are supplemented.23 Oftentimes,
subcutaneous or intramuscular routes of administration
may decrease the gastrointestinal symptoms.24 Erosions involving oral mucosa or cutaneous psoriatic
lesions are uncommon and should prompt investigation
for possible overdose. Folinic acid (leucovorin calcium or citrovorum factor) is the specific antidote for
MTX overdose. If an overdose is suspected early
empiric therapy with leucovorin 20 mg (10 mg/m2) is
advised without waiting for the results of MTX blood
levels. Pulmonary symptoms such as a dry cough or
shortness of breath should be evaluated at each visit for
possible MTX pneumonitis or pulmonary fibrosis.
As compared to cyclosporine A (CyA), the potential
for an increase risk of lymphoma in the MTX treated
psoriasis population is far lower with only anecdotal
reports in the literature. Cutaneous malignancies are
more common in patients that have rotated thru MTX
onto PUVA.25
LABORATORY
Acute toxicity may include hematologic abnormalities, specifically leucopenia and thrombocytopenia. For
leucopenia less than 3 500/mm3 or thrombocytopenia
<100 000/mm3, one should consider suspending thera-
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py and rechecking a CBC in 2 weeks.4, 13 Additionally,
as a macrocytic anemia may occur, folic acid supplementation 1-5 mg daily is traditionally added. Chronic
dosing with methrotrexate may lead to hepatotoxicity,
including cirrhosis, especially with increasing cumulative doses and with concomitant illnesses (e.g. hepatitis). The risk of hepatotoxicity increases with higher
cumulative doses.26 Interestingly, patients with RA have
a significantly lower incidence of hepatoxicity compared to psoriatics.27
underlying active malignancy are considered contraindications. Additionally, uncontrolled hypertension and renal dysfunction excludes patients from this
therapy. Unlike MTX, pregnancy is not a contraindication (category C); however Cy should not be administered to women who are breastfeeding. Finally,
patients who require live attenuated vaccination should
avoid Cy; and vaccinations in general may be less
effective while on this therapy.
Initiation of therapy
Cyclosporine
In 1978, the serendipitous finding that transplant
patient’s psoriasis improved after the introduction of
Cy 28, 29 for prophylaxis of transplant rejection shifted
the paradigm of therapy from targeting keratinocytes
to lymphocytes.30 A formal study supported these early observations and proved the efficacy in plaque psoriasis.31 Over 60% of patients achieve a 75% reduction
in their psoriasis area and severity index (PASI) scores
while on therapy.32
The original Cy formulation (Sandimmune®, Novartis) has a lower bioavailablity compared to newer
microemulsion formulations (Neoral®, Novartis or
Gengraf®, Abbott Laboratories). Conversion from
Sandimmune® to the microemulsion formulations
Neoral® or Gengraf® is a 1:1 dose conversion; however, some dose reductions may be required.33 For the
remainder of this paper, we will only discuss Cy in
its microemulsion formulation. Cy undergoes extensive
hepatic metabolism (including a prominent enterohepatic circuit) via the cytochrome p450 pathway.
Clinical usage
Indications
In 1997 the FDA approved Cy for the treatment of
severe recalcitrant psoriasis for up to 1 year of continuous dosing in the US, while in the UK, 2 years is
acceptable. While the efficacy of Cy and MTX for
plaque psoriasis is similar,34 when Cy is used for psoriatic joint disease, compared to MTX, patients are
less likely to continue chronic therapy due to increased
toxicity.35
All the baseline evaluations for Cy are similar to
MTX with the exception of serum magnesium and 2
blood pressure readings (2 separate evaluations separated in time). Medications that alter the CYP 450
pathway or decrease renal perfusion may increase the
toxicity of Cy. A long list of potential drug interactions which is updated periodically is on the Novartis
web site (www.pharma.novartis.com).
The response of psoriasis to Cy is dose dependent.36
Initial doses may range from 2.5 to 5 mg/kg/day (given in divided doses) depending on the severity of the
disease.33, 37 The microemulsion capsules should be
taken with food. The solution is usually dispersed in
apple or orange juice (not grapefruit since it has flavanoids which inhibit the CYP 450 pathway), and given in a glass (not plastic) container.
During therapy, laboratories are initially performed
every 2 weeks and once stable, every 4-6 weeks thereafter. Blood pressure readings are obtained daily for 2
weeks and then weekly. It is important for patients to
maintain a weekly blood pressure log as a gradual rise
in baseline blood pressure readings usually predates
changes in serum creatinine levels as an early indicator of CyA nephrotoxicity. All medications being taken concomitantly must be reviewed at each visit since
there are a number of drugs that affect the p450 pathway. As with MTX, full skin examinations are performed every 6 months for skin cancer surveillance.
Cy is usually used as part of sequential therapy
which was popularized by Koo.38 Rapid clearing is
obtained with Cy and then slow transition to a safer
drug (i.e. retinoid) for long-term maintenance occurs.
Adverse effects
Contraindication
CLINICAL
Similar to MTX, concomitant active infections
(including HIV or hepatitis), noncompliance, and
Side effects are dose dependent and most commonly
include headache, nausea, paresthesias, tremor, malaise,
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hypertrichosis and gingival hyperplasia.39 Patients
should check their blood pressure if they are having
headaches, especially noctural headaches, to evaluate
new onset hypertension. The most common reason
for discontinuation in the initial months is nausea
while hypertension or decreased renal function
accounts for discontinuations later in the course of
therapy.
While Cy is an immunosuppressant agent, the risk
of malignancy in patients with psoriasis treated with
cyclosporine appears to be primarily cutaneous malignancies.40 The risk of lymphoma in CyA treated transplant patients is well known and until recently has
been debated in psoriasis population.41 A recent European prospective study did not show any significant
increase risk of lymphoma over its 5-year observational period.42 The lymphoproliferative disorders are
commonly Epstein-Barr virus related and regress when
the medication is withdrawn.43 The incidence of cutaneous malignancies is substantially increased if patients
have been on phototherapy.44
LABORATORY
If the serum creatinine rises above 25% baseline
values, dose reduction is mandatory and increased
monitoring is required until renal function normalizes.45 A glomerular filtration rate study every 6-12
months while a patient is on Cy is appropriate since
serum creatinine is an unpredictable indicator of toxicity in some patients.46, 47 Dose reduction is also warranted if blood pressure elevates on therapy. In some
circumstances, addition of a calcium channel blocker
such as amlodipine is necessary. Interestingly, there is
data which supports the addition of calcium channel
blockers (specifically amlodipine) since they may protect patients from Cy induced nephrotoxicity.48
Lipids are frequently elevated with this therapy;
however, if a low-fat diet and increased exercise are initiated, medical intervention is rarely necessary.
Acitretin (Soriatane)
Historical perspective
Retinoids have been used in the treatment of psoriasis either as monotherapy or, more commonly, as
combination therapy for nearly 20 years. Etretinate, the
first widely used systemic retinoid for the treatment of
psoriasis was approved in 1986, and subsequently
242
replaced by acitretin 49 in 1997 on the basis of pharmacokinetic data showing the latter had a significantly shorter half-life.50 The half-lives of acitretin and
etretinate are 50 h and 120 days, respectively. A shorter half-life is attractive from a teratogenicity standpoint. Unfortunately, concomitant ethanol intake with
acitretin induces transesterification of acitretin to etretinate and results in a longer half-life. Therefore, ethanol
should be strictly avoided in women of childbearing
potential while on treatment and for 2 months after
the last pill since the wash-out for pregnancy is much
longer. Some physicians advocate the complete exclusion of women of childbearing potential from using this
medication since ethanol is ubiquitous in numerous
foods and remedies - a safer alternative is isotretinoin.
Retinoids are believed to improve psoriasis by modulating gene transcription. There are 6 different retinoid
receptors - RAR (α, β, γ) and RXR (α, β, γ). These
retinoid receptors form homodimers or heterodimers
with other nuclear hormone receptors which then act at
different points to modulate gene transcription. Acitretin
activates all RAR subtypes without measurable binding to the receptors. The end result is modulation of epidermal proliferation and differentiation and a reduction
in inflammation within the epidermis. Currently, short
half-life recepor selective retinoids are in clinical trials.
Clinical usage
INDICATION
While all forms of psoriasis may benefit from
retinoids, erythrodermic and pustular psoriasis have the
fastest and most dramatic responses. Acitretin is considered the treatment of choice for these severe forms
of psoriasis. Additionally, the addition of retinoids to
phototherapy regimens has been advocated for chemoprevention.
CONTRAINDICATIONS
Retinoids are contraindicated in women who may
become pregnant - contraceptive measures should be
maintained for 3 years after their last dose of acitretin.
Addittionally, patients with uncontrolled hyperlipidemia and significant hepatic compromise are not
acceptable patients.
Initiation of therapy
Dosing should begin with 10 to 25 mg daily with
food. Systemic retinoids have a much higher bioavail-
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ability when given with food. A gradual increase in
dose up to 50 mg daily in divided doses may be
required. The majority of side effects are dose dependent and appear to be more tolerable with slow escalation compared to high dose initiation.
Adverse effects
CLINICAL
The most common adverse effects of acitretin are
mucocutaneous in nature - cheilitis, alopecia, desquamation of the skin, drying of mucous membranes, and
pruritus. Arthralgias, myalgias, and rarely, pseudotumor cerebri are seen. Combining retinoids with tetracyclines should be avoided since each can cause
pseudotumor cerebri alone. The relationship between
retinoid use and diffuse idiopathic skeletal hyperostosis
(DISH) has long been debated. In a recent report, the
risk of DISH did not seem elevated over the general
population.51
LABORATORY
Hyperlipidemia occurs in 30% of patients and is
dose dependent. The primary concerns focus on an
increase in triglycerides, elevation of LDL and reduction of HDL. Fortunately, hyperlipidemia rarely necessitates changes in therapy and it is easily controlled with
life style modification (low fat diet and exercise) or
lipid-lowering medications.
Second line systemics:
hydroxyurea, 6-thioguanine, and sulfasalazine
6-Thioguanine is a purine analog used to treat
leukemia. The mechanism of action is thought to
involve T cell apoptosis in psoriatic skin.52 On retrospective review of 21 patients with refractory psoriasis whose TG dose was escaleted to obtain response (20
mg twice weekly up to 120 mg/d) revealed over 90%
improvement in those that tolerated the therapy (14/18
patients).53 In this study, myelosuppression was the
primary toxicity. Therefore, prior to initiation of therapy, a thiopurine methyltransferase (TMPT) level
should be obtained. Normal TMPT enzyme activity
is rarely seen in patients who develop profound
myelopsuppression. Hepatic veno-occlusive syndrome
(also seen with cytarabine, azathioprine, busulfan, and
6-mercaptopurine) is possible during therapy; how-
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ever, there is no predictive test for this idiosyncratic
reaction. Our usual starting dose is 40 mg twice daily
on Monday, Wednesday and Friday with gradual
increase in the number of days up to daily dosing. If
monthly laboratories are stable, a day per week can be
added every month until appropriate clinical response
is obtained. Laboratory abnormalities most often
encountered include myelosuppression and hepatic
enzyme elevations. Patients tolerate therapy reasonably
well; however gastrointestinal complaints including
nausea and diarrhea can occur.
Hydroxyurea (Hydrea) is an oral systemic cancer
medication - an antimetabolite. Since the 1970s its
utility in the treatment for psoriasis and lack thereof for
psoriatic arthritis has been reported. Patients with concomitant HIV or hepatitis C may benefit from this
therapeutic.54-56 To date, its mode of action is unclear.
After oral dosing, rapid absorption from the gastrointestinal tract gives a peak serum concentration in 2 h.
The medication is excreted via kidneys and is undetectable 24 h after the last dose.57 Therapy starts with
500 mg daily with slow escalation (add 500 mg/d every
month) up to 1.5-2 g daily if necessary as long as
monthly labs do not reveal significant myelosuppression. Adverse events may include an idiosyncratic
reaction (flu-like), vertigo, lassitude, and mucocutaneous reactions (alopecia, pigmentary nail changes,
ulcerations); however, the medication is usually well
tolerated. Nearly 50% of patients who achieve marked
improvement in their psoriasis develop bone marrow
toxicity - leucopenia and thrombocytopenia. On peripheral smears red blood cells appear megaloblastic (MCV
112-120); however, this does not require treatment.
Rarely, hepatotoxicity may occur in the first few weeks
of treatment. Additionally, rebound has been reported
on discontinuation - the exact definition of rebound
was not defined at the time. Hydrea is rarely combined with light since psoriasis flares (actinic psoriasis) and painful psoriasis lesions have been seen in
this setting.58
Mycophenolic acid was investigated for the treatment of psoriasis 3 decades ago.59, 60 More recently, the
pro-drug of mycophenolic acid, mycophenolate
mofetil, has been used for the treatment of psoriasis.61
Initiate therapy with 500 mg 3 times daily and increase
dose by 500 mg every month with escalation up to 3
g/day for disease control. Gastrointestinal symptoms,
including nausea, vomiting, and diarrhea, are common with higher doses. Leukopenia is associated with
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TABLE IV.—Combination therapy for psoriasis.
Monotherapy
Consider adding
Methotrexate
Cyclosporine
Soriatane
Hydroxyurea
6-Thioguanine
Mycophenolic Mofetil
Sulfasalazine
Retinoids, sulfasalazine
Retinoids, methotrexate
UV, methotrexate, cyclosporine
Retinoids
Retinoids, UV
Cyclosporine, methotrexate, retinoids
Methotrexate, cyclosporine, retinoids
doses higher than 3 g/d. Mycophenolate mofetil can be
used as a Cy-sparing drug and is therefore useful when
tapering Cy.62
Sulfasalazine is rarely associated with side effects.
Prior to initiation, a G6PD enzyme activity is performed. Starting doses are usually 500 mg per os t.i.d.
with escalation of dose by adding 1 pill every 5th day
as long as no adverse experiences occur to the target
dose of 3 g/day (1 g per os t.i.d.). While adverse experiences are rare with slow escalation, the most common
complaints include headache and gastrointestinal symptoms.
Combination therapies
The use of combination oral therapies may be
required for adequate control of moderate to severe
psoriasis.63, 64 Favorite combinations are listed in Table
IV.
MTX combinations
Several combinations with MTX are not advised
given the potential for increased toxicity. For example,
profound immunosuppression may occur when combining MTX with hydroxyurea or 6-thioguanine since
individually they can cause bone marrow suppression.4 Additionally, combination with phototherapy
must be carefully considered. Of note, combining
MTX with PUVA has resulted in a lower amount of
UVA exposure required to induce clearing,65 similar
benefits are seen when MTX is combined with UVB.66
However, MTX may increase sensitivity to ultraviolet
light and also increase the risk of skin cancers.25
Several combination regimens are beneficial. Combining MTX with retinoids has been cautioned by
some due to the possibility of increased hepatotoxic-
244
ity; however, this combination is helpful for refractory disease.67, 68 Although both drugs are bound by albumin, there is no displacement.69 Additionally, the safety of combining MTX with Cy has been questioned;70
however, we personally have found this combination
safe - as have several authors in certain cases of refractory RA 71 and psoriasis ± arthritis, allowing for lower dosages of each of the agents to be used.
Additionally, regarding combination with the biologics,72 there is a significant amount of data supporting the combination of MTX with either etanercept,73
infliximab,74 or adalimumab in psoriasis, psoriatic
arthritis, or other autoimmune diseases such as Crohn’s
disease or RA. A smaller number of patients (n<100)
have been treated with MTX and alefacept (Biogen
data on file). Additionally, combination trials with
efalizumab and MTX for RA did not detect any new
adverse events.
Cy combinations
Combination with retinoids has been reported;75
however, lipid levels must be followed more carefully since they are increased by both agents. We find
this combination helpful in thick, hyperkeratotic plaque
psoriasis that has not responded adequately to Cy
monotherapy. Additionally, as mentioned above, combination with MTX in select patients has been useful,
allowing for lower dosages of each.
Nine patients with severe psoriasis refractory to Cy
monotherapy benefited when mycophenolate mofetil
(maximum dose 3 g daily) was added to low-dose Cy
(mean dose 2.5 mg/kg/day). There were no new or
unexpected toxicities. Consider this combination for
psoriatic patients who are unresponsive to other treatments or who are at risk of developing nephrotoxicity at higher doses of Cy.76
A few combinations are concerning. For example,
since Cy is a known cause of increased skin cancer
risk, combination with ultraviolet therapy is contraindicated. An increased incidence of nonmelanoma
skin cancer has been seen in patients who have had Cy
and PUVA therapy.44, 77 While a small series of patients
with severe recalcitrant psoriasis benefited from low
dose Cy (2.5 mg/kg/d) and hydrea (500 mg/d), this
combination requires close monitoring.78 Hydrea is
renally excreted and there is concern that combining
with Cy may result in decreased renal excretion and an
increase in myelosuppression.
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Regarding the biologics, less is known regarding
the safety of Cy based combinations. Reports of combination therapy with TNF-antagonists are in the literature. We have used the combination of Cy with alefacept in a number of patients (especially when transitioning patients off CyA therapy) and have not noted any increased toxicity or CD4 count problems. A
formal combination trial is currently underway. Regardless, the numbers of patients treated with Cy and biologicals as combination therapy is small and it will
take years to establish the safety profiles.
Soriatane
Retinoids are the easiest agents to use in combination regimens.79 Oftentimes, sequential therapy is used
whereby medications that are fast acting, for example Cy or MTX are used to obtain quick disease control and then patients are transitioned over to a retinoid
for long term disease control.38 Combination therapy
with hydrea and soriatane has been used for refractory palmoplantar disease.2 Retinoids play a role in
chemoprevention, therefore combination with phototherapy regimens is an attractive strategy.8, 67
Retinoids used in combination with phototherapy
(PUVA, broad band UVB, and narrowband UVB)
decrease the amount of cumulative ultraviolet radiation
required for clearing as well as time to clearing (the
number of treatments).80-84 In patients with suboptimal
responses to PUVA or UVB, consider reducing the
phototherapy dose by 50% and introducing a retinoid
to increase efficacy.85
Conclusions
Numerous therapies are available for the treatment
of psoriasis. Appropriate patient selection and monitoring for drug interactions and toxicities is important. Newer agents are being developed to reduce the
potential for end organ toxicity.
Riassunto
Terapia orale della psoriasi
Per il trattamento della psoriasi sono stati utilizzati diversi farmaci somministrati per via orale. I trattamenti sistemici sono indicati nei casi di psoriasi refrattaria ai farmaci per
via topica, associata a una ridotta qualità di vita o a una for-
Vol. 140 - N. 3
ma moderata o grave (area corporea coinvolta maggiore del
10%, eritrodermica o pustolosa). Anche l’artrite psoriasica
necessita di un trattamento per via sistemica. Solo gli antagonisti del tumor necrosis factor prevengono la progressione dell’artropatia e di conseguenza un cambiamento nel
paradigma terapeutico, dai tradizionali farmaci somministrati per os ai più recenti farmaci (etanercept, infliximab o
adalimumab), è attualmente in atto nella pratica clinica per
questa indicazione. Questo articolo riassume i farmaci orali tradizionali più comunemente utilizzati per il trattamento
della psoriasi, soffermandosi sulla corretta selezione dei
pazienti, sul monitoraggio e sulle terapie di combinazione.
PAROLE CHIAVE: Psoriasi, diagnosi - Psoriasi, trattamento
farmacologico - Trattamento, risultati.
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G ITAL DERMATOL VENEREOL 2005;140:249-61
Natural killer and t-cell cytotoxic cutaneous lymphomas
E. BERTI 1, D. GAMBINI 2, M. LUCIONI 3, M. PAULLI 3
In the group of primary cutaneous T-cell lymphomas, T-cytotoxic and natural killer cell lymphomas have been recently recognized as distinct and rare clinicopathologic entities. Typically, cytotoxic granules associated proteins TIA-1, granulolysine and perforin, and cytotoxic-natural killer (NK) cell
markers CD8+, CD56+, CD94+, CD161+, NKp46+ are
expressed by tumoral cells. Five T-cytotoxic and NK cutaneous
lymphomas subtypes are actually recognized: subcutaneous
panniculitis-like T-cell lymphoma, extranodal nasal and nasaltype NK-T cell lymphoma, blastic NK cell lymphoma, aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, cutaneous gamma-delta peripheral T-cell lymphoma. In this review,
the most important clinical, histological, immunohistochemical
and molecular data are analyzed together with differential diagnostic aspects between these entities. T-cytotoxic and NK cutaneous lymphomas pursue a very aggressive course, with poor
outcome and high mortality rate, with few exceptions.
KEY WORDS: Lymphomas, immunology - Lymphocytes - Natural
killer cells.
C
utaneous T-cell lymphomas (CTCLs) include a
heterogeneous group of diseases diagnosed on
the basis of clinical presentation, outcome, histologic,
immunophenotypic and molecular features. In the
group of primary cutaneous T-cell lymphomas, T-cytotoxic and natural killer (NK) cell lymphomas represent
rare distinct clinicopathologic entities which have been
recognized during last years thanks to studies showing
the expression of cytotoxic associated proteins (TIA-1,
granzyme, perforin) and/or specific markers for NK
cells in lymphoma cells.
Address reprint requests to: Prof. E. Berti, Ospedale Maggiore IRCCS,
Università degli Studi di Milano-Bicocca, Via Pace 9, 20122 Milan, Italy.
Vol. 140 - N. 3
1Department of Dermatology
IRCCS, University of Milano-Bicocca, Milan, Italy
2Department of Dermatology
IRCCS, University of Milan, Milan, Italy
3Department of Pathological Anatomy
IRCCS San Matteo Hospital
University of Pavia, Pavia, Italy
As confirmed by a recent work 1 of the EORTC
(European Organization for Research and Treatment
of Cancer) Cutaneous Lymphoma Study Group, cutaneous lymphomas expressing a cytotoxic or NK cell
phenotype constitute a group of lymphoproliferative
disorders in which few agreements exist about best
classification and nomenclature. In effect, there is
open discussion among international experts if, at least
some of these malignancies could be considered primary cutaneous lymphomas or instead they could represent the first manifestation of a systemic lymphoma
which involves the skin secondarily, practically in all
cases, with a specific affinity. Both the recent WHO
(World Health Organization) lymphoma classification 2 and the EORTC cutaneous lymphoma classification 3 have paid a special attention to the category of
cutaneous T/NK lymphomas: between these 2 classifications, as pointed out in Table I, there are some controversies essentially regarding the definition of large
cell CD30 negative cutaneous T-cell lymphoma, the use
of the term “peripheral T-cell lymphoma, not otherwise
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
249
BERTI
NATURAL KILLER AND T-CELL CYTOTOXIC CUTANEOUS LYMPHOMAS
TABLE I.—WHO lymphoma classification and EORTC cutaneous
lymphoma classification.
A) T-cell and NK- lymphomas with frequent or constant skin involvement:
modified WHO 1997 lymphoma classification
A) Primary cutaneous T-cell lymphomas
A) — Mycosis fungoides
A) — Sézary syndrome
A) — Primary cutaneous CD30+ lymphoproliferative disorders
A) — Subcutaneous panniculitis-like T-cell lymphoma
A) Other T-or NK-cell lymphomas with primary or secondary skin
A) — involvement
A) — Extranodal NK/T-cell lymphoma, nasal type
A) — Blastic NK-cell lymphoma
A) — Precursor T-lymphoblastic lymphoma/leukemia
A) — Peripheral T-cell lymphoma, not otherwise specified (PTL NOS)
(WHO 2001)
B) Primary cutaneous T-cell lymphoma listed in the EORTC Classification
A) Indolent
A) — Mycosis fungoides (MF) and subtypes (MF + follicular mucinosis,
granulomatous slack skin, pagetoid reticulosis)
A) — Large cell CD30+ CTCL (anaplastic, immunoblastic, pleomorphic)
A) — Lymphomatoid papulosis
A) Aggressive
A) — Sézary syndrome
A) — Large cell CD30 negative CTCL
A) Provisional entities
A) — CTCL, pleomorphic small/medium-sized
A) — Subcutaneous panniculitis-like T-cell lymphoma
specified”, and the poorly defined group of the blastic
NK-cell lymphoma CD56+. Future studies on these
topics would probably clarify still unsolved matters.
Concerning NK and T-cell cytotoxic lymphomas,
listed in the WHO classification,2 they include the
subcutaneous panniculitis-like T-cell lymphoma, the
extranodal nasal and nasal-type NK-T cell lymphoma
and the blastic NK cell lymphoma. In the group of
peripheral T-cell lymphoma, not otherwise specified,
thanks to present knowledges, we can recognize some
distinct clinico-pathologic entities, such as the pleomorphic small/medium lymphoma (usually non-cytotoxic), the aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma and the cutaneous gamma-delta
positive T-cell lymphoma.
In the EORTC classification,3 on the contrary, only
the subcutaneous panniculitis-like T-cell lymphoma
is included among provisional entities with aggressive behaviour, while other T cytotoxic variants and NK
lymphomas would be better classified in the spectrum
of CD30 negative large T-cell lymphomas or in the
“rare entities”, actually not listed in this classification. Herein, the principal clinicopathologic features
250
Figure 1.—Panniculitis-like T-cell lymphoma (gamma-delta variant): clinical features showing the inflammatory panniculitic and ulcerative skin
lesions.
of the T and NK-cell cytotoxic lymphoma subtypes
are described.
Subcutaneous panniculitis-like T-cell lymphoma
Clinical features.—Subcutaneous panniculitis-like
T-cell lymphoma (SPLTCL) is a rare lymphoma subtype, tipically infiltrating the subcutaneous tissue;4 it
represents less than 1% of all non-Hodgkin lymphomas
(NHL) and pursues an aggressive course. Two distinct
forms can be recognized from clinicopathologic and
immunophenotypic features (alfa/beta and gamma/
delta variants). SPLTCL affects both sexes and, in the
literature, different age range cases are described,
including children and young adults. Cutaneous lesions
are generally characterised by multiple subcutaneous
nodules and/or erythematous infiltrated plaques mostly located at the trunk, extremities (Figure 1), and face.
Associated clinical symptoms include malaise, fever,
fatigue, myalgia and weight loss, while other possible
manifestations of systemic involvement are hepatosplenomegaly, mucosal ulcers and serosal effusions. Hemophagocytic syndrome may occur as a complication
often precipitating the clinical course: this reactive
process appears after macrophage activation, stimulated
by interferon gamma realesed by tumoral cell, to
phagocytize hematopoietic cell.5 In previous years,
the term “malignant cytophagic histiocytic panniculitis” (CHP) has been used to describe similar cases;
nowadays CHP and SPCTL are believed to represent
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
Giugno 2005
NATURAL KILLER AND T-CELL CYTOTOXIC CUTANEOUS LYMPHOMAS
BERTI
a clinicopathologic spectrum with a possible disease
progression from CHP to SPCTL.4
Histopathology.—The lymphoma cells typically
infiltrate the lobules of the subcutaneous tissue, giving
a lobular-panniculitis-like appearence. In early phases, there is a usual sparing of the overlying epidermis
and dermis. In the gamma/delta variant neoplastic cell
invade the dermis and involve the epidermis too.
Tumoral cells are small to medium sized lymphocytes
with moderate pale cytoplasm; the nuclei present round
to irregular to pleomorphic morphology and often
hyperchromatic. Single fat cells are typically surrounded by lymphoma cells resulting in a unique rimming pattern (Figure 2). Moreover, close to necrotic
areas, scattered reactive non-neoplastic histiocytes can Figure 2.—Panniculitis-like T-cell lymphoma (alfa/beta variant): histofeatures showing lobular lymphoid infiltrate; note rims of neobe observed. Apoptotic phenomena (karyorrhectic logical
plastic cells around fat cells and macrophages (hematoxylin-eosin ×200).
nuclear fragments) are often found while angiogentric and/or angiodestructive patterns are not a frequent
histological feature of the SPLTC.
panniculitis). Anyway, a definitive SPLTCL diagnosis
Immunohistochemistry, molecular biology and genet- may often require multiple sequential lesional biopsies
ic features.—SPLTC neoplastic cells express a periph- together with the positivity of molecular analyses and
eral CD2+; CD3+; CD45RO+ T-cell phenotype 6 and associated clinical features, as, for example, subcutapositivity for cytotoxic molecules (i.e. TIA-1, Granzyme neous lesions coupled with systemic symptoms.
Outcome and therapy.—Median survival for SPLTC
B and Perforin). About 25% of PLTCL derive from
gamma/delta cells but most cases have an alfa/beta ori- is usually less than 3 years. Perhaps, this lymphoma
gin and are CD8+, βF-1+. Gamma/delta cases may pursues an aggressive clinical course in most cases; in
have a double negative (null) CD4- CD8- phenotype, the end-stage, nodal and/or visceral spread are freare T-cell receptor (TCR).delta-1+ and frequently quent findings, as common and often fatal complicaCD56+. CD30 antigen is expressed in few cases, in a tions reported are haemophagocytic syndrome and
minority of lymphoma cells. Clonal rearrangement of sepsis. The lymphomas expressing a gamma-delta
the TCR is a common finding 7 while Ebstein-Barr phenotype have been associated with a poor prognovirus (EBV) search is always negative. No cytogenet- sis and an even more aggressive clinical course.8 To
ic alterations have been observed in SPLTC. Recently, date, no therapy has been really satisfactory; howeva defective expression of the perforin gene in a child er, aggressive systemic CHT, followed, in few cases,
affected by SPLTCL has been documented by our group by autologous bone marrow transplantation seems to
(data to be published). This abnormality is associated be the treatment of choice.9
with the familial form of hemophagocytic syndrome.
Differential diagnoses.—The subcutaneous tissue
is affected by numerous tumoral and inflammatory
pathologies. Histological and immunophenotypic features are not always so distinctive in differentiating
SPLTC from non-neoplastic mainly lobular panniculitis, cytophagic panniculitis and from other subtypes of CTCLs. However, the presence of pleomorphic hyperchromatic lymphoid cells forming a rim
around the individual fat cells may be indicative of a
SPLTC, whereas the presence of reactive B-follicle is
more indicative of an autoimmune disorder (lupus
Vol. 140 - N. 3
Extranodal nasal
and nasal type NK/T-cell lymphoma
Clinical features.—Nasal and nasal type NK/T-cell
lymphoma cases 10, 11 are more commonly described
in Asian, Mexican, Central and South American countries; few cases have been reported in Europe and
North America. Nasal cavity and nasopharynx are a
common site of predilection,10 but this lymphoma can
spread also to other extranodal tissues like the skin, gut
and soft-tissues;12 nodal sites are usually not involved.
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Figure 4.—NK/T cells extranasal lymphoma: clinical features showing a
fast growing nodular lesions on the right arm.
Figure 3.—NK/T cells nasal lymphoma: clinical features simulating ulcerative midline malignant granuloma.
In the literature, in past years, some patients presenting similar lesions located on the nose were diagnosed
as lethal midline granuloma (Figure 3). Unfortunately, at presentation, multiple extranodal disease localizations and peripheral blood involvement are usual features, indicating an advanced stage of disease; hemophagocytic syndrome may occur. Ulcerated nodules
(Figure 4) are the most common clinical presentation,
but numerous other skin lesions are described, like
plaques, purpura, erythematous macular-papular rashes and subcutaneous nodules. Nasal spread may follow
cutaneous presentation.
Histopathology.—Lymphomas arising in nasal and
extranasal sites present same histological findings. The
dermis and subcutaneous tissue are infiltrated by neoplastic cells, showing a diffuse growth pattern. Angiogentric and angiodestructive aspects are frequently
seen; fibrinoid changes, coagulative necrosis (Figure 5)
and numerous apoptotic bodies are other associated
findings. Usually, most lymphoma cases present medi-
252
um to large cell morphology, but cytological features of
neoplasia is variable from small to medium-sized to
large-anaplastic. Nuclei have irregular, elongated or
vesicular appearance; moderate and usually pale to
clear cytoplasm is the rule. A conspicuous reactive
inflammatory response, mainly constituted by histiocytes, plasma-cells and eosinophils, can be observed.
Immunohistochemistry, molecular biology and cytogenetics.—The lymphoma cells express a CD2+,
CD56+, cytoplasm CD3+ but surface CD3- , CD43+,
CD45RO+;10, 13 CD4, CD5, CD8, CD16 and CD57,
which represent other T-and NK cell markers, are usually negative. Recently, on frozen testable sections,
new specific NK-cell markers CD94, PEN-5 (CD161)
and NKp46 resulted positive.14 TIA-1, perforin and
granzyme B are generally positive, whereas CD7 and
CD30 may be sporadically expressed. In most cases,
Immunoglobulin and TCR genes do not present clonal rearrangement.15 A pathogenetic role for EBV is
suggested for this lymphoma because of strong association: EBV can be found almost always by immunohistochemistry studies, molecular and in situ hybridation investigations.16 Del(6)(q21q25) and i(6)(p10)
have been observed together with some other cytogenetic abnormalities. To date, no specific chromosomal translocation has been reported.17
Differential diagnoses.—Blastic NK lymphoma and
SPLTCL (other T/NK lymphomas), together with some
cases of CD30 negative peripheral T-cell lymphoma
and, rarely, inflammatory processes are the principal
differential matters. The demonstration of EBV posi-
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Figure 5. NK/T cells lymphoma: histological features showing a pleomorphic infiltrate in the whole dermis, with angiocentric and angionecrotic features (hematoxilin-eosin ×200).
tivity, by various techniques, is a very useful and distinctive diagnostic tool, which is always negative in the
blastic NK lymphoma; the contemporary usual absence
for CD4 is another typical parameter. At last, the differential diagnosis, between the rare cases of this lymphoma characterized by pronounced subcutaneous infiltrates and otherwise typical cases of SPLCTCL, is based
on multiple parameters: clinical features, EBV positivity, antigenic profile and TCR germline configuration.
Outcome and therapy.—CHT is the treatment of
choice; however, an aggressive clinical behaviour and
high mortality rates are associated with extranodal
nasal and nasal type NK/T-cell lymphoma. Therefore,
despite therapy, prognosis is still generally poor.10, 12
In the literature, there are no reports about real pre- Figure 6.—CD4+, CD56+ blastic NK lymphoma: clinical features showing purpuric/hemorrhagic skin lesions on the head.
dictive prognostic markers.
Blastic NK-cell lymphoma
Clinical features.—This lymphoma subtype is rare 18
and patients usually manifest the disease during middle
or old age. Multiple tissues are generally involved 19
with a predilection for the skin and soft tissues; anyway, other possible organs of presentation are lymph
nodes, peripheral blood and bone marrow. Moreover,
Vol. 140 - N. 3
also the nasal cavity is sometimes affected by this lymphoma. Clinically, reddish-bluish, often purpuric (Figure 6), nodules and/or infiltrated plaques, sometimes
ulcerated, are the usual reported skin lesions.20, 21
Histopathology.—Neoplastic cells densely infiltrate
dermal and often subcutaneous tissues, showing a periadnexial and perivascular distribution and generally
saving a thin upper dermal layer. Cytological features
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Figure 7.—CD4+, CD56+ blastic NK lymphoma: histological features
showing a dense infiltrate formed by medium size pleomorphic lymphocytes with small central nuclei (hematoxylin-eosin ×200).
of lymphoma cells are variable both in size and shape:
medium, pleomorphic and large elements, resembling
myeloid blasts (Figure 7), are commonly visible;
mitoses are numerous, nucleoli are not much evident
and chromatin is finely dispersed. Apoptotic bodies
and angioinvasive patterns are not a distinctive finding
in blastic NK lymphoma.
Immunohistochemistry, molecular biology and cytogenetics.—The lymphoma cells express a CD4+,
CD56+, CD43+, CD45RA±, CD123+, TDT1+, TCL1+, phenotype; CD68 is frequently positive, while
CD2, CD7, cytoplasmic CD3, TIA-1, granzyme-B
and perforin are rarely expressed;20, 21 CD34 results
positive in some patients.12 Rearrangement for the
TCR is always negative as the investigations for EBV.22
Differential diagnoses.—Diagnosis of blastic NK
lymphoma is sometimes very difficult because of the
morphologic and, in part, antigenic overlapping
between lymphoblastic and myeloblastic tumors. T-cell
and myeloid lineage must result unaffected and T-cell
and myeloid specific markers, like CD3s, MPO and
CD33, must be unexpressed. In the past, the tumoral
cell of origin was considered a NK-cell precursor, an
immature myelo-monocyte precursor or a mixed,
NK/myelomonocyte precursor; nowadays, blastic NKcell lymphoma is the term listed in the WHO lymphoma classification.2 Anyway, phenotypic features,
between blastic NK lymphoma and plasmacytoid dendritic cells (P-DC), are very similar, suggesting a possible origin of the neoplasia from this subpopulation.
254
Indeed, in vitro, researchers have been able to make
leukemia cells working as P-DC and to secrete interferon-alpha; from all these observations, it has been
proposed to rename this entity as “early pDC lymphoma”.20 However, to date, there is no uniform consensus between international experts about the cell
population of origin for the blastic-NK lymphoma.
Outcome and therapy.—Blastic NK lymphoma is a
very aggressive clinical entity; bone marrow infiltration, leukemia and sometimes neurological involvement often represent the end stage of the disease.19
Some studies revealed a poor survival period after
diagnosis ranging from 14 to 46 months (median survival: 30 months).20 Conventional CHT for nonHodgkin lymphomas is unsatisfactory, achieving only
sometimes a partial response thanks to aggressive regimen normally used for acute leukemia patients; unfortunately prompt relapses are the rule.20 Recently, an
attempt has been made with allotransplantation, but
only 2 patients had a longer survival.21 At last, some
investigations suggested a better prognosis in patients
with skin localized lesions, but these observations
need to be confirmed on larger series.23
Aggressive epidermotopic CD8+ cytotoxic
peripheral T-cell lymphoma
Clinical features.—Aggressive epidermotropic
CD8+ cytotoxic T-cell peripheral lymphoma (AeCD8
+cx) was first reported by Jensen et al. in 1980 24 and
represent a very rare subtype of cutaneous T-cell lymphoma. A recent complete clinical and pathological
study differentiated this newly recognized entity, characterised by an aggressive clinical course, from other
indolent lymphoma cases, expressing CD8 but classifiable as mycosis fungoides or CD30± like disorders.25
Clinically, AeCD8+cx lymphoma could manifest, in
localized or disseminated forms, with eruptive, centrally necrotic nodules (Figure 8), or with superficial,
verrucous patches and plaques as in Ketron-Goodman
type of pagetoid reticulosis.
Histopathology.—The epidermis is acanthotic or
atrophic, necrotic keratinocytes and variable spongiosis are commonly observed, together with blister formation. Neoplastic cells are small-medium or medium-large sized and reveal blastic or pleomorphic nuclei
(Figure 9). Nodular lesions present conspicuous epidermotropism; lymphoid cells may dispose in a lichen-
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Figure 8.—CD8+ epidermotropic cytotoxic aggressive lymphoma: clinical picture showing a fast growing large hemorrhagic-ulcerated plaque
on the trunk.
Figure 9.—CD8+ epidermotropic cytotoxic aggressive lymphoma: histological picture showing an epidermotropic lichenoid infiltrate formed by
medium to large pleomorphic hyperchromatic lymphocytes (hematoxilineosin ×100).
like pattern localizing in the basal cell layer or can occupy the entire epidermis with a pagetoid pattern; angiocentricity, angioinvasion, and adnexal involvement are
common findings in AeCD8+cx lymphoma.4, 26
differences, in overall survival, have been identified
among large cell CD30- lymphoma patients, both considering localized or multifocal disease and the CD4+
or CD8+ phenotype.28 Moreover, the 5-years overall
survival of this last group, expressing CD8 and cytotoxic markers, was 12%.28 In the study by Berti et
al.,25 the median survival of the 8 reported AeCD8+cx
lymphoma patients was 32 months.
Immunohistochemistry, molecular biology and cytogenetics.—Tumoral cells have a Beta-F-1±, CD3+,
CD8+, TIA-1+, CD45RA+, CD45RO-, CD2-, CD5-,
phenotype.4, 26 Cytotoxic granule associated proteins
(TIA-1, granzyme B, perforin) are positive. TCR gene
rearrangement is a common finding, but sometimes
it is not observed. To date, specific cytogenetic alterations as EBV association have not been demonstrated.
Differential diagnosis.—CD8+ can be expressed in
SPTCL, extranodal nasal and nasal type NK/T lymphoma, gamma-delta CTCL, rare cases of mycosis
fungoides, and CD30+ primary cutaneous anaplastic
lymphomas. Clinicopathologic and immunophenotype
aspects can help to specify the different entities.25, 27
Outcome and therapy.—AeCD8+cx lymphoma pursues an aggressive clinical behaviour, often showing
contemporaneous skin and internal organs involvement or progression to visceral organs in short time
(usually less than 180 days). In the literature, polychemotherapy regimens (doxorubicin based or not)
and radiotherapy are the first line treatments. From a
Dutch prospective study, the overall 5-years survival
of primary cutaneous peripheral T-cell lymphoma,
unspecified, was nearly 20%. No significant statistical
Vol. 140 - N. 3
Cutaneous gamma-delta
peripheral T-cell lymphoma
Clinical features.—Disseminated plaques and/or
necrotic nodules,29-32 more frequently affecting the
extremities (Figure 10), constitute the usual skin
lesions.32, 33 Spreading to extranodal organs and mucosal sites can be observed, while lymph nodes, spleen,
and bone marrow, are usually spared.
Histopathology—In these lymphomas, epidermotropic, dermal, and subcutaneous patterns of infiltration can be seen. These patterns can be observed
separately, but more frequently they coexist in the
same patient. Epidermal infiltration varies from mild
involvement to imposing pagetoid aspects.8, 34, 35 A
panniculitis-like or even more dense neoplastic infiltrate can be observed in the subcutis, lacking foamy histiocytes and the rimming of lymphocytes around individual fat cells. Neoplastic cells have variable morphology from medium to large pleomorphic cells, with
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Figure 10.—Primary cutaneous epidermotropic gamma-delta T-cell lymphoma: clinical features showing papulonodular ulcerated lesions on the
right arm.
cases are CD4+ or CD8+.29 Tumoral cells are positive for TIA-1 and the cytotoxic proteins granzyme
B, and perforin 36 and also CD56 is frequently
expressed. TCR gamma and TCR delta genes usually
show clonal rearrangement, while TCR beta may be
rearranged or deleted, but it is not expressed. EBV
search is usually negative.37
Differential diagnosis.—Some subcutaneous panniculitis-like T-cell lymphomas have a gamma-delta
phenotype and can not be distinguished from PCGDTCL. Other extranodal cytotoxic T-cell lymphomas,
generally CD8+, share similar findings to PCGDTCL;32 moreover, a possible overlapping disease has
been described in mucosal sites. At last, the exact relationship between gamma-delta TCLs, occurring primary in the skin versus other extranodal forms, need
further investigations.37
Outcome and therapy.—PCGD-TCLs present a very
aggressive clinical course, resistant to treatments. Multiagent chemotherapy regimens and/or radiation are
unsatisfactory. In a recent work,31 66% (22 of 33)
patients were dead within 5 years of diagnosis; in the
same study TCR-delta-1 expression resulted a negative
independent prognostic parameter, associated with
reduced survival. A worse prognosis seems to occur in
patients presenting subcutis involvement, compared
to those with dermal and/or epidermal infiltration.
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Figure 11.—Primary cutaneous epidermotropic gamma-delta T-cell lymphoma: immunohistochemical reaction (APAAP-method) showing the
strong reactivity of the neoplastic epidermotropic cells by using anti TCRdelta-1 monoclonal antibody (×200).
coarsely clumped chromatin and few large blastic cells
are usually evident, with vesicular nuclei and prominent nucleoli. Angioinvasion, apoptosis and necrosis
are common findings.
Immunophenotype, molecular biology and cytogenetics.—Peripheral cutaneous gamma-delta T-cell
lymphoma (PCGD-TCL) express a TCR-delta-1+ (Figure 11), CD3+, CD2+, CD7±, CD5- phenotype (30);
the βF-1, an alfa-beta TCR marker, is always negative. The majority of reported cases have a double negative (or null) CD4- and CD8- phenotype, but some
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Linfomi-T cutanei citotossici e natural killer
I
linfomi T cutanei (cutaneous T-cell lymphomas, CTCLs)
comprendono un eterogeneo gruppo di patologie che si
differenzia in base a caratteristiche cliniche, istologiche,
immunofenotipiche e molecolari. All’interno di questo grup-
Vol. 140 - N. 3
po, i linfomi T citotossici ed i linfomi che originano dalle cellule natural killer (NK) rappresentano patologie rare, riconosciute come entità clinico-patologiche distinte solo negli
ultimi anni, grazie a studi che hanno mostrato l’espressione
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nelle cellule neoplastiche di proteine associate ai granuli
citotossici (TIA-1, granulolisine/granzyme, perforina) e/o
di markers specifici per le cellule NK. Come recentemente
confermato da un lavoro del Gruppo di Studio Europeo sui
Linfomi Cutanei della European Organization for Research
and Treatment of Cancer (EORTC) 1, i linfomi cutanei che
esprimono un fenotipo citotossico o NK costituiscono un
gruppo di disordini linfoproliferativi in cui esistono pochi consensi riguardo la migliore classificazione e nomenclatura.
In particolare, non è ancora accertato, se, almeno alcune di
queste neoplasie, debbano essere considerate linfomi cutanei primitivi o piuttosto non rappresentino la manifestazione iniziale di un linfoma sistemico che interessa la cute in
maniera secondaria, ma costante. Sia la recente classificazione
dei linfomi della World Health Organization (WHO) 2 che la
classificazione EORTC dei linfomi cutanei 3 hanno prestato particolare attenzione al gruppo dei linfomi cutanei T e NK;
peraltro, come evidenziato in Tabella I, tra le 2 classificazioni
esistono alcune controversie che riguardano principalmente la definizione dei linfomi T a grandi cellule CD30 negativi, l’utilizzo del termine linfoma “T periferico, non altrimenti
specificato”, e il poco definito gruppo dei linfomi NK blastici
CD56+. Ulteriori studi su queste rare patologie ridurranno,
probabilmente in futuro, tali divergenze.
Per quanto concerne i linfomi T citotossici e NK, presenti
nella classificazione WHO 2, essi comprendono il linfoma T
sottocutaneo simil-panniculitico, il linfoma extranodale a
cellule T/NK, nasale e nasal-type, e il linfoma NK blastico.
Nel gruppo dei linfomi T periferici, non altrimenti specificati,
grazie alle attuali conoscenze, possono essere distinte alcune entità citotossiche come il linfoma cutaneo T gamma/delta e il linfoma T citotossico aggressivo CD8+.
Nella classificazione EORTC 3, invece, il solo linfoma T
sottocutaneo simil-panniculitico è incluso tra le entità provvisorie a decorso aggressivo, mentre le altri varianti citossiche e NK farebbero parte dei cosidetti linfomi a grandi cellule CD30- o delle «forme rare» non incluse nella classificazione. Di seguito, vengono presentati i principali aspetti clinico-patologici, attualmente noti, delle nuove entità riconosciute come linfomi T citotossici e NK.
Linfoma T cutaneo simil-panniculitico
Caratteristiche cliniche e istologiche. — Il linfoma T
cutaneo simil-panniculitico (subcutaneous panniculitis-like
T-cell lymphoma, SPLTCL) è un sottotipo di linfoma raro,
rappresentando meno dell’1% dei Linfomi non-Hodgkin, e
con decorso aggressivo, che caratteristicamente infiltra il
tessuto sottocutaneo 4. Se ne distinguono 2 varianti che originano rispettivamente dai linfociti-T alfa/beta o dai linfocitiT gamma/delta. Colpisce entrambi i sessi e, in letteratura,
sono riportati casi con presentazione a età molto variabile,
inclusi bambini e giovani adulti. Le lesioni cutanee sono
generalmente caratterizzate da noduli cutanei e/o placche
eritematose infiltrate, per lo più localizzate al tronco, alle
estremità (Figura 1) o al volto. Sintomi clinici associati inclu-
258
dono malessere, astenia, mialgie e perdita di peso; manifestazioni cliniche di interessamento sistemico sono rappresentate da febbre, epatosplenomegalia, ulcere della mucosa
orale e raramente effusioni pleurico-peritoneali. Alcuni
pazienti possono manifestare una sindrome emofagocitica,
complicanza che spesso precipita il decorso della malattia 5.
Si tratta di un processo reattivo alla neoplasia ed è causato da
un’attivazione dei macrofagi, che fagocitano le cellule del sangue, stimolati dall’interferon-γ rilasciato dalle cellule tumorali. In precedenza, casi simili erano stati diagnosticati come
panniculite citofagica istiocitica (cytophagic histiocytic panniculitis, CHP) «maligna», ma ulteriori studi hanno dimostrato l’esistenza di uno spettro clinico-patologico di progressione di malattia da CHP a SPLTCL 4.
Istopatologia.—Istologicamente, l’infiltrato neoplastico
linfocitario viene a occupare i lobuli del tessuto sottocutaneo,
con un tipico pattern lobulare, simil-panniculitico. Nelle fasi
iniziali, l’epidermide e il derma sono generalmente risparmiati. Le cellule neoplastiche sono di piccola o media taglia,
con scarso citoplasma di colore chiaro; i nuclei possono
variare da rotondi a irregolari, a indentati/pleomorfi, e sono
spesso ipercromatici. Le cellule linfomatose hanno la tendenza a circondare le singole cellule adipose con un tipico
aspetto «a corona» (Figura 2). Nei casi con fenotipo gamma/delta si può osservare coinvolgimento del derma in toto
e dell’epidermide. Può essere presente un numero variabile
di istiociti, generalmente distribuiti in maniera sparsa e localizzati in prossimità delle aree di necrosi. Spesso si evidenziano corpi apoptotici (frammenti nucleari in carioressi),
mentre un pattern angiocentrico e/o angiodistruttivo non è un
riscontro istologico tipico dei SPLTCL.
Immunoistochimica, biologia molecolare e citogenetica.
— Si riconoscono 2 varianti: le cellule tumorali presentano
un fenotipo T periferico CD2+, CD3+, CD45RO+ 6 ed esprimono le molecole citotossiche TIA-1, granzyme B e perforina. La maggioranza dei casi è causata da proliferazioni
sostenute da linfociti-T di origine alfa/beta (CD8+, βF1+),
ma circa il 25% dei SPLTCL deriva da cellule gamma/delta (TCRdelta-1+) e può esprimere il CD56, pur avendo spesso un fenotipo doppio negativo per CD4 e CD8. In rari casi
una minoranza di cellule neoplastiche esprime l’antigene
CD30. Un riarrangiamento clonale del recettore T-cellulare
(TCRγ) può essere dimostrato nella maggior parte dei casi 7;
la ricerca del genoma del virus di Ebstein-Barr (EBV) è
risultata sempre negativa. Finora, non si sono dimostrate
anomalie genetiche specifiche associate a questo linfoma.
Recentemente però (dati in pubblicazione), abbiamo dimostrato un’espressione difettiva del gene della perforina in un
bimbo affetto da SPLTCL, anomalia che è nota per essere
associata con la sindrome emofagocitica.
Diagnosi differenziale. — Diverse patologie, principalmente di tipo infiammatorio, possono interessare il tessuto
adiposo. La diagnosi differenziale, rispetto ad altre panniculiti
prevalentemente lobulari (vasculite nodulare, lupus-panniculite, panniculiti di accompagnamento ad altre malattie
autoimmuni, infiltrati linfocitari/pseudolinfomatosi, ect.) e
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rispetto ad altri linfomi T cutanei, generalmente si basa su
caratteristiche cliniche peculiari dei SPLTCL (lesioni sottocutanee associate a sintomi sistemici), piuttosto che su
caratteristiche citomorfologiche e immunofenotipiche. In
ogni caso, la presenza di un discreto infiltrato, costituito da
cellule linfoidi ipercromiche e pleomorfe, che formano
un’immagine «a corona» attorno a singole cellule adipose,
è suggestivo di un linfoma con coinvolgimento del tessuto adiposo. Al contrario, la presenza di centri follicolari reattivi a
fenotipo B è indicativa di un processo autoimmune, come nella panniculite lupica. Una diagnosi finale di SPLTCL spesso richiede diverse biopsie sequenziali su cute lesionale e
necessita di conferma con analisi molecolari.
Decorso e prognosi. — Il comportamento clinico e la prognosi dei SPLTCL è variabile, ma la sopravvivenza media è
generalmente inferiore ai 3 anni. Nella maggior parte dei
casi, questo tipo di linfoma ha un decorso clinico aggressivo; un interessamento nodale e/o viscerale può verificarsi
ma, in genere, nelle fasi finali della malattia. La sepsi e la sindrome emofagocitica rappresentano frequenti complicazioni, spesso fatali. Diversi Autori hanno evidenziato un decorso clinico ancora più aggressivo nel caso in cui il linfoma presenti un fenotipo gamma/delta 8. Il trattamento di scelta è la
polichemioterapia sistemica, seguita dal trapianto autologo
di midollo osseo 9.
Linfoma extranodale a celluleT/NK nasale e nasal type
Caratteristiche cliniche e istologiche. — I linfomi a cellule
NK/T nasali e nasal type 10, 11 sono relativamente frequenti
in Asia, Messico, America Centrale e del Sud e sono descritti solo sporadicamente nei paesi Europei. Questi linfomi
insorgono prevalentemente in tessuti extranodali, specialmente nella cavità nasale e nella regione nasofaringea 10, ma
anche a livello cutaneo, nei tessuti molli e nell’intestino 12;
l’estensione ai linfonodi non è comune. In passato, lesioni
simili, localizzate al naso, erano state definite come «granuloma maligno della linea mediana» (Figura 3). I pazienti
generalmente si presentano in uno stadio avanzato di malattia con localizzazioni multiple del linfoma in sedi extranodali e spesso con un interessamento del sangue periferico; la
sindrome emofagocitica è una complicazione possibile. Clinicamente, sulla cute, sono presenti lesioni papulo-nodulari, frequentemente ulcerate (Figura 4), ma sono state osservate anche lesioni in placca, purpuriche e/o bollose, esantemi maculo-papulosi e lesioni nodulari sottocutanee similpanniculitiche. Le localizzazioni più frequenti a livello cutaneo includono il volto, il tronco e le estremità; l’interessamento della regione del naso può seguire nel tempo la presentazione sulla cute.
Istopatologia. — Gli aspetti istologici di questa varietà di
linfoma sono simili, qualunque sia il sito primitivamente
coinvolto dalla neoplasia (regione nasale rispetto a regioni
extranasali). Il linfoma infiltra il derma e il tessuto sottocutaneo, evidenziando un pattern di crescita diffuso. Note angio-
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BERTI
centriche e angiodistruttive sono frequenti e associate a depositi di fibrina, necrosi coagulativa (Figura 5) e presenza di
numerosi corpi apoptotici. Le cellule linfoidi mostrano un
aspetto citologico assai variabile, da piccole, a medie a grosse cellule anaplastiche; comunque, generalmente, la popolazione cellulare dominante consiste di cellule a medie e larga
taglia. I nuclei possono essere irregolari, allungati o vescicolosi; il citoplasma è normalmente poco rappresentato e di
colore chiaro. Oltre alle cellule neoplastiche, può essere presente un notevole infiltrato infiammatorio di accompagnamento costituito da istiociti, plasmacellule ed eosinofili.
Immunoistochimica, biologia molecolare e citogenetica. —
Le cellule tumorali presentano un fenotipo CD2+, CD56+,
CD3+ citoplasmatico e non di membrana, CD43+,
CD45RO+ 10, 13; altri markers per le cellule T e NK, come il
CD4, CD5, CD8, CD16 e CD57 sono generalmente negativi,
mentre nuovi marcatori specifici per le cellule NK, cioè CD94,
NKG2A, PEN-5 (CD161) e NKp46, sono risultati positivi,
ma possono essere testati solo su sezioni di cute congelata 14.
Gli antigeni CD7 e CD30 possono essere espressi in maniera sporadica. Le proteine marcatrici dei granuli citotossici
(TIA-1, perforina e granzyme B) sono presenti nella quasi
totalità dei casi. Di solito, i geni per il TCR e per le Immunoglobuline non presentano riarrangiamenti monoclonali 15;
l’EBV può essere rilevato con diverse tecniche (immunoistochimiche, ibridazione in situ e indagini molecolari sul DNA
estratto dalle lesioni) nella stragrande maggioranza dei casi, per
cui si è considerato un probabile ruolo patogenetico dell’EBV
in questi linfomi 16. Sono state segnalate alcune anomalie
citogenetiche tra cui, in particolare, del(6)(q21q25) e i(6)(p10),
ma, finora, non sono state identificate traslocazioni cromosomiche specifiche associate a questi tumori 17.
Diagnosi differenziale. — La diagnosi differenziale si
pone nei confronti degli altri linfomi a cellule T/NK (linfoma/leucemia NK blastico e SPLTCL), di alcuni casi di linfoma T periferico CD30-negativo e, più raramente, con processi
infiammatori. La presenza di EBV, che è sempre negativa nei
casi di linfoma/leucemia NK blastici, è una caratteristica
peculiare e utile per la diagnosi se associato a una negatività
per il CD4. La presenza di EBV, gli aspetti immunofenotipici, la policlonalità per il TCR insieme alle caratteristiche
cliniche facilitano la distinzione dei rari casi in cui questo
linfoma si presenta con importanti infiltrati sottocutanei, tali
da porsi in diagnosi differenziale con casi di SPLTCL.
Decorso e prognosi. — La prognosi di questi linfomi è
variabile, ma la regola è un decorso clinico molto aggressivo 10, 12, associato ad alti tassi di mortalità nonostante protocolli chemioterapici aggressivi. Attualmente non si conosce nessun marker prognostico realmente predittivo.
Linfoma NK blastico
Caratteristiche cliniche e istologiche. — Questo sottotipo di linfoma è raro 18 e normalmente colpisce pazienti adul-
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NATURAL KILLER AND T-CELL CYTOTOXIC CUTANEOUS LYMPHOMAS
ti o anziani. Il linfoma può coinvolgere diversi organi 19 con
una predilezione per la cute e i tessuti molli; comunque, possono essere interessati anche linfonodi, sangue periferico e
midollo osseo. Inoltre, in taluni casi, la regione nasale può
risultare interessata della patologia. Clinicamente sono state osservate lesioni in placca o nodulari, a volte ulcerate, di
colore rosso-brunastro, spesso purpuriche (Figura 6) 20, 21.
Istologicamente si rileva un denso infiltrato tumorale dermoipodermico, che mostra solitamente una distribuzione
periannessiale e perivascolare e risparmia una sottile banderella di derma superficiale. La citologia delle cellule neoplastiche linfomatose è variabile sia come forma che come
grandezza, con elementi di media o grande taglia, pleomorfi, che ricordano cellule mieloidi blastiche (Figura 7); la cromatina si trova finemente dispersa e i nucleoli sono poco
evidenti. Nei linfomi NK blastici, di solito, non si evidenzia
un pattern angiocentrico/angiodistruttivo, né fenomeni apoptotici. Le mitosi sono numerose.
Immunoistochimica, biologia molecolare e citogenetica. —
Le cellule neoplastiche mostrano un fenotipo CD4+, CD56+,
CD43+, CD45RA±, CD123+, TDT±, TCL-1+; inoltre il
CD68 (marker della linea mieloide e delle cellule dendritiche plasmocitoidi) è frequentemente positivo, mentre altri
marcatori T-linfoidi come il CD2, CD7, CD3 citoplasmatico e i markers citotossici (TIA-1 e granzyme B) sono raramente positivi 20, 21; alcuni casi sono risultati positivi per
CD34. Il TCR non è riarrangiato e la ricerca di EBV è sempre negativa 22.
Diagnosi differenziale. — A causa della parziale sovrapposizione morfologica e antigenica, che si riscontra nelle
neoplasie linfoblastiche e mieloblastiche, la diagnosi di linfoma NK blastico richiede prudenza e può essere posta solo in
assenza di coinvolgimento delle linee mieloidi e T-linfoidi
(negatività per CD3 di membrana, MPO e CD33). Inizialmente queste neoplasie sono state classificate in maniera
variabile e si pensava che gli elementi tumorali originassero da un precursore delle cellule NK, da un precursore immaturo mielomonocitico o da un precursore misto NK/mielomonocitico. Nella classificazione WHO dei linfomi 2, questi casi sono stati classificati come linfomi blastici a cellule
NK. Comunque, negli aspetti fenotipici, esistono numerose
caratteristiche simili tra questo linfoma e le cellule dendritiche plasmocitoidi (plasmacytoid dendritic cells, P-DC),
suggerendo così una possibile relazione e origine del tumore da questa sottopopolazione cellulare. Tale ipotesi pare
confermata da esperimenti in vitro, per cui cellule linfomatose/leucemiche possono essere indirizzate a comportarsi
come P-DC e a produrre interferone-alfa. Su queste basi è stato proposto di rinominare questa entità come linfoma a cellule dendritiche plasmocitoidi 20. Peraltro, sono necessari
ulteriori studi sperimentali per chiarire definitivamente la
linea cellulare di origine di questi tumori.
Decorso e prognosi. — Questo linfoma presenta un decorso clinico molto aggressivo. Nel tempo, la malattia spesso
porta al decesso per un imponente infiltrato midollare, una
franca leucemia e, a volte, per un importante interessamento
260
neurologico 19. In un recente studio, la sopravvivenza media
dopo la diagnosi è stata di 30 mesi, con un range che oscillava tra 14 e 46 mesi 20. La risposta clinica ai protocolli terapeutici
convenzionali per i linfomi non-Hodgkin è scarsa, ma almeno una risposta parziale può essere ottenuta, in alcuni casi,
utilizzando un protocollo simile a quelli per le leucemie acute; sfortunatamente, rapide recidive sono la regola 20. In un altro
studio, solo 2 pazienti allotrapiantati sono sopravvissuti più a
lungo 21. Infine, sembra che i pazienti con un coinvolgimento solo cutaneo abbiano una prognosi migliore 23, ma tale
osservazione va confermata da studi di maggiori dimensioni.
Linfoma T periferico citotossico aggressivo
epidermotropo CD8+
Caratteristiche cliniche e istologiche. — Questo linfoma
è una forma molto rara di linfoma cutaneo a cellule T, inizialmente descritta da Jensen et al. nel 1980 24. Circa 20
anni dopo, Berti et al. 25 hanno studiato 8 casi di linfoma
CD8+ con caratteristiche di citotossicità, aggressività ed
epidermotropismo, paragonandoli a 9 casi di linfoma che
esprimevano il CD8+, ma che erano classificabili come linfomi a prognosi indolente (micosi fungoide o linfomi cutanei
CD30+). Dunque, sulla base di questi studi, si è ipotizzata la
presenza di un nuova entità rara di linfoma T cutaneo con un
comportamento clinico-prognostico aggressivo. La presentazione clinica è caratterizzata da una rapida comparsa, localizzata o generalizzata, di lesioni cutanee nodulari violacee
con necrosi centrale (Figura 8), oppure da chiazze e placche
ipercheratosiche, superficiali, come nella reticulosi pagetoide (variante di Ketron-Goodman).
Istopatologia. — All’istologia, il linfoma T periferico
citotossico aggressivo edpidermotropo CD8+ (AeCD8+cx)
mostra un’epidermide acantosica o atrofica, cheratinociti
necrotici o spongiosi di grado variabile, con possibile formazione di vescico/bolle. Le cellule tumorali sono di piccolamedia o media-larga taglia, con nuclei pleomorfi o blastici
(Figura 9). Un marcato epidermotropismo è stato osservato
anche in lesioni tumorali di vecchia data, con una disposizione
lineare in banda, simil-lichenoide, nello strato basale dell’epidermide oppure con un coinvolgimento dell’epidermide stessa a tutto spessore con un pattern pagetoide; è costante l’interessamento delle strutture annessiali, così come gli
aspetti angiocentrici e angioinvasivi 4, 26.
Immunoistochimica, biologia molecolare e citogenetica. —
I linfomi AeCD8+cx esprimono un caratteristico fenotipo
beta-F-1±, CD3+, CD8+, CD45RA+, CD45RO-, CD2-,
CD+5-, CD7- 4, 26. I markers citotossici TIA-1, perforina e
granzyme B, sono positivi. Talvolta il riarrangiamento del
TCR non è dimostrabile. Alterazioni citogenetiche costanti
associate, come pure il coinvolgimento di EBV o di altri
virus oncogenetici, non sono dimostrabili.
Diagnosi differenziale. — SPLTCL, linfomi a cellule
NK/T nasali e nasal type, linfomi cutanei T gamma-delta, rari
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NATURAL KILLER AND T-CELL CYTOTOXIC CUTANEOUS LYMPHOMAS
casi di micosi fungoide, e linfomi cutanei primitivi anaplastici CD30+ possono esprimere il marker CD8, talvolta in
associazione con il marker CD56, caratteristici delle cellule citotossiche. Il quadro clinico-patologico associato alle
peculiari caratteristiche immunofenotipiche, consentono di
ipotizzare una corretta diagnosi differenziale delle varie
patologie linfoproliferative riportate 25, 27, mentre le indagini molecolari non sono dirimenti.
Decorso e prognosi. — I pazienti frequentemente manifestano un concomitante interessamento della cute e degli
organi interni o una progressione a tali organi in meno di 6
mesi. Schemi polichemioterapici, con o senza doxorubicina,
e radioterapia sono le forme di trattamento più utilizzate in
letteratura. Da uno studio olandese, la sopravvivenza totale
a distanza di 5 anni dei linfomi primitivi cutanei periferici a
cellule T, non altrimenti specificati, è stata del 20%. Non
sono state dimostrate differenze di sopravvivenza statisticamente significative in pazienti affetti da linfoma periferico CD30-, sia considerando la presentazione localizzata o
generalizzata della malattia che il fenotipo CD4+ o CD8+.
In particolare, la sopravvivenza a 5 anni di questo ultimo
gruppo, con espressione del CD8 e dei markers citotossici,
è risultata del 12% 28. Nel lavoro di Berti et al. 25, la sopravvivenza media degli 8 pazienti studiati, affetti da linfoma
AeCD8+cx, è risultata di 32 mesi.
Linfoma T cutaneo periferico gamma-delta
Caratteristiche cliniche e istologiche. — Il linfoma T
cutaneo periferico gamma-delta (peripheral cutaneous gamma-delta T-cell lymphoma, PCGD-TCL è caratterizzato da
lesioni in placche disseminate e/o noduli tumorali necrotici,
prevalentemente localizzati alle estremità (Figura 10) 29-32.
Questo linfoma, in genere, non coinvolge i linfonodi, la milza e il midollo osseo, ma si può diffondere in regioni mucose e organi extranodali 32, 33.
BERTI
CD3+, CD2+, CD7±, CD5- 30; mentre il βF-1, marker del
TCR alfa-beta, è ovviamente negativo. La maggior parte dei
casi presenta fenotipo doppio negativo CD4-, CD8-, ma
alcuni casi possono essere CD4+ o CD8+ 29. Le cellule tumorali esprimono le proteine correlate ai granuli citotossici:
TIA-1, granzyme B e perforina 36. Anche il CD56 è frequentemente espresso. I geni del TCR gamma e del TCR
delta evidenziano un riarrangiamento clonale, mentre TCR
beta può essere riarrangiato o deleto, ma comunque non viene espresso. Le ricerche per EBV danno normalmente esito
negativo 37.
Diagnosi differenziale. — I PCGD-TCL si sovrappongono in alcuni casi ai linfomi sottocutanei simil-panniculitici
(SPLTCL), che, a volte, mostrano fenotipo gamma/delta.
Inoltre condividono alcuni aspetti comuni ad altri linfomi
T citotossici extranodali (generalmente CD8+) 32. Una patologia simile e chiaramente correlata è stata inoltre osservata in regioni mucose; infine, il rapporto, che può esistere tra
linfomi a cellule T gamma-delta primitivi della cute e forme
extranodali, è tuttora in fase di definizione 37.
Decorso e prognosi. — I pazienti presentano un decorso
clinico molto aggressivo, resistente a protocolli polichemioterapici e/o alla radioterapia. In un recente studio il 66%
dei pazienti (22 su 33) era deceduto a distanza di 5 anni dalla diagnosi 31. Nello stesso studio, l’espressione del TCR-delta-1 è risultata un indice prognostico indipendente statisticamente correlato ad una ridotta sopravvivenza. Infine, i
pazienti con interessamento istologico profondo (del sottocute) sembrano avere una prognosi peggiore rispetto ai
pazienti con il solo coinvolgimento epidermico o dermico.
Riassunto
Istologia. — Istologicamente, l’infiltrato è composto di cellule pleomorfe di medie e/o larghe dimensioni, con cromatina grossolanamente addensata e poche grandi cellule blastiche con nucleo vescicolare e nucleoli prominenti. Angioinvasione, apoptosi e necrosi sono aspetti comunemente incontrati. Sono stati osservati 3 diversi pattern istologici: epidermotropo, dermico e sottocutaneo. Peraltro, spesso, possono coesistere più quadri istologici all’interno della stessa
biopsia o in differenti biopsie nello stesso paziente. L’infiltrato epidermico è variabile; alcuni casi presentano modesto
epidermotropismo, altri evidenziano pattern pagetoidi molto marcati 8, 34, 35. L’interessamento del tessuto sottocutaneo può essere simil-panniculitico oppure con infiltrato più
compatto e denso, per lo più senza l’aspetto a corona dei
linfociti intorno alle cellule adipose e senza istiociti ad aspetto schiumoso.
Nel gruppo dei linfomi primitivi della cute, i linfomi-T citotossici e natural killer (NK) sono stati riconosciuti come
entità clinico-patologiche distinte solo negli ultimi anni e
rappresentano patologie rare. Caratteristicamente, le cellule tumorali esprimono alcune proteine che sono associate
alla presenza nel citoplasma di granuli citotossici (TIA-1, granulolisine, perforina) oppure esprimono marcatori di membrana specifici per le cellule citotossiche (CD8+, CD56+) o
NK (CD94, CD161, NKp46). Attualmente si riconoscono
5 varianti di linfomi citotossici e NK: il linfoma sottocutaneo simil-panniculitico, il linfoma extranodale a cellule
T/NK nasale e nasal-type, il linfoma NK blastico, il linfoma
T periferico citotossico aggressivo epidermotropo CD8+ e il
linfoma cutaneo periferico gamma-delta+. In questa rassegna vengono presentate le principali caratteristiche cliniche, istologiche, immunoistochimiche e molecolari delle
varie entità. Nel loro insieme i linfomi cutanei citotossici,
anche se piuttosto rari, presentano un decorso clinico aggressivo, con poche eccezioni.
Immunoistochimica, biologia molecolare e citogenetica. —
Le cellule neoplastiche sono TCR-delta-1+ (Figura 11),
PAROLE CHIAVE: Linfoma, immunologia - Linfociti - Cellule Natural killer.
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G ITAL DERMATOL VENEREOL 2005;140:263-70
Erythrokeratodermia variabilis: an update on clinics and genetics
G. RICHARD
Erythrokeratodermia variabilis (EKV) is a heritable disorder
of cornification associated with non-inflammatory erythema.
The majority of EKV patients harbor autosomal dominant
missense mutations in the connexin genes for Cx31 or Cx30.3,
which are expressed in the upper differentiated layers of the epidermis. Mutations exert a dominant negative effect and can
interfere with protein folding and intracellular trafficking as
well as with gap junction function, thus hindering gap junction
communication and epidermal differentiation. Certain Cx31
mutations have been shown to induce cell death when expressed
in vitro, yet the biological relevance of this finding remains to
be established. The clinical presentations of Cx31 and Cx30.3
defects are strikingly similar, although circinate or gyrate erythema appear to be a specific feature of Cx30.3 mutations. In
addition, there is new molecular evidence for the existence of
an autosomal recessive variant of EKV due to homozygous
mutations in Cx31, which has important implications for determining the recurrence risk for EKV in families with a sporadic case. Finally, connexin gene mutations account for EKV
in most but not all individuals, underscoring that other gene(s)
might be involved in the pathogenesis of EKV. Hence, a complex
understanding of the different clinical forms of erythrokeratodermas and their etiology beckons further thorough clinical and molecular analyses in large cohorts of patients.
KEY WORDS: Erythrokeratodermia variabilis, diagnosis - Erythrokeratodermia variabilis, genetics - Genetics.
E
rythrokeratodermas (sometimes written erythrokeratodermia) are a diverse group of hereditary
Address reprint requests to: G. Richard, Department of Dermatology and
Cutaneous Biology, Thomas Jefferson University, 233 S. 10th St, BLSB,
Suite 409, Philadelphia, PA 19107.
E-mail: [email protected]
Vol. 140 - N. 3
Department of Dermatology and Cutaneous Biology
Jefferson Medical College and Jefferson Institute
of Molecular Medicine
Thomas Jefferson University, Philadelphia, PA
disorders of cornification usually characterized by circumscribed areas of hyperkeratosis and erythema.
These disorders span a broad spectrum of phenotypes,
of which erythrokeratodermia variabilis (EKV; OMIM
#133200) is the best-defined clinical entity. Other disorders or rare variants, such as progressive symmetric
erythrokeratoderma (Darier-Gottron type; OMIM
#602036), erythrokeratoderma with ataxia (OMIM
#133190), genodermatose en cocardes (Degos disease), keratolytic winter erythema (OMIM #148370;
erythrokeratolysis hiemalis; Oudtshoorn skin), KID
syndrome (OMIM #148210), keratosis extremitatum
transgrediens et progrediens Greither (OMIM
#133200), or reticular erythrokeratoderma often pose
a diagnostic challenge due to their broad overlap with
each other, EKV, the ichthyoses or the palmoplantar
keratodermas.1-3 In addition, each disorder demonstrates considerable phenotypic variability making a
reliable classification difficult based solely on clinical
grounds. The recent advances of molecular genetics and
the identification of numerous disease genes in different disorders of cornification provided new insights
into the etiology of erythrokeratodermas and have
incited an anew and controversial debate on how to
better categorize and distinguish these disorders.3, 4
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RICHARD
ERYTHROKERATODERMIA VARIABILIS: AN UPDATE ON CLINICS AND GENETICS
Figure 1.—Clinical features of EKV and their underlying mutations in GJB3 (Cx31) and GJB4 (Cx30.3). (a) Characteristic coexistence of transient,
erythematous patches and symmetric, sharply demarcated hyperkeratotic plaques, mutation F209L in Cx31. (b) Symmetric, figurate outlined, erythematous
and hyperkeratotic plaques, mutation F137L in Cx30.3. (c) EKV with generalized thick, brown-gray hyperkeratosis, hypertrichosis and figurate,
fleeting erythema, mutation F137L in Cx31. (d) Histopathological features (H/E) include basket-weaved orthokeratotic hyperkeratosis, acanthosis, papillomatosis, and dilated capillaries in the superficial dermis. (e) Gyrate erythema, same patients as in (b), mutation F137L in Cx30.3. (f) Circinate erythema, mutation T85P in Cx30.3. (g) Target-like erythema, mutation T85P in Cx30.3.
In the following, the new and sometimes perplexing
genetic data and emerging genotype-phenotype correlations for EKV will be discussed.
Clinical features of EKV
The first cases of EKV were recognized and
described in the Netherlands by de Buy Wenninger in
1907.5 Eighteen years later, Mendes da Costa presented a detailed clinical description of the disease in
a mother and daughter, reviewed 8 similar cases previously published, and coined the name “erythro- et
keratodermia variabilis”.6 He graphically depicted the
key features of EKV with relatively fixed patches of
hyperkeratosis and erythematous patches “characterized by capriciously formed outlines, like the boundary lines of seacoasts on maps”. Over the following
decades, multiple case reports and extensive family
studies emerged in the Northern European literature,
including large Dutch and Swiss EKV kindreds.2, 7, 8 To
date, well over 200 unrelated patients and families of
diverse genetic backgrounds have been reported worldwide.9-14 In the United States, the author knows of at
least 60 affected individuals from 22 families.
The hallmark of EKV is the coexistence of fleet-
264
ing, bizarre outlined, erythematous patches that constantly change their appearance and more stable hyperkeratosis. More then 90% of EKV patients present at
birth or within the first year of life with randomly
occurring, sharply demarcated, intensely red patches
occasionally surrounded by an anemic halo.15, 16 The
red marks last for minutes to hours, sometimes for
days, and can involve any part of the integument,
appearing on normal skin as well as within hyperkeratotic areas. They have a geographic, circinate or target-like appearance, and may coalesce into large figurate areas (Figure 1). The remarkable variability in
number, size, shape, location and duration of erythematous patches is reflected by the name of the disease. Although these lesions are usually asymptomatic,
about 1/3 of patients experience a burning sensation
preceding or accompanying the erythema. Occasionally, this can cause serious discomfort. Although
severity and extent greatly vary between patients,
the erythematous component of EKV tends to be
more prevalent during childhood. Elder patients may
lack any evidence for transient erythema but almost
always present a history of such lesions, especially
provoked by exposure to cold, skin irritation or emotional upset 17, 18 (author’s observation). This makes the
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occurrence of transient, figurate red patches the most
reliable diagnostic feature for EKV.
Simultaneously or within weeks to months after the
onset of erythema, plaques of thickened, rough skin
develop preferentially at the distal extremities. The
majority of patients present with sharply demarcated,
yellow or reddish-brown, thickened plaques with figurate outlined borders, which bear in more than 75%
of EKV patients no relationship to the variable erythemas 19 (author’s observation). They progressively
involve the limbs, buttocks and trunk in a striking symmetrical distribution (Figure 1). The surface may be
ridged or verrucous, sometimes showing a collarettelike peeling, or fine, attached scales. Most common are
relatively fixed lesions over knees, elbows, Achilles tendons, dorsum of the feet and the belt area, which persist over months to years, although complete clearing
and periodic recurrence are not unusual. In about half
of all patients the thickening of the skin includes the
palms and soles, while the flexures, face and scalp
tend to be spared. Extend and severity of palmoplantar keratoderma widely range from generalized involvement with glove-like appearance, patchy hyperkeratosis over pressure points to inconspicuous skin peeling.15, 18, 20 More than 1/3 of EKV patients with severe
disease have persistent generalized hyperkeratosis
with exaggerated skin markings, fine scaling, and a
darker or grayish appearance, which can mask the erythematous component of the disease (Figure 1) 20, 21
Particularly on the lower extremities, these patients
may develop thick, dark plates of hyperkeratosis with
a spiny, hystrix-like appearance.21 Less known features of EKV are marked hypertrichosis, which accompanies hyperkeratosis in 2/3 of all patients, and hyperkeratosis, follicular plugging and telangiectasias of
the pinnae.20, 22 Both the erythema and hyperkeratosis
may be precipitated by internal and/or external factors. The most prevalent triggers reported by 83% of
EKV patients (author’s observation) were sudden
changes in temperature, especially coldness, and
mechanical irritation of the skin.16, 23, 24 Flares in
females during pregnancy or with oral contraceptives
or periodic improvement or clearing have also been
described.18, 23
Clinical studies in several extended families demonstrated considerable variations of the disease phenotype
both between and within families.2, 15, 16, 18, 23, 25, 26
There were interfamilial and age-dependent differences in the degree of hyperkeratosis and erythema,
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palm/sole involvement and hypertrichosis. While the
EKV phenotype was relatively consistent within some
families, it greatly varied between affected individuals of others.16, 18
EKV is a chronic skin disorder without other organ
manifestations and a normal life span. After progression throughout infancy and childhood, EKV tends to
stabilize after puberty and persists throughout life,
often with hyperkeratosis as predominant feature.
Depending on extent and severity, skin lesions in EKV
can be severely disfiguring and have a tremendous
psychosocial impact on patients.
The histopathologic features in EKV are non-specific and include hyperkeratosis, moderate to severe
acanthosis with prominent granular layer, and papillomatosis (Figure 1). In contrast to many other disorders
of cornification, the hyperkeratosis is orthokeratotic
with a normal basket-weaved appearance. There are
dilated, elongated capillaries with very little perivascular inflammation in the papillary dermis. Severe papillomatosis with suprapapillary thinning may result in a
“church spire” configuration of the epidermis.13, 27-29
Ultrastructural studies have revealed conflicting results,
including a reduced number of lamellar bodies in the
granular layer.28, 30
The treatment of EKV is symptomatic, targeting the
hyperkeratosis. Topical management with keratolytic
agents such as lactic acid, urea, a-hydroxy acids, and
tretinoin is usually sufficient for mild disease.31, 32 Systemic retinoids such as etretinate, isotretinoin and
acitretin have been treatment of choice in extensive
EKV.28, 29, 33-35 They often induce dramatic improvement or complete clearing of hyperkeratosis and significant moderation of the erythema, although the latter
cannot be completely suppressed.36 The minimal maintenance dose for patients with EKV is very low compared to that of other disorders of cornification,10, 28, 29
which perhaps might be due to the down-regulation of
Cx31 expression by retinoids.37
The genetics of EKV: autosomal dominant connexin
mutations and genetic heterogeneity
EKV is usually inherited in an autosomal dominant
pattern with nearly complete penetrance as evident from
numerous multigenerational pedigrees.2, 15, 16, 18, 23, 25, 26
However, a respectable number of sporadic cases and a
few families with autosomal recessive inheritance have
been reported.10, 15, 18, 21, 24, 32, 38 Interestingly, EKV was
one of the first genetic disorders, in which blood group
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Figure 2.—Schematic of a generic gap junction protein showing major functional characteristics of the structural domains, the topographic location
of pathogenic connexin mutations in GJB3 (Cx31) and GJB4 (Cx30.3), and their phenotypes. The structural motifs of connexins are NT: amino-terminus; M1-M4: transmembrane domains 1-4; E1/ E2: extracellular domains 1 and 2; CL: cytoplasmic loop; CT: carboxy-terminus. The clinical phenotypes are: EKV: Autosomal dominant Cx30.3 mutations in RED; Autosomal dominant Cx31 mutations in BLUE; Autosomal recessive Cx31 mutations in LIGHT BLUE. Sensorineural hearing loss: Autosomal dominant and recessive Cx31 mutations in BLACK. Sensorineural hearing loss and peripheral neuropathy: Autosomal dominant Cx31 mutation in GREEN.
serum markers were successfully used for genetic linkage studies to map disease genes to human chromosomes. As early as in 1984, the gene for EKV was localized near the Rh blood group locus on the short arm of
chromosome 1 in a Dutch family,39 which was studied
already by Noordhoek (1950) 2 and might go back to the
first cases of EKV described in the Netherlands.6 Thirteen years later, Richard et al. refined these data and
linked EKV in 4 large families of different origins to a
2.6 cM region on chromosome 1p34-p35.1 (maximum
multipoint LOD score: 12.88), demonstrating locus
homogeneity in EKV.26 This genomic interval was found
266
to harbor a cluster of 4 connexin (Cx) genes encoding
the gap junction proteins Cx30.3 (GJB4), Cx31 (GJB3),
Cx31.1 (GJB5), and Cx37 (GJA4).40
Since then, genetic studies revealed that EKV is genetically heterogeneous and may be caused by mutations in
different genes.18, 40, 41 Two disease genes have been
identified to date, GJB3 encoding connexin 31 (Cx31)
and GJB4 encoding connexin 30.3 (Cx30.3) (Figure 2).
The majority of disease-causing mutations in these genes
are autosomal dominant in nature and newly acquired
mutations are responsible for EKV in sporadic cases.
Richard et al. in 1998 first revealed in 4 EKV patients and
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families of Northern European origin distinct heterozygous mutations in the Cx31 gene, each of which completely co-segregated with the autosomal dominant EKV
phenotype.40 Other reports of pathogenic Cx31 mutations
followed, including an Italian family.18, 21, 42, 43 To date,
a total of 7 distinct missense mutations of the Cx31 gene
(GJB3) have been identified in 9 EKV families. Nevertheless, mutations of the Cx31 gene did not account
for all cases of EKV tested. Macari et al. in 2000
studied a large Israeli-Kurdish EKV family with
peculiar erythematous patches resembling erythema
gyratum repens 12 and showed linkage to the EKV locus
on 1p. Although no mutation was found in the Cx31
gene, they identified a pathogenic missense mutation in
yet another connexin gene (GJB4) encoding Cx30.3.41
Recently, Richard et al. described 5 novel or recurrent
missense mutations of the Cx30.3 gene in 6 unrelated
EKV families of various origins, thus conclusively confirming the causal role of autosomal dominant Cx30.3
mutations in EKV.18
milder phenotype with localized hyperkeratotic plaques.
In contrast, certain Cx31mutations (G12D, C86S,
F137L) were found to result in severe, generalized
hyperkeratosis with hystrix-like appearance.18, 40 Most
interesting is the finding that certain Cx30.3 mutations
(T85P, F137L) may produce rapidly changing erythematous patches with prominent, circinate or gyrate
borders reminiscent of erythema gyratum repens (Figure 1), strongly suggesting that this feature is specific
for Cx30.3 defects.18, 41 It seems likely that previous cases of variable erythrokeratoderma with irregular, polycentric, rosette-like configurations reported as “genodermatose en cocardes” (Degos) represent the Cx30.3
variant of EKV.19, 47, 48 Finally, although it has been
suggested that certain other GJB3 (Cx31) mutations
may play a causal role in sensorineural hearing loss
and perhaps peripheral neuropathy (Figure 2),49-51 EKV
is not associated with any of these disorders.52
Genotype-phenotype correlations
The existence of an autosomal recessive variant of
EKV has engendered some debate. In 2002, genetic
studies of a Kurdish EKV family provided for the first
time molecular evidence for the existence of an autosomal recessive variant of EKV. Two siblings with EKV
were found to carry on both alleles of Cx31 the missense
mutation L34P (Figure 2), while both unaffected parents
were heterozygous carriers.38 This mutation was predicted to disturb the structure of the first transmembrane helix of Cx31. Expression of the Cx31-L34P
mutant in transfected HeLa cells resulted in abnormal
cytoplasmic accumulation and lack of gap junction formation, not unlike the findings for autosomal dominant
mutations (see below). Recently, Terrinoni et al. reported another EKV family with similar findings, in which
an affected child was homozygous for mutation E100K
(Figure 2), while both parents and numerous other unaffected relatives were mutation carriers.10 The detection
of autosomal recessive Cx31 mutations has important
implications for genetic counseling of families with a
sporadic case of EKV. While the majority of these cases likely result from dominant de novo mutations in
Cx31 or Cx30.3 and will not be associated with an
increased recurrence risk in subsequent pregnancies,
autosomal recessive Cx31 mutations have to be considered, especially in families of inbred populations,
and carry a 25% recurrence risk.
Nevertheless, the validity of the clinical diagnosis in
these families, the pathogenicity of the reported Cx31
It is of interest to note that all autosomal dominant
EKV mutations in Cx31 and Cx30.3 represent single
nucleotide substitutions and that the nature and location of mutations in both genes is strikingly similar
(Figure 2). Each mutation leads to the replacement of
a highly conserved amino acid residue in Cx31 or
Cx30.3. A majority of mutations is located within the
transmembrane domains (Figure 2), which are evolutionary conserved among all connexin proteins and
across different species. These 4 domains anchor the
protein in the cell membrane and line the pore of gap
junction channels.44 Hence mutations have been predicted to hinder regulation of voltage gating or alter the
kinetics of channel closure. Other mutations substitute glycine 12 in the cytoplasmic amino-terminus
with a highly charged residue, which could interfere
with the flexibility of this domain, connexin selectivity, or gating polarity of gap junction as shown for
other connexin molecules,45, 46 or replace phenylalanine
209 with leucine in the carboxy-terminus.43
In general, the clinical phenotype of Cx31 and Cx30.3
mutations is indistinguishable. Mutations in both genes
demonstrate considerable variability of severity and
extent of hyperkeratosis, erythema, and palmoplantar
involvement. Although the cohort of EKV patients with
known mutations is still very small, it currently appears
that Cx30.3 mutations are associated with a somewhat
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The genetics of EKV: autosomal recessive mutations
in Cx31
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mutations and thereby the existence of autosomal
recessive EKV have been challenged.53 In response,
Terrinoni and Melino provided more convincing clinical and histological information supporting the diagnosis of EKV in the reported family.54 Further, they
excluded a causative mutation in the keratin 1 gene,
refuting the diagnosis of epidermolytic hyperkeratosis
with cyclic ichthyosis, which shares several features
with EKV.54, 55 This dispute vividly underscores the
diagnostic dilemma in erythrokeratodermas even for
experienced dermatologists, ensuing from the scarcity of solid diagnostic criteria for EKV and other disorders with similar or overlapping features.
Despite all these findings, a small number of EKV
patients do not harbor pathogenic connexin gene mutations and the molecular basis of the disorder in these
patients still remains elusive.18, 56, 57 These individuals
might carry mutations in regulatory gene regions of
GJB3 and GJB4, in another disease gene not yet identified, or perhaps might indeed have a different form
of erythrokeratoderma as discussed above.
Epidermal connexins and functional implications of
mutations in EKV
Connexins are a multigenic family of transmembrane proteins that assemble to plaques in the cell
membrane and form aqueous intercellular channels
connecting the cytoplasm of one cell with that of a
neighboring cell. These channels permit the diffusional exchange of ions, small metabolites (less than
1 kDa) and crucial signaling molecules, and thus control and coordinate a plethora of cellular functions.
Each channel is composed of 2 hemichannels (“connexons”), which are formed by oligomerization of 6
connexin molecules.58 The hemichannels and complete gap junction channels formed by each of the 21
known human connexin proteins have specific electrophysiological, biochemical and gating properties.59
However, they may be comprised of more than one
connexin type depending on their inherent compatibility code, thus resulting in mixed channels with
unique characteristics.60 To further increase the complexity and diversity of the gap junction system, most
cell types of the body express two or more different
connexin types. A good example is the human epidermis, where at least 9 distinct connexin proteins are
expressed in a differentiation-specific manner.52, 61
Cx31 and Cx30.3 are preferentially expressed by differentiated keratinocytes in the spinous and granular
268
layers of human epidermis, where also Cx43, Cx30
and others can be found. Although both gap junction
proteins are prevalent in a few other tissues, mutations
only interfere significantly with epidermal differentiation resulting in EKV, suggesting that tissue-specific mechanisms are at play.61, 62 These findings provide compelling evidence for the crucial role of gap
junction intercellular signaling for keratinocyte differentiation and skin function.
Recent functional studies have shed some light on the
pathological mechanisms of autosomal dominant mutations in EKV and disclosed a dominant negative interference of mutant Cx31 or Cx30.3 with their normal
oligomerization partners.62, 63 In vitro expression studies in HeLa cells and keratinocytes demonstrated that
most of these amino acid substitutions impede cytoplasmic trafficking of the mutant Cx31/Cx30.3 protein itself and of coexpressed wildtype protein to the cell
membrane.62, 64 This defect in connexin transport likely stems from protein misfolding, leading in turn to
the degradation of the proteins at the exit of the endoplasmic reticulum.62 Similarly, trafficking defects have
been observed for mutant connexin 32 in X-linked
Charcot-Marie-Tooth disease 65, 66 and for autosomal
dominant mutations of Cx26 and Cx30 with a cutaneous phenotype (i.e., palmoplantar keratoderma associated with sensorineural hearing loss and Clouston
syndrome, respectively).67, 68 Furthermore, the perinuclear accumulation of Cx31 in the epidermis of an individual heterozygous for Cx31 mutation R42P suggested a disruptive effect of this mutation on protein trafficking in vivo.64 In addition, there is experimental evidence that Cx31 and Cx30.3 mutations alter the function of gap junction channels. For example, both loss
(Cx31 mutation G12D) or gain (Cx31 mutation G12R)
of function can occur when mutant Cx31 subunits are
incorporated into channels.69, 70 Several studies showed
a significant increase in cell death with in vitro expression of Cx31 mutations (including F137L), suggesting that faulty function of hemi or complete gap junction channels might impair cellular homeostasis.64, 70 In
contrast, a similar mutation in Cx30.3 (F137L) did not
affect cell survival, consistent with the lack of obvious cell death in lesional EKV skin.62, 63
In an elegant study, Plantard et al. recently demonstrated direct molecular interactions between Cx31
and Cx30.3 and evidence for their co-oligomerization into mixed connexin hemichannels in the endoplasmic reticulum (ER) before passage through the
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Golgi apparatus.62 Compared to the expression of
Cx31 or Cx30.3 alone, their coexpression and cooligomerization into mixed hemichannels significantly enhanced number and size of gap junction
plaques and intercellular communication, consistent with a synergistic effect. These important findings could explain the observed dominant-negative
effect of Cx31 and Cx30.3 mutations as well as their
matching clinical phenotype. Since the complete
absence of Cx30.3 in individuals harboring a common frameshift mutation leading to premature termination of translation has been not associated with
any skin disease,18, 71, 72 it becomes clear once again
that the presence of a faulty structural protein, such
as Cx31 or Cx30.3, can be far more detrimental than
its mere loss.
Riassunto
Eritrocheratodermia variabile: un aggiornamento sugli
aspetti clinici e genetici
L’eritrocheratodermia variabile (EKV) è un disturbo ereditario della corneificazione associato ad eritema non infiammatorio. La maggior parte dei pazienti con eritrocheratodermia variabile ha mutazioni erronee autosomiche dominanti
nel gene connessina per Cx31 o Cx30.3, che vengono espressi negli strati superficiali differenziati dell’epidermide. Le
mutazioni esercitano un effetto dominante negativo e possono
interferire con il ripiegamento delle proteine e sul traffico
intracellulare, così come sulle giunzioni serrate (gap junction),
ostacolando di conseguenza la comunicazione giunzionale
serrata e la differenziazione epidermica. Certe mutazioni
Cx31 hanno dimostrato in vitro di indurre morte cellulare, ma
la rilevanza clinica di questo dato è ancora da stabilire. Le presentazioni cliniche dei difetti di Cx31 e Cx30.3 sono estremamente simili, sebbene l’eritema circinato o convoluto
sembra essere un quadro specifico delle mutazioni Cx30.3.
Inoltre, vi sono nuove evidenze su base molecolare dell’esistenza di una variante autosomica recessiva di eritrocheratodermia variabile dovuta a mutazione omozigote in Cx31,
che ha importanti implicazioni nel determinare il rischio di
comparsa della patologia nell’ambito di famiglie con un
caso sporadico. Infine, le mutazioni a carico del gene connessina hanno importanza per l’eritrocheratodermia variabile
in molti ma non in tutti i soggetti, sottolinenando che un
altro gene o più geni possano essere coinvolti nella patogenesi della malattia. Di conseguenza, la complessa comprensione delle diverse forme cliniche di eritrocheratodermia e
della loro eziologia richiedono ulteriori studi clinici e molecolari su ampie coorti di pazienti.
PAROLE CHIAVE: Eritrocheratodermia variabilis, diagnosi Eritrocheratodermia variabilis, genetica – Genetica.
Vol. 140 - N. 3
RICHARD
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23-32.
38. Gottfried I, Landau M, Glaser F, Di WL, Ophir J, Mevorah B et al. A
mutation in GJB3 is associated with recessive erythrokeratodermia
variabilis (EKV) and leads to defective trafficking of the connexin 31
protein. Hum Mol Genet 2002;11:1311-6.
39. van der Schroeff JG, Nijenhuis LE, Meera Khan P, Bernini LF, Schreuder GM, van Loghem E et al. Genetic linkage between erythrokeratodermia variabilis and Rh locus. Hum Genet. 1984;68:165-8.
40. Richard G, Smith LE, Bailey RA, Itin P, Hohl D, Epstein JEH et al.
Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Nat Genet 1998;20:366-9.
41. Macari F, Landau M, Cousin P, Mevorah B, Brenner S, Panizzon R et
al. Mutation in the gene for connexin 30.3 in a family with erythrokeratodermia variabilis. Am J Hum Genet 2000;67:1296-301.
42. Wilgoss A, Leigh IM, Barnes MR, Dopping-Hepenstal P, Eady RA,
Walter JM et al. Identification of a novel mutation r42p in the gap junction protein beta-3 associated with autosomal dominant erythrokeratoderma variabilis. J Invest Dermatol 1999;113:1119-22.
43. Morley SM, White MI, Rogers M, Wasserman D, Ratajczak P, McLean
WHI et al. A new, recurrent mutation of GJB3 (Cx31) in erythrokeratodermia variabilis. Br J Dermatol (submitted).
44. Skerrett IM, Aronowitz J, Shin JH, Cymes G, Kasperek E, Cao FL
et al. Identification of amino acid residues lining the pore of a gap junction channel. J Cell Biol 2002;159:349-60.
45. Purnick PE, Benjamin DC, Verselis VK, Bargiello TA, Dowd TL.
Structure of the amino terminus of a gap junction protein. Arch
Biochem Biophys 2000;381:181-90.
46. Lagree V, Brunschwig K, Lopez P, Gilula NB, Richard G, Falk MM.
Specific amino-acid residues in the N-terminus and TM3 implicated
in channel function and oligomerization compatibility of connexin43. J Cell Sci 2003;116:3189-201.
47. Degos R, Delzand O, Morival H. [Congential or Familial Desquamative erythema in plaques, a new genodermatosis?]. Annales Dermatol Syphiligr 1947;7:442.
48. Rajagopalan B, Pulimood S, George S, Jacob M. Erythrokeratoderma
en cocardes. Clin Exp Dermatol 1999;24:173-4.
49. Xia JH, Liu CY, Tang BS, Pan Q, Huang L, Dai HP et al. Mutations
in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment. Nat Genet 1998;20:370-3.
50. Liu XZ, Xia XJ, Xu LR, Pandya A, Liang CY, Blanton SH et al.
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Mutations in connexin31 underlie recessive as well as dominant nonsyndromic hearing loss. Hum Mol Genet 2000;9:63-7.
Lopez-Bigas N, Olive M, Rabionet R, Ben-David O, Martinez-Matos
JA, Bravo O et al. Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment. Hum Mol Genet 2001;10:947-52.
Richard G. Connexins: a connection with the skin. Exp Dermatol
2000;9:77-96.
van Steensel MA, van Geel M. Does Recessive EKV Exist? J Invest
Dermatol 2005;152:155-8.
Terrinoni A, Merlino G. Recessive EKV. J Invest Dermatol. In press.
Sybert VP, Francis JS, Corden LD, Smith LT, Weaver M, Stephens K
et al. Cyclic ichthyosis with epidermolytic hyperkeratosis: a phenotype conferred by mutations in the 2B domain of keratin K1. Am J Hum
Genet 1999;64:732-8.
Ishida-Yamamoto A, Kelsell D, Common J, Houseman MJ, Hashimoto M, Shibaki H et al. A case of erythrokeratoderma variabilis without mutations in connexin 31. Br J Dermatol 2000;143:1283-7.
Arita K, Akiyama M, Tsuji Y, Onozuka T, Shimizu H. Erythrokeratoderma variabilis without connexin 31 or connexin 30.3 gene mutation: immunohistological, ultrastructural and genetic studies. Acta
Derm Venereol 2003;83:266-70.
Harris AL. Emerging issues of connexin channels: biophysics fills
the gap. Q Rev Biophys 2001;34:325-472.
Sohl G, Willecke K. Gap junctions and the connexin protein family.
Cardiovasc Res 2004;62:228-32.
White TW, Bruzzone R. Multiple connexin proteins in single intercellular channels: connexin compatibility and functional consequences.
J Bioenerg Biomembr 1996;28:339-50.
Di WL, Rugg EL, Leigh IM, Kelsell DP. Multiple epidermal connexins are expressed in different keratinocyte subpopulations including connexin 31. J Invest Dermatol 2001;117:958-64.
Plantard L, Huber M, Macari F, Meda P, Hohl D. Molecular interaction of connexin 30.3 and connexin 31 suggests a dominant-negative
mechanism associated with erythrokeratodermia variabilis. Hum
Mol Genet 2003;12:3287-94.
Rouan F, Yi LS, Uitto J, Richard G. Pathogenic mutations affecting
Cx31and Cx30.3 impair gap junction function and induce cell death
in vitro. J Invest Dermatol 2003;121:A603.
Di WL, Monypenny J, Common JE, Kennedy CT, Holland KA, Leigh
IM et al. Defective trafficking and cell death is characteristic of skin
disease- associated connexin 31 mutations. Hum Mol Genet 2002;11:
2005-14.
Deschenes SM, Walcott JL, Wexler TL, Scherer SS, Fischbeck KH.
Altered trafficking of mutant connexin32. J Neurosci 1997;17:9077-84.
Yum SW, Kleopa KA, Shumas S, Scherer SS. Diverse trafficking
abnormalities of connexin32 mutants causing CMTX. Neurobiol Dis
2002;11:43-52.
Marziano NK, Casalotti SO, Portelli AE, Becker DL, Forge A. Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have
a dominant negative effect on connexin 30. Hum Mol Genet 2003;12:
805-12.
Common JE, Becker D, Di WL, Leigh IM, O'Toole EA, Kelsell DP.
Functional studies of human skin disease- and deafness-associated connexin 30 mutations. Biochem Biophys Res Commun 2002;298:651-6.
Rouan F, Lo CW, Fertala A, Wahl M, Jost M, Rodeck U et al. Divergent effects of two sequence variants of GJB3 (G12D and R32W) on
the function of connexin 31 in vitro. Exp Dermatol 2003;12:191-7.
Diestel S, Richard G, Doring B, Traub O. Expression of a connexin31
mutation causing erythrokeratodermia variabilis is lethal for HeLa
cells. Biochem Biophys Res Commun 2002;296:721-8.
Lopez-Bigas N, Melchionda S, Gasparini P, Borragan A, Arbones
ML, Estivill X. A common frameshift mutation and other variants in
GJB4 (connexin 30.3): Analysis of hearing impairment families. Hum
Mutat 2002;19:458.
van Geel M, van Steensel MA, Steijlen PM. Connexin 30.3 (GJB4) is
not required for normal skin function in humans. Br J Dermatol
2002;147:1275-7.
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G ITAL DERMATOL VENEREOL 2005;140:271-8
Urticaria
T. SURRENTI, 1 W. STERRY, 2 T. ZUBERBIER 2
Urticaria is a very heterogeneous disease that has been classified in different subtypes by the increasing understanding of the
mechanisms involved in its pathogenesis. However, a clear distinction of the subtypes is required to choose the correct measures in diagnosis and management and to value the available
data in research. The different clinical types of urticaria can be
grouped into: 1) spontaneous urticaria, which includes acute
and chronic urticaria; 2) physical urticaria; 3) special types
of urticaria including the contact urticaria; 4) diseases historically related to urticaria, like urticaria pigmentosa. Since the
urticaria subtypes compromise strictly the quality of life, an
effective treatment is therefore required in case the diagnostic
procedures do not reveal a specific cause which can be treated
itself. For symptomatic treatment, non-sedating H1-antihistamines represent the first choice in most subtypes of urticaria,
however, double-blind controlled studies have shown that
dosages required may exceed those recommended for other
diseases, e.g. allergic rhinitis. Alternative treatments should
be reserved to patients unresponsive to traditional therapy.
KEY WORDS: Urticaria, diagnosis - Urticaria, physiopathology Urticaria, therapy.
D
uring the last decades, different subtypes of
urticaria have been recognised by the increasing
understanding of the molecular mechanisms involved
in its pathogenesis. At this time, there is growing evi-
This study was supported by the European Centre for Allergy Research Foundation (www.ECARF.org).
Address reprint requests to: Prof. T. Zuberbier, Department of Dermatology and Allergy, Charité-University of Medicine Berlin, Charité Campus Mitte, Schumanstrasse 20-21, 10117 Berlin, Germany.
E-mail:[email protected]
Vol. 140 - N. 3
1Department of Dermatology
University of L’Aquila, L’Aquila, Italy
2Department of Dermatology
University of Charité, Berlin, Germany
dence for the heterogeneity of urticaria and for its high
impairment of the quality of life, consequently an individual approach can be essential. Poon et al.1 report a
study in 170 patients attending a specialist urticaria
clinic which showed that especially patients with
delayed pressure urticaria and cholinergic urticaria
have the highest impairment of the quality of life comparable to that in atopic dermatitis patients and higher than in chronic urticaria patients, which was still
similar to the quality of life impairment seen in patients
affected by psoriasis and acne.
This review has considered the studies published
until 2003 and includes the suggestions of the European
Academy of Allergology and Clinical Immunology
(EAACI) position paper on physical urticaria,2 the
guidelines on urticaria by the British Association of
Dermatologists 3 and the most recent consensus reports
of the Clinically Oriented ESDR Symposium “Urticaria
2000”. In the latter, more than 100 specialists from
over 15 countries have come to a consensus regarding
definition, classification, routine diagnosis and management of urticaria. Evidence based suggestions had
been prepared by a panel in advance and were then
discussed using a voting system.4, 5
The analysis of divergent data regarding eliciting
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TABLE I.—Classification of urticaria on the basis of its duration, frequency and causes. Modified according to Zuberbier et al.4
Duration
a. Spontaneous urticaria
Acute urticaria
Chronic urticaria
1. Chronic continuous urticaria
2. Chronic recurrent urticaria
<6 weeks
>6 weeks
Frequency
Spontaneous wheals appearing most days
Spontaneous appearance of wheals
Daily or most days of the week
Symptom free intervals ranging from days to weeks
Eliciting factor
b. Physical urticaria
1. Dermographic urticaria
2. Delayed pressure urticaria
3. Cold contact urticaria
4. Heat contact urticaria
5. Solar urticaria
6. Vibratory angioedema/urticaria
Mechanical shearing forces (wheals arising after 1-5 min)
Vertical pressure (Wheals arising with a 3-8 hrs latency)
Cold air/water/wind
Localized heat
UV and/or visible light
Vibratory forces, e.g. pneumatic hammer
c. Special types of urticaria
1. Cholinergic urticaria
2. Adrenergic urticaria
3. Contact urticaria (allergic or pseudoallergic)
4. Aquagenic urticaria
d. Different diseases related to urticaria for historical reasons
1. Urticaria pigmentosa (mastocytosis)
2. Urticarial vasculitis
3. Familial cold urticaria (vasculitis)
causes for subtypes of urticaria and their therapeutic
responsiveness is, however, sometimes complicated
due to the difference between population studied.
the mid to lower dermis.7 Frequently, in uninvolved
skin areas, alterations of adhesion molecules8 and
cytokine expression has been also identified.9 All these
recent findings emphasize the complex nature and heterogeneity of urticaria.
Clinical appearance and histopathology
Urticaria is clinically characterized by the sudden
appearance of wheals sometimes accompanied by
angioedema. A wheal is characterised by a central
swelling of variable size, almost invariably surrounded by a reflex erythema. The wheal presents a classic
transient evolution with a duration of usually 1-24 h.
Ichting or sometimes burning are habitually associated. Angioedema is defined by a sudden, marked
swelling of the lower dermis and subcutis with frequent involvement of mucous membranes, accompanied by pain rather than itching. The healing is slower than for wheals and can take up to 72 h.
Histopathologically, the wheal reveals edema with
an upregulation of endothelial adhesion molecules, a
mixed inflammatory perivascular infiltrate of variable
intensity, consisting of neutrophils and/or eosinophils,
macrophages and T-helper lymphocytes.6 In delayed
pressure urticaria the infiltrate is situated typically in
272
Classification
The range of clinical manifestations of different
urticaria subtypes is very broad. Furthermore, in 1 patient
2 or more different subtypes of urticaria can coexist.
Table I 4 presents a classification for clinical use. Physical urticarias are grouped separately because they depend
on the presence of their specific eliciting physical factors,
whereas in acute and chronic urticaria wheals occur
spontaneously without any external physical stimuli.
The features of the different subtypes will be shortly summarised in the following paragraphs.
Spontaneous urticaria
ACUTE URTICARIA
The life-time prevalence of acute urticaria, valued by
questionnaires, ranges from 12-15% 10, 11 or even
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TABLE II.—Prevalence of upper respiratory infections in acute urticaria.
Study
Prevalence
Kauppinen et al.17
Zuberbier et al.14
Legrain et al.16
Simons et al.15
Aoki et al.18
28.0%
39.5%
50.0%
54.5%
62.0%
23.5%.12 In an own prospective study, in a rural area
of Brandenburg we found a 1-year incidence of
0.154%, which equals a life-time prevalence of 12.32%
based on a life expectancy of 80 years.13, 14 However,
there is no possible way to recognize the number of
patients regarding affected possibly by mild symptoms and who did thus not get in contact with any
physician, which is well conceivable in a rural area in
a disease that is mostly self-remitting. Thus the true lifetime prevalence for the area may be estimated to be
higher.
The prevalence of acute urticaria is more elevated in
atopic patients, thus hay fever, allergic asthma or atopic
dermatitis were found in 50.2% associated with acute
urticaria in the cited study.14 Moreover, Simons 15
reports on a prospective study in more than 800 12-24month-old children with atopic dermatitis, an association in 16.2% with acute urticaria in the study group
not treated with antihistamines (n=396) over a period
of 18 months.
About the etiology, this prospective study in acute
urticaria showed that, although 63% of the patients
supposed food to be the cause, in only 1of 109 patients
food was the causing agent upon examination, which
shows that patient history, specially in acute urticaria,
may be ambiguous.14 However, Legrain et al. reported that food, in particular cow’s milk, is relevant for
acute urticaria in 10 of 12 infants.16 Kauppinen et al.17
observed in older children with urticaria (6 months-16
years) a prevalence of food intolerance of 15% as eliciting factor for the acute urticaria, whereas Aoki et
al.18 found any single case of food allergy in an epidemiological study in 50 adult patients.
However, the most frequent cause for acute urticaria
appears to be viral infections, especially of the upper
respiratory tract, which begin usually a few days before
the onset of whealing (Table II).14-18
Finally, drugs can elicit acute urticaria both as allergens and as pseudoallergens. Penicillin is the most
frequent cause of an IgE-mediated drug induced
Vol. 140 - N. 3
urticaria, whereas acetyl salicylic acid is the most common example of a pseudoallergen.
CHRONIC URTICARIA
Because of the lack of cross-sectional studies, there
is not available data regarding the prevalence of chronic urticaria.
Like in acute urticaria type I – allergic reactions are
only rarely responsible for the development of chronic urticaria.19, 20 In some subsets of patients with chronic urticaria, pseudoallergic reactions against food and
food additives have been discussed in the past separately from infectious or autoimmune etiology. A
review of studies on pseudoallergy is summarized in
Table III,19-33 however, only few have used the gold
standard of double-blind, placebo controlled food challenge tests. The variation of the results may also be
due to the differences in study populations and study
conditions. In fact, in some countries referrals to specialists are only possible in case of severe symptoms
and some studies have included not only patients with
chronic urticaria but also patients with physical
urticaria. In other cases, the elimination diets were
only used for a short period of time. Own results 20
show that, in the patients improving on a diet low in
pseudoallergens, 30% demonstrate a decrease of symptoms only after 10-14 days on diet. The study included unselected patients with chronic continuous urticaria
who had not received any diagnostic work-up before.
Approximately 50% of the responders did not express
a total clearance of symptoms, suggesting that other
possible co-factors are involved in the pathogenesis. In
this group a high incidence of pseudoallergic reactions against food was demonstrated. These results
were confirmed by Pigatto et al.33 who investigated a
group of 202 patients with chronic urticaria using the
same diet. In this study, 126 patients improved on
exclusion diet, whereas 35 patients did not show any
benefit from the diet and 41 patients dropped out. In
both studies reactions to food additives were only seen
in a minority of patients (19% and 37%, respectively),
which points at the relevance of naturally occurring
pseudoallergens. Especially aromatic compounds found
in vegetables and food appear to be important. An
open provocation test in 31 chronic urticaria patients
showed that 71% of patients responding to a low
pseudoallergen diet reacted to tomatoes and 44% to distillates of tomatoes containing aromatic compounds
free of protein and salicylic acid. In contrast, less than
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TABLE III.—Review of studies on pseudoallergy in urticaria.
Author(s)
Disease studied
No. of patients Positive reactions
to food additives
Warin et al., 1976 21
Chronic urticaria
111
Genton et al., 1985 22
Michaelsson et al., 1973 23
Chronic urticaria
Chronic urticaria
and angioedema
Chronic urticaria
17
52
Provocation
59.5% (incl. ASS)
75%*
100
62% (incl. ASS)
Single blind
Urticaria
Chronic urticaria
and angioedema in 9%
Chronic urticaria
620
330
26.6% (incl. ASS)
31%
Single blind
Single blind
93.3%*
81.3% free of symptoms*
6.3% improvement*
80.6% improvement*
19.4% spontaneous
improvement*
>60% improvement*
No data
70
59.6% (incl. ASS)
Chronic urticaria
Chronic urticaria
158
75
31.6%
Follow-up
Single blind,
placebo controlled
—
Study
Verschave et al., 1983 29
Gibson et al. C, 1980 30
Chronic urticaria
Chronic urticaria
67
76
No
up to 54%
—
Single blind,
placebo controlled
Kirchhof et al., 1982 31
Chronic intermittent urticaria
100
39%
43
24%
67
19%
202 of 348
37.3%
Double blind,
placebo controlled
Double blind,
placebo controlled
Double blind,
placebo controlled
Double blind,
placebo controlled
Thune et al., 1975 24
Wüthrich et al.,1981 25
Juhlin, 198119
Ortolani et al., 1984 26
Rudzki et al., 1980
Ros et al., 1976 28
27
Supramaniam et al., 1986 32 Urticaria and angioedema
in 74.4%
Zuberbier et al., 1995 20
Chronic urticaria
and/or angioedema
Pigatto et al., 2000 33
Chronic urticaria
Single blind,
placebo controlled
(antihistamine treatment)
88.2% (incl. ASS)
Single blind
75% (incl. ASS)
Single blind
Improvement on diet
No data
No data
24% free of symptoms*
57% improvement*
55% of all patients
71.1% free of symptoms
19.7% improvement
9.2% refused diet
of all patients
44%*
87.5%*
73% of all patients
62.4% improvement
17.3% no improvement
20.3% disrupted diet
of all patients
After positive provocation
7% reacted to histamine, protein and salicylate-rich
residue.34
Many studies have investigated the occurrence of
anti-FcεRI-α-autoantibodies, which have been
described to be of pathophysiological relevance in
some patients with urticaria.35-37 In an own study these
autoantibodies were found in the same frequency as
described earlier. Moreover, they could be found in
both patients with idiopathic chronic urticaria (7 of
22) as well as in patients with pseudoallergy against
food whose symptoms cleared on elimination diet (6
of 17).38 In addition, it has been shown that these
autoantibodies are crosslinking the IgE-receptor when
it is not occupied by the antibody, which is rarely possible under physiological conditions.39, 40 These evidences can be explained supposing that the FcεRI-α autoantibodies are not of pathophysiological relevance
in all patients with urticaria or that a synergism between
274
the autoantibodies and other eliciting stimuli, e.g. food,
is necessary for the appearance of clinical symptoms
in some patients. Further studies in this field are necessary to answer this question.
The anti-IgE receptor autoantibodies and thyroid
autoantibodies appear to be associated with chronic
urticaria,41 although the pathomechanism is not clearly understood.
Chronic urticaria can be associated with several
infections like viral infections by hepatitis A and B, bacterial infections, e.g. of the nasopharynx or Helicobacter pylori of the gastrointestinal tract,42 which need an
appropriate treatment. However, the role of Helicobacter pylori in urticaria is still controversial.43-45 Since
Helicobacter infection is frequent, it is well conceivable that the infection triggers urticaria only in some
Helicobacter positive urticaria patients. A final proof
could only be reached by studies according to Koch’s
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URTICARIA
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postulates which would require a reinfection, which is
not ethical in patients. However, several studies report
that chronic urticaria patients who had gone into remission after elimination of Helicobacter pylori had a
relapse with an reinfection, which again cleared after
eradication.20 The parasites are a rare cause of urticaria
in industrial countries and require an appropriate treatment. In the past, intestinal candidosis has been regarded as a highly important eliciting factor for chronic
urticaria,11 but recent findings fail to support a significant causative role.20 Nevertheless, the treatment of the
massive candidosis is recommended. In general, the frequency and relevance of infectious diseases as cause
for chronic urticaria varies between different patients
groups and in different regions. For example, hepatitis virus infections are a more frequent cause for chronic urticaria in southern Europe but a rare cause in
northern Europe.
Apart from infections, also non-infectious chronic
inflammatory processes have been identified to cause
urticaria in some patients. This group include gastritis, reflux esophagitis, inflammation of the bile duct or
bile gland,20, 46 or rarely autoimmune disorders, e.g. systemic lupus erythematosus, and neoplasia.
Physical urticaria
GENERAL ASPECTS
The distinctive feature of all forms of physical
urticaria is the urticarial reaction to different external
specific physical stimuli (mechanical, cold, heat, light).
The most part of the underlying pathogenesis is unclear,
although it is known that mast cell degranulation is
involved and in some forms, e.g. light urticaria, even
IgE-sensitization has been demonstrated.
Cholinergic urticaria had been classified initially
as physical urticaria,2 but in the last consensus this
disease was grouped under the heading special types
of urticaria, since the eliciting factor is not an external
physical force but an increase of the body core temperature independent of the cause, e.g. also emotional distress.4
The prevalence of the physical urticarias varies with
different studies reported in literature. One reason for
this is the fact that they depend on the strength of the
physical stimulus. Thus, Henz et al.47 have shown that
in normal subjects 44.6% can react with an urticarial
dermographism if a considerably increased pressure is
used for testing. Under daily life-conditions these sub-
Vol. 140 - N. 3
jects are, however, not showing any signs of urticaria.
Similarly, the incidence of cold urticaria is more frequent in countries with colder climate.
DERMOGRAPHIC URTICARIA
Dermographic urticaria (synonym: factitial urticaria)
is defined by whealing induced by shearing forces on
the skin. In the most cases the wheals appear rapidly
and are associated with an intense itching. Dermographic urticaria represent the most frequent form of
physical urticaria, affecting mainly young adults with
a mean duration of 6.5 years.
DELAYED PRESSURE URTICARIA
The typical lesions in this type of urticaria are deep,
painful swellings developing 4-8 h after exposure to a
vertical static pressure, persisting for 8-48 h. Some
body areas are typically involved like palms and soles
as well as buttocks and the back when exposed to pressure, e.g. on a hard chair.
The pressure urticaria is more frequent in males
than females, with an average age of onset of 30 years
and a mean duration of 6-9 years. Pressure urticaria can
develop into a disabling disease in jobs requiring
important physical work.
The main feature of the delayed pressure urticaria is
the threshold of the pressure required to elicit symptoms. Since pressure is defined as force per area, it is
important to advice the patient about simple measures,
as avoiding sharp edges or using gel-filled soles in the
shoes, that can be extremely helpful.
COLD URTICARIA
Cold urticaria is defined as an urticarial reaction on
exposure to cold. Nine different subtypes have been
described, including immediate and late reaction,
localised cold urticaria as well as subtypes with generalised responses also in areas of skin not directly
exposed to cold. In the most cases firm cold bodies
or cold water can elicit cold urticaria, although in some
patients only cold air will provoke symptoms.
Cold urticaria is more frequent in women than in
men, affecting mainly young adults with a mean duration of the disease of 4.2 years.
This form of urticaria is idiopathic in the majority of
patients. However, unlike in other types of physical
urticaria, the disease can also arise due to infections,
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neoplasia, or autoimmune disease. The infectious diseases which can induce cold urticaria include syphilis,
borreliosis, measles, varicella, hepatitis, infectious
mononucleosis, and HIV infections. However, also so
far unrecognised bacterial infections have to be discussed, since in an open study 20-50% of patients with
idiopathic cold urticaria responded to antibiotic treatment.48
HEAT URTICARIA
Heat urticaria is a rare form of physical urticaria
induced by direct contact of the skin with warm objects
or warm air. At this moment, there is no epidemiological data available since its first description by Duke
in 1926,49 only little more than 20 cases have been
described. The eliciting temperature ranges from 38°C
to more than 50°C and affected areas can remain refractory for 24 h or more. This feature can be used for
therapeutic means by hardening the skin through
repeated exposure to heat, which has been used successfully in one of our patients.48
SOLAR URTICARIA
In solar urticaria wheals are elicited by light of wavelengths ranging between 280-760 nm. The eliciting
wavelength varies with the patient, but mostly UVlight is responsible.
As in other urticaria subtypes, women are more frequently affected and the disease usually starts in young
adulthood. Leenutaphong et al.50 have demonstrated
that involvement of serum factors acting as IgE-dependent photoallergens may be involved in the pathogenesis. Areas of the body constantly exposed to sunlight, like face and hands, are frequently not affected,
which led to the development of treatment regimens
with photo-hardening and even a rush protocol is available.51
VIBRATORY ANGIOEDEMA
Vibratory angioedema is a rare condition in which
strong vibrating mechanical forces, like those caused
by work with a pneumatic hammer, induce angioedema. Only a few case reports have been published so far,
so that epidemiological data is not available.52 However, it can be assumed that a higher frequency would
be found in cross-sectional studies, since in this condition it is particularly easy to avoid the stimulus in dai-
276
ly life, if the patients are not exposed to strong vibrating forces during the work.
Special types of urticaria
CHOLINERGIC URTICARIA
In contrast to physical urticaria, in which the elicitation of symptoms is caused by an external stimulus,
the lesions of cholinergic urticaria are due to a rapid
increase of the body core temperature. The most frequent reasons are physical exercise, passive warmth,
e.g. hot bath, and emotional stress, but rarely also
warm or spicy food or alcoholic beverages can induce
a brief rise in body core temperature.
The classic clinical feature are pin-sized wheals surrounded by an erythema, but larger wheals can occur.
Cholinergic urticaria is more frequent in young
adults with a prevalence of 11.2% in the age group of
16-35 years. In the majority of cases symptoms are
mild and 80% of affected persons do not look for medical advice for this condition. However, some patients
are severely affected with symptoms occurring already,
e.g. after a light walk, and systemic symptoms, like
dizziness, nausea and headache, are observed in up to
11% of the patients. The main differential diagnosis
includes exercise-induced anaphylaxis.
ADRENERGIC URTICARIA
Adrenergic urticaria is an extremely rare condition,
characterized by pin-point sized red wheals with a white
halo, in contrast to cholinergic urticaria.53 The clinical
appearance is elicited by stress and not by exercise or an
increase of body core temperature. The remission of
symptoms is obtained by treatment with β-adrenoreceptor-blocker, propanolol, which can be used both for
diagnostic purposes as well as to prevent attacks.
CONTACT URTICARIA
Contact urticaria is defined by the appearance of
wheals at sites where chemical substances have come
into contact with the skin. The disease can be strictly
confined to the areas of contact, like in nettles (urtica
urens or urtica dioica, which gave urticaria its name),
or can be associated with generalised systemic symptoms, especially in IgE-mediated allergic contact
urticaria. The more common eliciting factors include
food, plants, drugs, cosmetics, industrial chemicals, animal product and textiles.
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Edematous swelling of the skin
Deep
Superficial
Fleeting
>24 h
With urticeria
Without urticaria
Biopsy
Vasculitis
No special
angioedema related cause
Urticaria
angioedema
Non vasculitis°
<6 weeks
duration
C-INH abnormal
level/functional
Positive
pressure test
Eliciting drugs,
e.g. ACE
inhibitors
>6 weeks
duration
Questionaire,
test for
dermographism
Urticarial
vasculitis
Acute
urticaria
Physical and
cholinergic
urticaria
Chronic
urticaria
Further tests to exclude
autoimmune diseases
Limited specific
diagnostic measures,
symptomatic therapy
For tests see
Table II
For tests see
Table II
Hereditary
angioedema
Acquired Clesterase deficiency
angioedema
°deep dermal infiltrate
may be due to delayed
pressure urticaria
Delayed pressure
urticaria*
* often associated with
chronic urticaria
Figure 1.—Flow sheet as an aid in the stepwise procedure for the therapy of urticaria.
AQUAGENIC URTICARIA
Aquagenic urticaria is a distinct form which must
be differentiated from contact urticaria because the
water is not itself the causative agent, but properly liberates a water-soluble allergen from the stratum
corneum, which then acts as an allergen after diffusion into the dermis. The disease is 5 times more frequent in females than in males, with an average onset
in young adulthood. The lesions resemble those of
cholinergic urticaria with mostly pin-sized wheals
in the trunk.
Diseases grouped under the heading urticaria for historical reasons
This group of diseases is heterogeneous and includes,
among others, urticaria vasculitis syndrome, hereditary
Vol. 140 - N. 3
angioedema, and urticaria pigmentosa. Although in
these diseases wheals or angioedema may occur, they
clearly have to be distinguished due to the differences
in their pathogenesis. These disease cannot be extensively discussed within this review.
Diagnosis of urticaria
Due to the heterogeneity of the disease with its many
subtypes, guidelines for diagnosis can only cover a
routine programme (Figure 1). In fact, all guidelines do
not suggest intense or expensive general screening
programmes for urticaria. Standardized diagnostic
tests for a number of urticaria subtypes are shortly
described in Table IV.4 Further tests may be specifically
required but should be reserved for selected patients.
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TABLE IV.—Suggested standard routine diagnostic programme. This
table gives a selection of frequent urticaria subtypes to be considered
in diagnosis or differential diagnosis. Additional measures may
have to be considered depending on patient history. Modified according to Zuberbier et al.4
Routine diagnostic tests
a. Acute urticaria
b. Chronic urticaria
No routine diagnostic tests
(unless strongly suggested by patient
history)
Differential blood count, ESR (as indication of severe systemic disease)
Omission of suspected drugs, e.g. NSAID
possibly:
autologous serum skin test;
test for helicobacter, gastroscopy, ANA,
stool for worm eggs/parasites, skin tests,
specific IgE, thyroid hormones and
autoantibodies
pseudoallergen-free diet for 3 weeks
c. Physical urticaria
1. Dermographic urticaria
Elicit dermographism
differential blood count and ESR
(as indication of severe systemic disease)
2. Delayed pressure urticaria Pressure test (0.2-0.4 kg/cm2 for 10 and
20 min)
3. Cold urticaria
Cold provocaton test (ice cube, cold
water) use of different temperature to
identified threshold possibly: exposure to
cold wind (ventilator) differential blood
count, ESR, cryoglobulins
4. Heat contact urticaria
Warm arm bath (42°C; vary temperature
to detect thereshold)
5. Solar urticaria
UV and visibile light of differential
wave lengths
d. Special types of urticaria Exercise or hot bath according to patient
cholinergic urticaria
history
e. Other diseases
Biopsy, differential blood count, ESR,
urticarial vasculitis
ANA, biochemistry urine test
Management
Although the different forms of urticaria are elicited by numerous factors, its treatment essentially follows some basic principles. These are:
— avoidance or elimination of the eliciting stimulus;
— inhibition of mast cell mediator release;
— therapy of target tissues of mast cell mediators.
Avoidance of eliciting stimuli
With this therapeutic approach, an accurate diagnosis is the basic prerequisite.
Drugs
Drugs suspected should be omitted entirely or substituted by another class of molecules. In particular,
drugs causing pseudoallergic reactions (prototype
being aspirin) can both elicit urticaria as well as aggravate pre-existing chronic urticaria.54
PHYSICAL STIMULI
Detailed information about the physical properties
of the respective stimulus helps to control exposure
in daily life. Thus, it is important in dermographic
urticaria as well as in delayed pressure urticaria to
point out that pressure is defined as force per area and
that the use of some practical advices like broadening of the handle of heavy bags may already be sufficient.
REMOVAL OF INFECTIOUS AGENTS AND TREATMENT OF
INFLAMMATORY PROCESSES
At present, the only generally available test to screen
for autoantibodies against the IgE receptor is the autologous serum skin test. This needs to be performed
with utmost care since infections could be transmitted,
particularly if by mistake patients are not injected with
their own serum.
Furthermore, for the diagnosis of urticaria it’s important to consider that in one patient different subtypes
of urticaria can coexist, e.g. chronic urticaria and dermographic urticaria. It may thus happen that diagnosis reveals the causing factor for one of the subtypes
only, which then goes into remission after the appropriate treatment, while the other subtype remains
unchanged.
278
In physical urticaria infections represent the causative
agent only in a few cases with cold and dermographic urticaria, in contrast chronic urticaria appears to be
more often associated with a variety of inflammatory
or infectious processes.
REMOVAL OF FCεRI AUTOANTIBODIES
At this moment, there is modest experience in the treatment of chronic urticaria by removal of autoantibodies.
Temporary benefit in individual, severely affected patients
have been obtained with plasmapheresis.55, 56 Alternatively, immunological treatment with agents inhibiting
antibody formation like cyclosporin 57-60 or high dose
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TABLE V.—Treatment in urticaria. Modified according Zuberbier et al.5.
Standard treatment
(#efficacy proven by double-blind placebo controlled studies)
Alternative treatment
a. Acute urticaria
b. Chronic urticaria
Non-sedating H1-antihistamines 15
Non-sedating H1-antihistamines 0 73-79-increase dosage if necessary
Initially prednisolone, 50 mg/d for 3 days 14
Combination: dapsone (50-150 mg/d) and pentoxifyllin
(2x600mg/d) 80
Combination: H1 and H2-blocker 80
Combination: H1-blocker and β-sympathomimetics or
nifedipin 81,82
Doxepin 81
Danazol (initially 400-600 mg/d) 83
Leukotriene antagonists (e.g. montelukast 10 mg/d) 84, 85
Sulfazalazine (3x500-600 mg/d) 86
Corticosteroids 80
Cyclosporin A (4 mg/kg) 57
Interferon 87
PUVA 65
Plasmapheresis 55
Immunoglobulins 61
Cumarin (Quick, ca. 40-50%) 88
c. Physical urticaria
1. Dermographic urticaria
Always consider avoidance of stimuli
Non sedating H1-antihistamines 89 – increase dosage
if necessary
Type of urticaria
2. Delayed pressure urticaria
3. Cold contact urticaria
High dose non sedating H1-antihistamines 70
Non sedating H1-antihistamines 91
Short term corticosteroids leukotriene antagonists 90
Trial over 3 weeks with penicillin, 3x1.2 Mil IU/d parenterally, or doxycycline 2x100 mg/d p.o.48 Induction of
physical tolerance (cold bath),92 leukotriene antagonists
93
Non sedating H1-antihistamin
4. Solar urticaria
d. Special types of urticaria
1. Cholinergic urticaria
Induction of physical tolerance (hardening with UV
light) 51
Non sedating H1-antihistamines 71-increase dosage if
necessary
immunoglobulin infusions 61 have been proven to be
helpful.
DIETARY MANAGEMENT
IgE-mediated food allergy is rare in urticaria.19, 20 In
a subgroup of chronic urticaria patients pseudoallergic reactions to naturally occurring food ingredients and in some cases to food additives are
described.19-21, 62 In these cases a diet with low levels of natural as well as artificial food pseudoallergens maintained for a period of at least 3-6 months
permit to attain a spontaneous remission in approximately 50% of patients. It should be underlined that
avoidance of type I – allergens clears urticaria symptoms within 24-48 h if relevant allergens are rapidly eliminated, whereas in pseudoallergy a diet has
often to be maintained for 2-3 weeks before beneficial effects can be observed. Usually diet is not helpful in other subtypes of urticaria than chronic continuous urticaria.
Vol. 140 - N. 3
Danazol (initially 400-600 mg) 5
MAST CELL DIRECTED THERAPY
Corticosteroids are very efficient drugs in the treatment of urticaria. Although, use of high dosages should
be avoided for long-term treatment because their obligatory side effects. Cyclosporin A also has a moderate, direct effect on mast cell mediator release,63 but due
to high costs is reserved as alternative treatment.
PUVA reduces the numbers of mast cells and has
been successfully used in mastocytosis.64, 65 UV-A and
UV-B has also been studied as additive treatment in
urticaria.66, 67
Therapy at the target organ
The urticaria symptoms are mainly mediated by
H1-receptors. The development of second generation
non-sedating or low-sedating antihistamines has largely improved the quality of life of urticaria patients. In
addition, new generation antihistamines should be preferred, since they also exert anti-inflammatory effects
such as inhibition of cytokine release from basophils
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and mast cells.68, 69 The effect of antihistamines in
urticaria is dose-dependent 70, 71 and higher dosages are
usually well tolerated. However, it must be remembered that side-effects like sedation can occur more
frequently at higher dosages. Apart from terfenadine
and astemizole, which should no longer be used for the
danger of cardiac side-effects, second generation antihistamines, have an excellent safety profile and must
be considered as first choice for the symptomatic treatment of urticaria. Increasing the dosage is advised
since this has less side-effects than alternative treatment.5, 72
Further therapeutic possibilities
Use of alternative treatments should be reserved for
patients unresponsive to higher dosages of antihistamines. Since the side-effects of many of these substances are considerable, it may be wise to try to use
them as add-on therapy to antihistamines first, or to use
combinations to be able to have lower dosages of the
alternative medication. Many of the alternatives are
based on open trials or case reports.
Table V 5,14,15,48,51,55,57,61,65,70,71,73-94 summarizes the
current standard drug treatment and alternatives suggested for several subtypes of urticaria. Since the severity of urticaria may change, and the spontaneous remission may occur at any time, it is recommended that
the necessity for continued or alternative drug treatment
should be reevaluated every 3-6 months.
Conclusions
Since urticaria severely reduces the quality of life,
the management should be prompt and requires a close
cooperation with the patient. An individual approach
is necessary due to the complexity of the disease. Management is based on the avoidance of triggering factors,
treatment of associated diseases and symptomatic
pharmacological treatment. Symptomatic relief can
be achieved in the majority of patients by new generation antihistamines, which have a very low adverse
effect profile and should be used at higher dosages in
non-responding patients. Alternative treatment should
be considered for unresponsive patients only.
Ackowledgements.—The authors would like to thank Mrs. Wallner for helping preparing the manuscript and K. Peris, MD (Department of Dermatology, University of L’Aquila, Italy) for his critical
revision of the manuscript.
280
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state treatment in the skin of healthy volunteers. Fundam Clin Pharmacol 2000;14:409-13.
75. Monroe EW, Bernstein DI, Fox RW, Grabiec SV, Honsinger RW,
Kalivas JT et al. Relative efficacy and safety of loratadine, hydroxyzine,
and placebo in chronic idiopathic urticaria. Arzneimittelforschung
1992;42:1119-21.
76. Nelson HS, Reynolds R, Mason J. Fexofenadine HCl is safe and
effective for treatment of chronic idiopathic urticaria. Ann Allergy
Asthma Immunol 2000;84:517-22.
77. Ring J, Hein R, Gauger A, Bronsky E, Miller B. Once-daily desloratadine improves the signs and symptoms of chronic idiopathic
urticaria: a randomized, double-blind, placebo-controlled study. Int J
Dermatol 2001;40:72-6.
78. Zuberbier T, Henz BM. Use of cetirizine in dermatologic disorders.
Ann Allergy Asthma Immunol 1999;83:476-80.
79. Parsad D, Panhi R, Juneja A. Stanozolol in chronic urticaria: a double blind placebo controlled trial. J Dermatol 2001;28:299-302.
80. Henz BM, Zuberbier T, Monroe E. Urticaria therapy. In: Henz BM,
Zuberbier T, Grabbe J, Monroe E editors. Urticaria. Clinical, diagnostic
and therapeutic aspects. Berlin: Springer; 1998. p. 161-81.
81. Soter NA. Urticaria: current therapy. J Allergy Clin Immunol 1990;86:
1009-14.
82. Bressler RB, Sowell K, Huston DP. Therapy of chronic idiopathic
urticaria with nifedipine: demonstration of beneficial effect in a double-blinded, placebo-controlled, crossover trial. J Allergy Clin Immunol
1989;83:756-63.
83. Brestel EP. Danazol in chronic urticaria. J Allergy Clin Immunol
1990;85:1112.
84. Ellis MH. Successful treatment of chronic urticaria with leukotriene
antagonists. J Allergy Clin Immunol 1989;102:876-7.
85. Pacor ML, Di Lorenzo G, Corrocher R. Efficacy of leukotriene receptor antagonist in chronic urticaria. A double-blind, placebo-controlled
comparison of treatment with montelukast and cetirizine in patients
with chronic urticaria with intolerance to food additive and/or acetylsalicylic acid. Clin Exp Allergy 2001;31:1607-14.
86. Hartmann K, Hani N, Hinrichs R, Hunzelmann N, ScharfetterKochanek K. Successful sulfasalazine treatment of severe chronic
idiopathic urticaria associated with pressure urticaria. Acta Derm
Venereol 2001;81:71.
87. Czarnetzki BM, Algermissen B, Jeep S, Haas N, Nürnberg W, Müller
K et al. Interferon treatment of patients with chronic urticaria and
mastocytosis. J Am Acad Dermatol 1994;30:500-1.
88. Parslew R, Pryce D, Ashworth J, Friedmann PS. Warfarin treatment
of chronic idiopathic urticaria and angio-oedema. Clin Exp Allergy
2000;30:1161-5.
89. Sharpe GR, Shuster S. The effect of cetirizine on symptoms and
whealing in dermographic urticaria. Br J Dermatol 1993;129:580-3.
90. Berkun Y, Shalit M. Successful treatment of delayed pressure urticaria
with montekulast. Allergy 2000;55:203-4.
91. Neittaanmaki H, Fraki JE, Gibson JR. Comparison of the new antihistamine acrivastine (BW 825C) versus cyproheptadine in the treatment of chronic idiopathic urticaria. Dermatologica 1988;177:
98-103.
92. Claudy A. Cold urticaria. J Invest Dermatol Symp Proc 2001;6:
141-2.
93. Hani N, Hartmann K, Casper C, Peters T, Schneider LA, Hunzelmann N et al. Improvement of cold urticaria by treatment with the
leukotriene receptor antagonist montelukast. Acta Derm Venereol
2000; 80:229.
94. Bilsland D, Ferguson J. A comparison of cetirizine and terfenadine in
the management of solar urticaria. Photodermatol Photoimmunol
Photomed 1991;8:62-4.
Orticaria
N
el corso degli ultimi decenni, la migliore comprensione dei meccanismi molecolari coinvolti nella patogenesi
dell’orticaria ha permesso di distinguere numerose varianti
cliniche. Sulla base di tali nuove acquisizioni si comprende
come l’approccio terapeutico individuale assuma una notevole importanza. Inoltre è stato dimostrato che l’orticaria
compromette severamente la qualità di vita del paziente.
Uno studio condotto da Poon et al.1 su 170 pazienti ricoverati presso una clinica specialistica per l’orticaria, ha evidenziato che i soggetti affetti da orticaria da pressione e da
orticaria colinergica presentavano un’elevata compromissione della qualità di vita, paragonabile a quella di pazienti
affetti da dermatite atopica e superiore a quella di pazienti con
orticaria cronica, la quale era simile a quella di pazienti affetti da psoriasi e acne.
Per la stesura di questa review sono stati valutati gli studi
pubblicati sino al 2003, inclusi i suggerimenti dell’articolo di
posizione dell’European Academy of Allergology and Clinical Immunology (EAACI) riguardo l’orticaria fisica 2, le linee
guida sull’orticaria della British Association of Dermatolo-
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gists 3 e le più recenti pubblicazioni del Consensus del Clinically Oriented ESDR Symposium: “Urticaria 2000”. Nel corso di quest’ultimo, un centinaio di specialisti provenienti da
oltre 15 nazioni hanno raggiunto un accordo sulla definizione, sulla classificazione, sugli esami diagnostici di routine e sulla terapia dell’orticaria. Le indicazioni basate sull’evidenza clinica sono state preparate precedentemente da un gruppo di
esperti e discusse con un sistema di votazione 4, 5.
L’interpretazione dei dati divergenti relativi alle cause dei
diversi sottotipi di orticaria e alla loro diversa risposta terapeutica è spesso complicata dalla considerevole eterogeneità delle popolazioni in studio.
Aspetti clinico-patologici
L’orticaria è caratterizzata clinicamente dall’improvvisa
insorgenza di pomfi, talvolta accompagnati da angioedema.
I pomfi si manifestano con un edema centrale di dimensioni variabili, quasi sempre circondato da eritema da riflesso.
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Il prurito o, talvolta, una sensazione di bruciore rappresentano sintomi di costante riscontro nell’orticaria. Il pomfo ha
una tipica evoluzione fugace, con durata variabile da 1 a 24
h. L’angioedema si definisce come un improvviso e pronunciato edema del derma profondo e del tessuto sottocutaneo con frequente coinvolgimento delle membrane mucose,
accompagnato da sensazioni di prurito o, più frequentemente, di dolore. La risoluzione dell’angioedema è più lenta rispetto al pomfo, potendo richiedere sino a 72 h.
Le caratteristiche istopatologiche del pomfo sono rappresentate dall’edema, con aumentata espressione delle molecole di adesione endoteliale e da un infiltrato infiammatorio
perivascolare di intensità variabile, costituito da neutrofili e/o
eosinofili, macrofagi e linfociti T-helper 6. Nell’orticaria da
pressione tale infiltrato si localizza caratteristicamente nel derma medio e profondo 7. Nelle aree di cute non coinvolta,
sono state inoltre frequentemente descritte alterazioni delle
molecole di adesione 8 e dell’espressione delle citochine 9.
L’insieme di tali recenti evidenze sottolinea la complessità
e l’eterogeneità di questa patologia.
Classificazione
Lo spettro delle manifestazioni cliniche dei differenti sottotipi
di orticaria è molto vasto. Inoltre, in uno stesso paziente, possono coesistere 2 o più varianti cliniche. La Tabella I 4 riporta
una classificazione a impiego clinico. In tale classificazione,
le orticarie fisiche vengono raggruppate separatamente in
quanto dipendono dalla presenza di specifici fattori fisici
scatenanti, a differenza delle altre forme, in cui le manifestazioni cliniche insorgono spontaneamente in assenza di
stimoli fisici esterni.
Nei seguenti paragrafi verranno descritte le principali
caratteristiche delle diverse forme di orticaria.
Orticaria spontanea
ORTICARIA ACUTA
La prevalenza dell’orticaria acuta, valutata mediante questionari, varia dal 12% al 15% 10, 11 fino al 23,5% 12. In un
nostro studio prospettico, condotto in un’area rurale del
Brandeburgo, abbiamo riportato un’incidenza annuale di
0,154%, pari a una prevalenza del 12,32%, calcolata su un’aspettativa di vita di 80 anni 13, 14. Tuttavia, non è stato possibile valutare il numero di pazienti che non ricorrono al
medico in quanto presumibilmente affetti da lieve sintomatologia. Questa eventualità è altamente probabile in un’area rurale e per una patologia che, nella maggioranza dei
casi, si risolve spontaneamente. Pertanto, nell’area geografica da noi esaminata, la prevalenza reale potrebbe raggiungere valori più elevati.
La prevalenza dell’orticaria acuta è più elevata in soggetti atopici. Nello studio sopra citato 14, la febbre da fieno, l’asma bronchiale allergico e la dermatite atopica sono stati diagnosticati nel 50,2% dei pazienti affetti da orticaria acuta.
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Inoltre, lo studio prospettico condotto da Simons 15 su oltre
800 bambini di età compresa tra i 12 e i 24 mesi, affetti da dermatite atopica, ha evidenziato, in un periodo di oltre 18 mesi,
un’associazione con l’orticaria acuta nel 16,2% dei pazienti
appartenenti al gruppo di studio non trattato con anti-istaminici (n=396). Inoltre, per quanto riguarda l’eziologia, tale
studio ha mostrato che, sebbene il 63% dei pazienti attribuisca al cibo la causa dell’orticaria, solo in 1 su 109 pazienti,
dopo appropriate indagini, gli alimenti sono risultati essere il
fattore causale. Ciò dimostra in che misura la raccolta dei dati
anamnestici, specialmente in casi di orticaria acuta, possa
essere fuorviante 14. Tuttavia, gli alimenti hanno un’importanza
fondamentale nei bambini, come dimostrato da Legrain et
al.16, i quali hanno evidenziato in 10 su 12 casi, come alcuni
cibi e, in particolare, il latte vaccino, siano determinanti nell’induzione dell’orticaria acuta. Kauppinen et al.17 hanno
riportato una prevalenza del 15% di intolleranze alimentari,
quale fattore determinante l’orticaria acuta in bambini di età
compresa tra 6 mesi e 6 anni. Al contrario, lo studio epidemiologico condotto da Aoki et al.18 su 50 adulti non ha rilevato alcun caso di allergia alimentare.
Le cause più frequenti di orticaria acuta, tuttavia, sembrano essere rappresentate dalle infezioni virali, in particolare a carico delle alte vie respiratorie, usualmente presenti
qualche giorno prima dell’insorgenza delle manifestazioni cliniche dell’orticaria (Tabella II) 14-18.
Infine, i farmaci possono indurre orticaria acuta, agendo
in qualità sia di allergeni che di pseudoallergeni. La penicillina
rappresenta la causa più frequente di orticaria IgE-mediata
indotta da farmaci, al contrario dell’acido acetil-salicilico
che viene considerato il più comune esempio di pseudoallergene.
ORTICARIA CRONICA
A causa dell’assenza di studi rappresentativi, non sono
attualmente disponibili dati affidabili relativi alla prevalenza dell’orticaria cronica.
Analogamente all’orticaria acuta, le reazioni allergiche
di tipo I sono solo raramente responsabili dello sviluppo
dell’orticaria cronica 19, 20. In alcuni gruppi di pazienti affetti da orticaria cronica, le reazioni pseudoallergiche nei confronti di alimenti e additivi alimentari sono state considerate in passato separatamente rispetto a quelle a eziologia infettiva o autoimmune. Uno schema degli studi sulle pseudoallergie è riassunto in Tabella III 19-33; tuttavia, solo alcuni di
essi hanno utilizzato test di provocazione alimentare controllati versus placebo che rappresentano il gold standard. Le
variazioni dei risultati sono dovute alle differenze tra popolazioni di studio e condizioni di studio. Infatti, in alcune nazioni, la visita specialistica viene effettuata solo in caso di sintomatologia severa, e alcuni studi hanno incluso non solo pazienti affetti da orticaria cronica ma anche pazienti con orticaria fisica. In altri casi, le diete di esclusione sono state condotte solo
per brevi periodi di tempo. I nostri risultati 20 dimostrano che,
nei pazienti che migliorano eseguendo una dieta a basso
contenuto di pseudoallergeni, il 30% raggiunge la riduzione
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della sintomatologia dopo almeno 10-14 giorni di dieta. Lo
studio ha incluso pazienti non selezionati con orticaria cronica continua, non sottoposti precedentemente ad alcuna
indagine diagnostica. Circa il 50% dei pazienti responsivi non
ha raggiunto la completa remissione della sintomatologia,
suggerendo che altri possibili cofattori siano coinvolti nella
patogenesi. In questo gruppo è stata riscontrata un’alta incidenza di reazioni pseudoallergiche verso gli alimenti. Tali
risultati sono stati confermati da Pigatto et al.33 i quali hanno esaminato 202 pazienti affetti da orticaria cronica, utilizzando la stessa dieta. In questo studio, 126 pazienti hanno riportato un miglioramento della sintomatologia dopo
dieta di esclusione, 35 pazienti non hanno ottenuto alcun
beneficio e 41 pazienti sono usciti dallo studio. In entrambi
gli studi le reazioni agli additivi alimentari erano state rilevate solo in una bassa percentuale di pazienti (19% e 37%,
rispettivamente), prospettando l’importanza di pseudoallergeni presenti in natura. A tale proposito, soprattutto alcuni
composti aromatici isolati in vegetali e alimenti sembrano
essere rilevanti. Un test di provocazione aperto su 31 pazienti affetti da orticaria cronica ha dimostrato che il 71% dei
pazienti responsivi alla dieta povera in pseudoallergeni reagiva ai pomodori e il 44% ai distillati di pomodoro contenenti
composti aromatici privi di proteine e acido salicilico. Al
contrario, meno del 7% reagiva all’istamina, proteine e residui ricchi di salicilati 34.
Diversi studi hanno analizzato il ruolo degli anticorpi antiFcεRI-α, che sembrano avere un ruolo determinante nella
patogenesi di una percentuale elevata di pazienti con orticaria 35-37. In un nostro studio, tali autoanticorpi sono stati evidenziati con valori di frequenza analoghi a quelli precedentemente riportati da altri Autori. Tuttavia, essi sono stati rilevati sia in pazienti con orticaria cronica idiopatica (7 su 22)
che in pazienti con pseudoallergia agli alimenti (6 su 17), i
cui sintomi miglioravano con la dieta di eliminazione 38. È
stato, inoltre, dimostrato che tali autoanticorpi cross-reagiscono con il recettore delle IgE, quando non è occupato dall’anticorpo, evento che può verificarsi raramente in particolari condizioni fisiologiche 39, 40. Tali evidenze possono essere spiegate ipotizzando che gli autoanticorpi anti-FcεRI-α non
abbiano importanza fisiopatologica in tutti i pazienti con
orticaria, oppure che sia necessario un sinergismo tra autoanticorpi e altri fattori causali, quali, ad esempio, gli alimenti,
affinché si abbia la comparsa dei sintomi clinici in alcuni
pazienti. Ulteriori studi in tale ambito sono necessari per
chiarire quale sia il reale meccanismo coinvolto.
Oltre agli autoanticorpi anti-recettore delle IgE, anche gli
autoanticorpi tiroidei possono essere associati all’orticaria cronica 41, sebbene il meccanismo patogenetico responsabile non
sia stato ancora identificato.
L’orticaria cronica può, in alcuni casi, associarsi a processi infettivi come infezioni virali da virus dell’epatite A e
B, infezioni batteriche del nasofaringe o infezioni del tratto
gastrointestinale da Helicobacter pylori 42, per le quali si
rende necessario un trattamento adeguato. Il ruolo dell’Helicobacter pylori nell’orticaria è, tuttavia, ancora controverso 43-45. Dal momento che l’infezione da Helicobacter è
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piuttosto frequente, è plausibile che essa inneschi l’orticaria
solo in quei pazienti positivi per Helicobacter pylori. L’accertamento della supposta correlazione tra i 2 eventi potrebbe essere ottenuto mediante studi che, in accordo con i postulati di Koch, richiederebbero un processo di reinfezione, che
deve essere escluso in quanto non eticamente corretto nei
confronti del paziente. Tuttavia, alcuni studi hanno descritto pazienti affetti da orticaria cronica che hanno ottenuto
una remissione clinica dopo l’eliminazione di Helicobacter
pylori, e recidiva dopo reinfezione, seguita da nuova risoluzione dopo eradicazione 20.
Le infestazioni da parassiti costituiscono rare cause di
orticaria nelle aree industriali e, pertanto, necessitano di specifiche misure terapeutiche. In passato, la candidosi intestinale è stata considerata un importante fattore determinante
l’orticaria cronica 11, anche se evidenze recenti non ne hanno confermato il presunto ruolo causale 20. In generale, la frequenza e l’importanza delle patologie infettive nel determinare l’orticaria cronica subiscono variazioni nell’ambito di
diversi gruppi di pazienti e diverse regioni. Ad esempio, le
epatiti rappresentano una causa più frequente di orticaria
cronica nel Sud Europa rispetto al Nord Europa.
Oltre alle patologie infettive, alcuni processi infiammatori
cronici non infettivi sono stati considerati probabili fattori causali in alcuni casi di orticaria. In tale ambito, sono stati
descritti più frequentemente gastriti, reflusso gastroesofageo, infiammazioni delle vie biliari o della colecisti 20, 46 o,
più raramente, disordini autoimmuni quali lupus eritematoso sistemico o neoplasie.
Orticaria fisica
ASPETTI GENERALI
L’elemento distintivo di tutte le forme di orticaria fisica è
costituito da una reazione orticarioide a differenti stimoli
fisici esterni (meccanico, freddo, caldo, luce). La gran parte dei meccanismi patogenetici non è sufficientemente nota
anche se si ritiene che sia coinvolta la degranulazione mastocitaria e che, in alcune forme, come l’orticaria fotoindotta,
sia stata anche dimostrata una sensibilizzazione di tipo IgE.
Nelle prime linee guida proposte, l’orticaria colinergica
veniva considerata un tipo di orticaria fisica 2. Tuttavia, nell’ultimo Consensus questa patologia è stata classificata tra i
tipi speciali di orticaria, in quanto il fattore causale non è
un’energia fisica esterna ma un aumento della temperatura
corporea indipendente dalla causa, come, ad esempio, uno
stress emotivo 4.
La prevalenza delle orticarie fisiche varia nei diversi studi riportati in letteratura, in relazione alla potenza dello stimolo fisico. A tale proposito, Henz et al.47 hanno evidenziato
che il 44,6% dei soggetti sani, che nelle usuali attività quotidiane non presenta alcun segno di orticaria, reagisce con un
dermografismo orticarioide qualora la pressione utilizzata per
il test venga progressivamente aumentata. Le stesse considerazioni valgono per l’orticaria da freddo, la cui incidenza
è maggiore nei Paesi a clima rigido.
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ORTICARIA DERMOGRAFICA
L’orticaria dermografica o orticaria factitia è definita dall’insorgenza di pomfi indotti da sfregamento o frizione sulla cute. Nella maggioranza dei casi, i pomfi insorgono rapidamente e si associano a un’intensa sintomatologia pruriginosa. L’orticaria dermografica costituisce la variante più frequente di orticaria fisica e interessa principalmente giovani
adulti, con una durata media di 6,5 anni.
ORTICARIA DA PRESSIONE
Al contrario dell’orticaria dermografica, le lesioni patognomoniche di questa forma di orticaria consistono in un
edema profondo e doloroso, che insorge in zone sottoposte
a una forte pressione statica verticale, persistente per 8-48 h,
4-8 h dopo l’esposizione allo stimolo. Alcune aree risultano
tipicamente interessate, come le regioni palmari e plantari,
i glutei e il dorso quando sottoposti a pressione, come spesso si verifica dopo prolungata permanenza in posizione seduta.
L’orticaria da pressione interessa prevalentemente soggetti di sesso maschile. L’età media all’esordio è di 30 anni
e la durata media di malattia è di 6-9 anni. Tale patologia può
risultare particolarmente invalidante nel caso di individui
che svolgono attività professionali che richiedono un considerevole impegno fisico.
Una peculiare caratteristica dell’orticaria da pressione è la
soglia di pressione richiesta per determinare l’insorgenza
dei sintomi. Poichè la pressione si definisce come una forza
per unità di area, è importante informare il paziente a riguardo e relativamente all’adozione di semplici accorgimenti
che possono risultare estremamente utili, come, ad esempio, evitare l’appoggio su estremità acuminate o utilizzare
suole riempite di gel nelle scarpe.
ORTICARIA DA FREDDO
L’orticaria da freddo si definisce come una reazione orticarioide all’esposizione al freddo. Sono stati descritti 9 distinti sottotipi, incluse reazioni immediate e ritardate, orticaria
da freddo localizzata e sottotipi con risposte generalizzate
anche in aree di cute non direttamente esposte al freddo.
Nella maggioranza dei casi l’orticaria viene scatenata dal
contatto con corpi solidi freddi o acqua fredda, tuttavia, in
alcuni pazienti, solamente dell’aria fredda può determinare
la comparsa di orticaria.
L’orticaria da freddo è più frequente nelle donne che negli
uomini e interessa preferenzialmente giovani adulti, con una
durata media di malattia di 4,2 anni.
Nella grande maggioranza dei casi, l’orticaria da freddo
è idiopatica, tuttavia, al contrario delle altre forme di orticaria
fisica, può essere causata da infezioni, neoplasie o malattie
autoimmuni. Le patologie infettive che possono indurre
un’orticaria da freddo includono: sifilide, borelliosi, morbillo, varicella, epatiti, mononucleosi infettiva e infezione da
HIV. Sulla base delle evidenze riportate da uno studio aper-
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to in cui il 20-50% dei pazienti con orticaria da freddo idiopatica rispondeva a terapia antibiotica, è stato ipotizzato un
ruolo eziologico per alcuni agenti infettivi batterici non ancora identificati 48.
ORTICARIA DA CALDO
L’orticaria da caldo è una rara forma di orticaria fisica
indotta dal contatto diretto della cute con oggetti caldi o aria
calda. Attualmente non sono disponibili dati epidemiologici relativi a tale varietà clinica di orticaria, poiché dalla prima descrizione del 1926 49 solo poco più di 20 casi sono
stati riportati in letteratura. La temperatura di induzione varia
dai 38°C a più di 50°C e le aree colpite hanno la caratteristica
di rimanere refrattarie allo stimolo per oltre 24 h. Questa
proprietà può essere utilizzata a scopo terapeutico al fine di
desensibilizzare la cute per mezzo di ripetute esposizioni al
calore, come abbiamo osservato con successo in uno dei
nostri pazienti 48.
ORTICARIA SOLARE
Nell’orticaria solare, i pomfi sono provocati da radiazione ultravioletta di lunghezza d’onda compresa tra i 280 e i 760
nm (UVB/UVA, luce visibile). La specifica lunghezza d’onda determinante può subire variazioni interindividuali anche
se la gran parte delle radiazioni ultraviolette è in grado di scatenare l’insorgenza dei sintomi.
Analogamente ad altri sottotipi di orticaria, le donne sono
più frequentemente affette e la patologia esordisce comunemente nell’età giovane-adulta. Leenutaphong et al.50 hanno dimostrato che alcuni fattori sierici attivi, quali fotoallergeni IgE-dipendenti, potrebbero essere coinvolti nella
patogenesi. Aree corporee cronicamente fotoesposte, come
volto e mani, spesso risultano risparmiate. Tale evidenza ha
portato allo sviluppo di regimi terapeutici di tolleranza per
i quali è anche disponibile un protocollo di attacco 51.
ANGIOEDEMA VIBRATORIO
L’angioedema vibratorio è una rara condizione in cui forti forze meccaniche vibranti, come, ad esempio, quelle generate da un martello pneumatico, inducono angioedema. Fino
ad oggi sono stati riportati solo alcuni casi, pertanto non
sono disponibili dati epidemiologici 52. Tuttavia, si ritiene che
una più elevata frequenza potrebbe essere rilevata da studi rappresentativi poiché, in questa condizione, è particolarmente semplice l’allontanamento dello stimolo scatenante, qualora i soggetti non risultino esposti a forti forze vibranti
durante il lavoro.
Tipi speciali di orticaria
ORTICARIA COLINERGICA
Al contrario dell’orticaria fisica, la cui sintomatologia
risulta indotta da stimoli esterni, le lesioni dell’orticaria coli-
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nergica sono dovute a un transitorio aumento della temperatura corporea interna. Le cause più frequenti sono rappresentate dall’esercizio fisico, dal riscaldamento passivo come
in seguito a un bagno caldo e a stress emotivo, mentre alimenti
caldi o piccanti e bevande alcoliche possono indurre solo
raramente un innalzamento della temperatura corporea.
Le tipiche manifestazioni cliniche sono rappresentate da
pomfi puntiformi circondati da eritema, anche se vi sono
evidenze di pomfi di maggiori dimensioni.
L’orticaria colinergica è più frequente nell’età giovaneadulta con una prevalenza dell’11,2% nel gruppo di età compresa tra i 16 e i 35 anni. Nella maggioranza dei casi, la sintomatologia è modesta e pertanto l’80% degli individui affetti non ricorre all’ausilio medico. Più raramente, sono stati
riportati casi di sintomatologia severa a esordio improvviso,
come, ad esempio, dopo una breve passeggiata, e nell’11%
dei pazienti sono stati descritti sintomi sistemici quali vertigini, nausea e cefalea.
L’anafilassi indotta dall’esercizio fisico deve essere considerata quale principale diagnosi differenziale.
ORTICARIA ADRENERGICA
L’orticaria adrenergica è una condizione estremamente
rara, caratterizzata da pomfi puntiformi di colore rosso con
alone bianco, al contrario dell’orticaria colinergica 53. La
manifestazione clinica risulta indotta dallo stress emotivo
ma non dall’esercizio fisico o dall’aumento della temperatura corporea. La sintomatologia regredisce con l’impiego di
β-bloccanti come il propanololo, i quali possono essere utilizzati sia a scopo diagnostico che per prevenire le manifestazioni cliniche.
ORTICARIA DA CONTATTO
L’orticaria da contatto è definita dall’insorgenza di pomfi in corrispondenza del punto di contatto di sostanze chimiche
con la cute. La patologia può essere confinata alle aree esposte come in seguito al contatto con l’ortica (dal latino: urtica urens o urtica dioica da cui l’orticaria ha preso il suo
nome), o associarsi a una sintomatologia sistemica, come
si verifica nell’orticaria allergica da contatto IgE-mediata.
I fattori causali più frequentemente riportati includono: alimenti, piante, farmaci, cosmetici, prodotti chimici industriali, prodotti animali e tessili.
ORTICARIA ACQUAGENICA
L’orticaria acquagenica rappresenta un’entità clinica distinta la quale deve essere differenziata dall’orticaria da contatto in quanto l’acqua non rappresenta essa stessa l’agente
causale, ma più probabilmente agisce solubilizzando un
allergene idrosolubile dallo strato corneo, che successivamente è in grado di diffondere nel derma in presenza di
acqua.
La patologia è 5 volte più frequente nel sesso femminile,
con un’età media di esordio nell’età giovane-adulta. La mani-
286
festazione clinica, analoga a quella dell’orticaria colinergica, è caratterizzata da pomfi puntiformi elettivamente localizzati a livello del tronco.
Patologie incluse nel gruppo delle orticarie per ragioni storiche
Questo gruppo di patologie è eterogeneo e include, tra le
altre, la sindrome orticaria vasculite, l’angioedema ereditario e l’orticaria pigmentosa. Nonostante in queste patologie
possano manifestarsi pomfi o angioedema, esse devono essere nettamente distinte dall’orticaria, data la patogenesi distinta. Tuttavia, tali patologie non verranno analizzate approfonditamente nell’ambito di questa review.
La diagnosi di orticaria
A causa dell’eterogeneità di questa patologia e delle numerose varianti cliniche, è possibile suggerire linee guida per la
diagnosi limitatamente a un programma di routine (Figura 1).
Nelle linee guida, infatti, non vengono suggeriti programmi
di screening generale, intensivi e costosi per la diagnosi di
orticaria. In Tabella IV 4 sono riassunti test diagnostici standardizzati per alcuni sottotipi di orticaria. Ulteriori test possono essere specificamente richiesti in casi selezionati.
Attualmente, il solo test generalmente disponibile per lo
screening degli autoanticorpi anti-recettore delle IgE è il
test cutaneo al siero autologo. Quest’ultimo deve essere
effettuato con estrema cura a causa delle infezioni che potrebbero trasmettersi al paziente qualora non gli venisse iniettato il proprio siero.
Per la diagnosi di orticaria è necessario considerare che,
in uno stesso paziente, possono coesistere diversi sottotipi di
orticaria, come, ad esempio, l’orticaria cronica e l’orticaria
dermografica. In tal caso, potrebbe accadere che solo 1 dei
2 sottotipi venga diagnosticato e adeguatamente trattato.
Terapia
Sebbene le varianti cliniche di orticaria risultino determinate da un elevato numero di fattori causali, il trattamento della sintomatologia si basa essenzialmente su alcuni punti cardine:
— allontanamento o eliminazione dello stimolo determinante;
— inibizione del rilascio dei mediatori dei mastociti;
— terapia dell’organo bersaglio dei mediatori dei mastociti.
Allontanamento dello stimolo determinante
Sulla base di tale approccio terapeutico, la formulazione
di una corretta diagnosi rappresenta una condizione necessaria.
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URTICARIA
SURRENTI
FARMACI
Farmaci sospettati di scatenare i sintomi dell’orticaria
dovrebbero essere assolutamente evitati e sostituiti con un’altra classe di molecole. In particolare, i farmaci responsabili di reazioni pseudoallergiche, il cui prototipo è l’aspirina,
sono in grado sia di indurre orticaria che di aggravare una
preesistente orticaria cronica 54.
STIMOLI FISICI
Un’informazione dettagliata relativa alle caratteristiche
fisiche di un determinato stimolo è certamente opportuna
allo scopo di controllarne l’esposizione nella vita quotidiana. Pertanto, è importante sottolineare, sia nell’orticaria dermografica che in quella da pressione, che la pressione è definita come una forza per unità di area, e che l’uso di alcuni
accorgimenti pratici come, ad esempio, l’ampliamento del
manico di borse pesanti potrebbe costituire una misura sufficiente a ridurre o perfino prevenire la comparsa delle lesioni.
ERADICAZIONE
Terapia diretta sui mastociti
I corticosteroidi sono farmaci molto efficaci nel trattamento dell’orticaria. L’impiego di dosaggi elevati permette
di ottenere una buona risoluzione dei sintomi anche se la
somministrazione a lungo termine deve essere evitata a causa della comparsa di effetti collaterali. La ciclosporina A,
pur avendo un’azione immunosoppressiva e un moderato
effetto diretto sul rilascio dei mediatori dei mastociti 63, viene considerata un trattamento alternativo a causa del costo elevato.
La PUVA riduce il numero dei mastociti ed è stata utilizzata con successo nelle mastocitosi 64, 65. Le radiazioni UVA e UV-B sono state solo recentemente valutate quale ulteriore opzione terapeutica in caso di orticaria 66, 67.
Terapia dell’organo bersaglio
DI AGENTI INFETTIVI E TERAPIA DI PROCESSI
INFIAMMATORI
Nel caso dell’orticaria fisica, le infezioni rappresentano l’agente eziologico in un numero esiguo di casi di orticaria da
freddo e dermografica, diversamente dall’orticaria cronica che
è più frequentemente associata a una varietà di processi
infiammatori o infettivi.
RIMOZIONE DEGLI AUTOANTICORPI PER IL FCεRI
Attualmente non sono disponibili dati soddisfacenti relativi al trattamento dell’orticaria cronica mediante rimozione
degli autoanticorpi. Un temporaneo miglioramento clinico è
stato ottenuto dopo plasmaferesi in casi isolati di pazienti che
presentavano una severa sintomatologia 55, 56. Inoltre, il trattamento immunologico con farmaci immunosoppressori
quali ciclosporina 57-60 e infusioni di immunoglobuline ad alte
dosi ha dimostrato una buona efficacia 61.
MANAGEMENT DIETETICO
L’allergia alimentare IgE-mediata è di raro riscontro nell’orticaria 19, 20. In un sottogruppo di pazienti con orticaria
cronica sono state descritte reazioni pseudoallergiche a ingredienti naturalmente presenti negli alimenti e, in alcuni casi,
ad additivi alimentari 19-21, 62. In questi casi, un regime dietetico a basso contenuto di pseudoallergeni sia naturali che
artificiali, e protratto per almeno 3-6 mesi, consente di ottenere remissioni cliniche nel 50% circa dei pazienti. È importante sottolineare che, qualora gli allergeni vengano rapidamente eliminati con la dieta, la sintomatologia dell’orticaria
si risolve entro 24-48 h in caso di reazione allergica di I tipo,
mentre in caso di pseudoallergia, il regime dietetico deve
essere mantenuto per almeno 2-3 settimane prima di poter
Vol. 140 - N. 3
osservare qualche miglioramento clinico. Al contrario, il
management dietetico non si è rivelato di alcun ausilio nel trattamento di altri sottotipi di orticaria, ad esclusione dell’orticaria cronica continua.
La sintomatologia dell’orticaria risulta mediata principalmente dai recettori H1. L’impiego clinico degli anti-istaminici di seconda generazione non sedativi o scarsamente
sedativi ha notevolmente migliorato la qualità di vita dei
pazienti con orticaria. Inoltre, gli anti-istaminici di nuova
generazione hanno un ruolo fondamentale nella gestione
terapeutica dell’orticaria in quanto esplicano anche effetti
anti-infiammatori inibendo il rilascio di citochine da parte di
basofili e mastociti 68, 69. L’effetto degli anti-istaminici nell’orticaria è dose dipendente 70, 71 e dosaggi elevati sono
solitamente ben tollerati. È, tuttavia, necessario ricordare
che gli alti dosaggi possono, in alcuni casi, provocare sedazione. Ad eccezione di terfenadina e astemizolo, che non
dovrebbero essere usati a lungo termine per i possibili effetti collaterali cardiaci, gli anti-istaminici di seconda generazione costituiscono il trattamento sintomatico di prima scelta nella terapia dell’orticaria in considerazione dell’elevata
tollerabilità. È consigliabile incrementare il dosaggio qualora
gli effetti collaterali siano inferiori a quelli riportati con trattamenti alternativi 5, 72.
Ulteriori possibilità terapeutiche
L’impiego di terapie farmacologiche alternative dovrebbe essere limitato a pazienti non responsivi ad alti dosaggi di
anti-istaminici. In considerazione dei possibili effetti collaterali e al fine di ridurre la posologia, è preferibile somministrare più farmaci in combinazione o in associazione con
anti-istaminici. Studi clinici aperti e singoli case report forniscono i dati clinici attualmente disponibili relativi alle terapie alternative. La Tabella V 5, 14, 15, 48, 51, 55, 57, 61, 65, 70, 71, 7394 elenca le principali terapie farmacologiche tradizionali e
alternative suggerite per ciascun tipo di orticaria.
L’orticaria ha un’evoluzione clinica variabile con pos-
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URTICARIA
sibilità di remissione spontanea. Si raccomanda, pertanto,
di rivalutare dopo periodi di 3-6 mesi la necessità di proseguire un eventuale trattamento farmacologico alternativo.
Conclusioni
L’orticaria compromette severamente la qualità di vita
del paziente e pertanto richiede un efficace trattamento della sintomatologia. A causa della multifattorialità della patologia, è preferibile instaurare un approccio terapeutico individuale allo scopo di ottenere una buona compliance da parte del paziente. La terapia si basa sull’allontanamento dei
fattori scatenanti, il trattamento delle eventuali patologie
associate e sull’impiego di farmaci sintomatici. In particolare,
nella maggior parte dei pazienti, i sintomi regrediscono utilizzando gli anti-istaminici di nuova generazione, i quali
hanno un buon profilo di tollerabilità e possono essere somministrati a dosaggi elevati in pazienti meno responsivi. I
trattamenti alternativi andrebbero riservati ai casi in cui le terapie tradizionali non consentano di ottenere alcun miglioramento clinico.
Ringraziamenti. — Gli Autori ringraziano la Sig.ra Wallner per
l’aiuto fornito nella stesura del manoscritto e la Prof. K. Peris (Clinica Dermatologica, Università degli Studi di L’Aquila) per aver eseguito la revisione critica dell’articolo.
288
Riassunto
L’orticaria è una patologia estremamente complessa che
solo nel corso degli ultimi decenni, grazie alla più approfondita conoscenza dei meccanismi eziopatogenetici, è stato possibile classificare in differenti varianti cliniche. Pertanto, l’accurata distinzione tra forme diverse di orticaria si rende ormai
necessaria al fine di individuare adeguate misure diagnostiche
e terapeutiche e di interpretare correttamente i dati disponibili
in letteratura. Le varianti cliniche di orticaria si distinguono in:
1) orticaria spontanea, che include l’orticaria acuta e cronica;
2) orticaria fisica; 3) forme speciali di orticaria tra cui l’orticaria da contatto; 4) patologie storicamente correlate all’orticaria, quali l’orticaria pigmentosa.
Poiché l’orticaria compromette severamente la qualità di vita
del paziente, efficaci misure terapeutiche risultano indispensabili anche qualora le indagini diagnostiche non rivelino la specifica causa determinante. Per il trattamento della sintomatologia associata, gli anti-istaminici anti-H1 non sedativi rappresentano la terapia di prima scelta nella maggioranza dei
sottotipi di orticaria, anche se alcuni studi caso-controllo in doppio cieco hanno evidenziato che i dosaggi necessari per il controllo dei sintomi potrebbero superare quelli indicati per altre
patologie, quali, ad esempio, la rinite allergica. L’uso di terapie alternative andrebbe considerato esclusivamente in caso di
pazienti non responsivi agli schemi terapeutici tradizionali.
PAROLE CHIAVE: Orticaria, diagnosi - Orticaria, patogenesi Orticaria, terapia.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
Giugno 2005
CASI CLINICI
G ITAL DERMATOL VENEREOL 2005;140:289-94
Hydroquinone-induced ochronosis
C. TOMASINI, Z. SEIA, E. SORO, V. TRASHLIEVA, C. ADDESE, M. PIPPIONE
A case of exogenous ochronosis associated with topical application of a hydroquinone-containing preparation is reported.
The patient was a 42-year-old Nigerian woman who had intermittently applied a bleanching cream to her skin for 5 year.
Examination revealed numerous discrete, pin-point, blueblack macules distributed in a symmetric fashion on the zygomatic regions and, to a lesser extent, the nose, chin, and upper
and lower extremities. The sclerae, conjunctivae, ears, and
oral mucosa were normal. Histopathologic examination of a
skin biopsy from a dyscromic area revealed within the papillary dermis and mid reticular dermis, multiple scattered,
banana-shaped or arciform, yellow-brown, swollen collagen
bundles. Scrutiny of the epidermis overlying the ochronotic
deposits showed evidence of a vacuolar interface dermatitis
with some necrotic keratinocytes. To the best of our knowledge, these findings have not been described in patients with
the endogenous form of ochronosis and could be related to
the toxic effects of hydroquinone on the epidermal keratinocytes and melanocytes.
KEY WORDS: Exogenous ochronosis - Alkaptonuria - Histopathology.
E
xogenous ochronosis was described in 1975 by
Findlay et al. who described black African patients
who had developed ochronosis, especially on the face,
after prolonged use of 6% to 8% hydroquinone creams
Received: January 27, 2004
Accepted for publication: May 19, 2005
Address reprint requests to: Dr. C. Tomasini, Clinica Dermatologica
II, Università degli Studi di Torino, Via Cherasco 23, 10126 Torino, Italy.
E-mail: [email protected]
Vol. 140 - N. 3
Second Dermatologic Clinic
University of Turin, Turin, Italy
applied to bleach the skin.1 Subsequently reports
appeared of exogenous ochronosis in black women in
the United States who used, for the same purposes,
concentration of hydroquinone less than 3%.2, 3 Unlike
the bleaching effect sought, some subjects developed
punctate, yellow-brown-black discoloration of the skin
to which the hydroquinone cream was applied.
A case of ochronosis induced by topical application of a hydroquinone-containing preparation in a
black woman is described.
Case report
A 42-year-old Nigerian female, resident in Italy for 10
years, presented with a 3-year history of progressive hyperpigmentation of the skin on the face and upper and lower
extremities. Over a period of approximately 5 years she had
intemittently applied to the dyscromic areas a cream containing 2% hydroquinone to bleach her skin. Her general
health conditions were good and there was no history of previous dermatoses or drug assumption.
Examination revealed numerous discrete, pin-point, blueblack macules distributed in a symmetric fashion on the
zygomatic regions and, to a lesser extent, the nose, chin, and
upper and lower extremities (Figure 1). The patient had also
small areas of hypopigmentation intermingled with hyperpigmented lesions. The sclerae, conjunctivae, ears, and oral
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Figure 3.—Interface dermatitis, vacuolar type above the dermal ochronotic deposits.
Figure 1.—Numerous discrete, pin-point, bluish macules in a periorbital
distribution.
Figure 4.—Ochre-yellow granules in the papillary dermis below foci of
damaged epidermis.
Figure 2.—Punch biopsy from hyperpigmented skin shows deposits of
ochronotic pigment in the dermis.
mucosa were normal. Urine did not change in colour on
standing, and contained undetectable levels of homogentisic acid.
A 5 mm punch biopsy specimen was obtained from the
hyperpigmented skin of right forearm. Light microscopy
290
revealed, within the papillary dermis and mid reticular
dermis, multiple scattered, banana-shaped or arciform,
yellow-brown, swollen collagen bundles (Figure 2). High
magnification showed tiny ochre-yellow to brown granules
of pigment interspersed within the degenerated collagen
bundles and in the surrounding stroma in a perivascular distribution (Figure 3). Scrutiny of the epidermis overlying
the ochronotic deposits showed in some foci vacuolar
degeneration of the basal keratinocytes in concert with a
few necrotic keratincytes. Ochre-yellow to brown granules
of pigment were seen free in the upper papillary dermis
below these areas (Figure 4). The ochronotic pigment
stained black with methylene blue, but remained unstained
with specific stains for elastic tissue (Van Gieson, orcein),
carbohydrate (PAS), melanin (Masson-Fontana silver),
lipofuscin (Schmorl’s ferricyanide) and iron (Perl’s reac-
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Giugno 2005
HYDROQUINONE-INDUCED OCHRONOSIS
tion). No inflammatory infiltrate was seen. Topical hydroquinone application was stopped; the dermatosis did
become worse, but it did not improve after a 3 year-followup. The use of cosmetic camouflage proved acceptable in
this patient.
Discussion and conclusions
The term “ochronosis” refers to the ochre colored,
nonmelanin, dermal pigmentation histologically
observed in specimens from hyperpigmented skin of
2 different diseases: endogenous ochronosis, which
is inherited as an autosomal recessive trait and exogenous ochronosis, which most often occurs after prolonged application of a hydroquinone cream to exposed
areas of the skin in order to lighten the colour of dark
skin. Endogeneous ochronosis and localized exogenous ochronosis are complete different diseases in
respect to prognostic implications, although they share
some clinical, histopathologic, and pathogenetic
aspects.
Endogenous ochronosis (alkaptonuria) is caused
by deficiency of homogentisic acid oxidase, the sole
catabolic enzyme for homogentistic acid (HGA), a
breakdown product in the metabolic pathway of
phenylalanine and tyrosine.4, 5 In patients with alkaptonuria, the biochemical defect leads to an accumulation of HGA which undergoes renal excretion
with resulting blackening of urine. However, some of
HGA gradually accumulates in certain tissues, particularly fibrous and cartilaginous tissues because of
its affinity with collagen to which it is irreversibly
bound as a polymer after oxidation to benzoquinoneacetic acid. At this level, HGA apparently inhibits
the enzyme lysil hydroxilase, impairing the structural integrity of collagen by inhibiting hydroxylysine
crosslikage.
Specimens from patients with alkaptonuric ochronosis show so distinct changes that they can readily be
seen at scanning magnification of a conventional microscope. In the upper dermis there are numerous, ochreyellow to brown, curvilinear and bizzarre shaped collagen bundles. At higher magnification, ochre-yellow
to brown granules of polymerized HGA are seen in
close apposition to degenerated collagen bundles, but
also free in the dermis, in macrophages, in endothelial
cells, and in the basement membrane region of eccrine
secretory cells. Deposition of HGA around individual collagen fibrils within collagen fibers, as revealed
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TOMASINI
by electron microscopy studies, would cause the collagen fibrils to lose their periodicity and to degenerate.
Over time, the collagen fibrils disappear as they are
replaced by further deposition of HGA. Ultimately,
the HGA occupies entire collagen fibers and, by fusion,
entire collagen bundles to produce larger, irregular
deposits of ochronotic pigment. The degree of
histopathologic changes correlates with the stage of the
process.
Exogenous ochronosis has almost exclusively been
reported in South African black people as a result of
the prolonged topical application of hydroquinone
creams.6-9 In fact, the cosmetic use of bleanching
products is a common practice in dark-skinned woman
from sub-Saharan Africa, accounting for at least 52%
of a representative sample of 368 adult women visiting a dermatology center in Dakar (Senegal).9 The
active principles used in this series included hydroquinone, glucocorticoids, mercur iodide, and caustic
agents. Concerning steroids, superpotent (class 1)
glucocorticoid predominated. Hydroquinone at concentration of between 4% and 8% was used by all
patients with exogenous ochronosis and by those in
which skin diseases appeared to be influenced by
bleanching products (hydroquinone alone or in combination with other substances) with a chronology
suggesting causality. In addition, certain modalities of
the use of bleaching products, namely applying hydroquinone without sun protection, application to the
whole body, and/or in combination with large quantity of class 1 steroid might have facilitated complications, such as contact dermatitis, lupus-like eruptions, phototoxic dermatitis, striae distensae, infections, and acneiform eruption.
Although it was originally believed that only high
concentration of hydroquinone were causal, there have
been reports of ochronosis after use of 2% hydroquinone preparations.2, 8 It has also been suggested
that the percentage of hydroquinone quoted by the
manufacturer may not necessarily represent the true
concentration in a product 10 Among depigmenting
agents, mercury, phenol and resorcinol have also been
used but these substances have almost completely been
eliminated by legislation because of the risk of severe
systemic reactions.11
Exogenous ochronosis clinically begins as asymptomatic, progressive, blue-black macules, most often
on the mala areas, forehead, temples, lower cheeks,
and lateral aspect of the neck. Clinically and
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histopathologically the condition resembles alkaptonuria, but it does not show any systemic complications or urinary abnormalities. In 1979 Dogliotte et
al.12 described 3 stages of exogenous ochronosis: 1)
erythema and mild pigmentation; 2) hyperpigmentation, black colloid milia and scant atrophy; and 3)
papulonodules with or without surrounding inflammation.
Histopathologically, changes alike those observed
in alkaptonuria are repoted to occur in skin biopsies
from patients with exogenous ochronosis caused by
topical application of a hydroquinone cream.8 The
source of ochronotic fibers in hydroquinone-induced
ochronosis is still controversial. It has been shown
that hydroquinone inhibits the activity of HGA oxidase,13 the same enzyme whose activity is markedly impaired in alkaptonuria. In exogenous ochronosis, the topically applied hydroquinone might inhibit the activity of HGA oxidase in the skin, resulting
in local accumulation of the ochronotic pigment as
it occurs in alkaptonuria. 14 Melanocytes may be
involved; most cases involve sun-exposed areas 15
and one case of ochronosis that avoided areas of
vitiligo is reported.16 Because the major source of
HGA in the skin is in the melanocytes, it is reasonable to assume that the uptake of hydroquinone by
melanocytes leads to an intracellular accumulation
of HGA. Over time, this process might result toxic
for the melanocytes, which would release HGA down
to the papillary dermis where it polymerizes forming ochronotic pigment. The complete absence of
hydroquinone-induced ochronosis in areas of vitiligo would support that melanocytes are necessary
for the deposition of the pigment. If this assumption is correct, one would expect to see some evidence of these events by studying histopathologic
specimens from skin biopsy of patients with hydroquinone-induced ochronosis. In our case of hydroquinone-induced ochronosis, scrutiny of the epidermis overlying the ochronotic deposits allowed
us to recognize some necrotic melanocyte at the dermoepidermal junction; furthermore, ochre-yellow
to brown pigment granules were seen free in the
upper papillary dermis in close contiguity to the
necrotic melanocytes. To the best of our knowledge,
these findings have not been described in patients
with the endogenous form of ochronosis.
Nowadays, in Italy commercially hydroquinonebased preparations for cosmetic skin-bleaching are no
292
more available, because of the risk of long-term effects.
In fact, renal adenomas and leukaemia occurred in
animal experiments indicating the nephrotoxicity and
carcinogenic properties of the substance.17 Alternatives such as azalaic acid and thioctic acid (alphalipoic acid) are available.
Treatment of exogenous ochronosis is difficult. The
suspension of the offending agent may lead to some
improvement;5 a combination of dermoabrasion and
carbon dioxide laser,9 and Q-switched ruby laser may
prove effective.18
References
1. Findlay GH, Morrison JGL, Simson IW. Exogenous ochronosis and
pigmented colloid milium from hydroquinone bleaching creams. Br
J Dermatol 1975;93:613-22.
2. Lawrence N, Bligard CA, Reed R, Perret WJ. Exogenous ochronosis
in the United States. J Am Acad Dermatol 1988;18:1207-11.
3. Levin CY, Maibach H. Exogenous ochronosis. An update on clinical
features, causative agents and treatment opinions. Am J Clin Dermatol 2001;2:213-7.
4. LaDu BN. Alkaptonuria. In: Scriver CS, Beaudet AL, Sly WS, Valle
D editors. The Metabolic Basis of Inherited Disease. 6th ed. New
York: McGraw-Hill; 1989.p.775-8.
5. Albers SE, Brozena SJ, Glass LF, Fenske NA. Alkaptonuria and
ochronosis: case report and review. J Am Acad Dermatol 1992;27:
609-14.
6. Hoshaw RA, Zimerman KG, Menter A. Ochronosislike pigmentation from hydroquinone bleaching creams in American blacks. Arch
Dermatol 1985;121:105-8.
7. Phillips JI, Isaacson C, Carman H. Ochronosis in black South Africans
who used skin lighteners. Am J Dermatopathol 1986;8:14-21.
8. Tidman MJ, Horton JJ, MacDonald DM. Hydroquinone-induced
ochronosis - light and electron microscopic features. Clin Exp Dermatol
1986;11:224-8.
9. Mahè A, Ly F, Aymard G, Dangous JM. Skin diseases associated with
the cosmetic use of bleaching products in women from Dakar, Senegal. Br J Dermatol 2003;148:493-500.
10. Brauer EW. Safety of over-the-counter hydroquinene bleaching creams.
Arch Dermatol 1985;121:1239.
11. Diven DG, Smith EB, Pupo RA, Lee M. Hydroquinone-induced localized exogenous ochronosis treated with dermoabrasion and CO2 laser.
J Dermatol Surg Oncol 1990;16:1018-22.
12. Dogliotte M, Liebowits M. Granulomatous ochronosis-a cosmeticinduced skin disorder in blacks. S Afr Med J 1979;56:757-60.
13. Snider RL, Thiers BH. Exogenous ochronosis. J Am Acad Dermatol
1993;28:662-4.
14. Shepartz B. Inhibition and activation of the oxidation of homogentisic
acid. J Biol Chem 1953;205:185-92.
15. Hoshaw RA, Zimmermann KG, Menter A. Ochronois-like pigmentation from hydroquinone bleaching creams in American blacks. Arch
Dermatol 1985;121:105-8.
16. Hull PR, Procter PR. The melanocyte: an essential link in hydroquinone-induced ochronosis. J Am Acad Dermatol 1990;22:529-31.
17. Kooyers TJ, Westerhof W. Toxicological aspects and health risks
associated with hydroquinone in skin bleaching formula. Ned Tijdschr
Geneeskd 2004;148:768-71.
18. Hruza GJ, Dover JS, Flotte TJ, Goetschkes M, Watanabe S, Anderson
RR. Q-switched ruby laser irradiation of normal human skin. Arch Dermatol 1991;127:1799-805.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
Giugno 2005
HYDROQUINONE-INDUCED OCHRONOSIS
TOMASINI
Ocronosi esogena da idrochinone
L
a prima segnalazione di ocronosi esogena risale al 1975,
quando Findlay et al. descrissero il caso di una donna
africana che aveva sviluppato lesioni cutanee simili a quelle dell’ocronosi endogena in seguito all’uso prolungato di una
crema schiarente contenente idrochinone all’8% 1. Successivamente, sono stati riportati casi di ocronosi esogena in
donne afro-americane indotti da applicazione per lunghi
periodi di creme schiarenti con concentrazioni di idrochinone inferiori al 3% 2, 3.
Gli Autori descrivono le caratteristiche cliniche e istopatologiche di una paziente affetta da ocronosi esogena indotta da applicazione di una crema schiarente all’idrochinone.
Caso clinico
Paziente nigeriana di 42 anni, residente in Italia da 10
anni, si presentava per una visita dermatologica per la comparsa da circa 3 anni di chiazze brunastre al volto e agli arti,
asintomatiche, tendenti all’estensione. Dall’anamnesi emergeva che la paziente aveva applicato sulle zone discromiche
una crema schiarente contenente idrochinone al 2% per almeno 5 anni.
La paziente risultava in buona salute e con anamnesi negativa per assunzione di farmaci.
L’esame obiettivo rivelava la presenza di numerose macule di colorito grigio-brunastro distribuite in maniera simmetrica a livello degli zigomi e, in minor misura, a livello del
naso, delle guance e della fronte (Figura 1). Erano, inoltre,
presenti chiazze ipopigmentate. Le sclere, le mucose congiuntivali e la mucosa orale erano normali. All’esame delle
urine non si osservavano alterazioni cromatiche e il dosaggio dell’acido omogentisinico era negativo. Veniva effettuato un prelievo cutaneo a livello di una chiazza ipercromica
del braccio sinistro. L’esame istologico mostrava diffuse
aree di collagene addensato che formava elementi arciformi
di colorito giallastro nel derma papillare e reticolare (Figura 2). A un’attenta osservazione, l’epidermide sovrastante i
depositi ocronotici mostrava fenomeni di degenerazione
vacuolare dei cheratinociti e dei melanociti dello strato basale con presenza di elementi necrotici e incontinenza di pigmento (Figure 3, 4). Nel derma papillare sottostante erano
visibili granuli di pigmento giallo-brunastro. Il pigmento
ocronotico assumeva un colorito nerastro con la colorazione con blu di metilene, ma era inerte alle colorazioni per le
fibre elastiche (Van Gieson, orceina), per i glucidi (PAS),
per la melanina (Masson-Fontana), per le lipofuscine (Schmorl’s) e per il ferro (Perls). Non era presente infiltrato
infiammatorio.
Nonostante la sospensione del preparato schiarente, le
lesioni rimanevano invariate per un periodo di 3 anni circa.
Venivano ottenuti risultati soddisfacenti con l’impiego di
prodotti coprenti.
Vol. 140 - N. 3
Discussione e conclusioni
Con il termine «ocronosi» si intende il deposito dermico
di pigmento non melanico, di colore ocraceo, osservabile
nei preparati istologici relativi a prelievi di lesioni iperpigmentate di 2 distinte entità: l’ocronosi endogena, dovuta a un
disordine genetico trasmesso per via autosomica dominante, e l’ocronosi esogena, generalmente causata dall’applicazione prolungata di creme schiarenti su cute fotoesposta.
Le 2 forme differiscono essenzialmente per la prognosi,
mentre condividono gran parte degli aspetti clinici, patogenetici e istopatologici.
L’ocronosi endogena (alcaptonuria) è una malattia sistemica causata da un deficit dell’enzima ossidativo dell’acido omogentisinico, deputato al catabolismo di questo composto derivante dal ciclo metabolico della fenilalanina e
tirosina 4, 5. Nei pazienti affetti da alcaptonuria, l’acido
omogentisinico in eccesso viene in gran parte eliminato
per via renale conferendo alle urine un caratteristico colore brunastro, mentre la quota non eliminata si accumula
progressivamente nei tessuti, in particolare a livello cartilagineo e connettivale, per un’elevata affinità con le fibre
collagene a cui si lega irreversibilmente in forma di polimero
dopo ossidazione ad acido benzochin-acetico. Qui, l’acido
omogentisinico inibisce l’enzima lisil-idrossilasi con arresto della formazione di legami crociati tra le fibre collagene e grave perturbazione dell’integrità strutturale del collagene.
Il quadro istopatologico nelle 2 forme di ocronosi appare sostanzialmente sovrapponibile, con differenze minime,
per lo più quantitative. Nei pazienti affetti da alcaptonuria,
infatti, le alterazioni del collagene sono più ecclatanti, con presenza di aggregati grossolani e falciformi a tintorialità giallo-brunastra nel derma superficiale e medio. A maggiore
ingrandimento si scorgono granuli di colorito giallo-brunastro ascrivibili a depositi di polimeri di acido omogentisinico associati alle fibre collagene o in forma libera, all’interno dei macrofagi, nelle cellule endoteliali e a livello della
membrana basale delle ghiandole e dotti eccrini. Studi di
microscopia elettronica hanno evidenziato che la degenerazione del collagene nell’ocronosi è dovuta ai depositi di acido omogentisinico che provocano la perdita della struttura
periodica delle fibrille le quali, infine, si addensano in aggregati irregolari. Con il tempo, i depositi di acido omogentisinico polimerizzato tendono a rimpiazzare le fibrille collagene
degenerate fino a formare cospicui depositi irregolari di pigmento ocronotico. Infine, i depositi di acido omogentisinico occupano l’intera fibra di collagene e la successiva fusione di fibre collagene tra loro forma nel derma i grossolani
ammassi di pigmento ocronotico visibili istologicamente.
Il grado delle alterazioni microscopiche si correla alla fase
del processo.
L’ocronosi esogena si osserva principalmente in sogget-
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TOMASINI
HYDROQUINONE-INDUCED OCHRONOSIS
ti di colore dopo uso prolungato di topici a base di idrochinone 6-9. Infatti, l’applicazione di prodotti schiarenti è una pratica piuttosto frequente per le donne di colore del sud Africa; su un campione di 368 donne adulte afferente a un centro di riferimento dermatologico di Dakar (Senegal) almeno
il 52% presentava dermatosi causate direttamente o aggravate
dall’uso di prodotti schiarenti 9. I principi attivi incriminati
includevano principalmente idrochinone, steroidi ultrapotenti (di classe 1), ioduro di mercurio e sostanze caustiche.
In tutti i casi di ocronosi e di dermatosi correlata all’uso di
schiarenti erano stati utilizzati prodotti contenenti idrochinone
a concentrazione tra 4% e 8% e/o in combinazione con altre
sostanze. In questa casistica, l’impiego di tali prodotti senza fotoprotezione, su vaste aree di superficie corporea o con
l’aggiunta di steroidi topici ultrapotenti, potrebbe aver favorito l’insorgenza di complicanze tra cui dermatiti da contatto, eruzioni lupus-like, dermatiti fototossiche, strie distense,
infezioni microbiche e eruzioni aneiformi.
Benché, inizialmente, si ritenesse che solo l’impiego di alte
concentrazioni di idrochinone potesse eventualmente indurre la discromia, sono stati successivamente segnalati casi di
ocronosi in seguito all’impiego di idrochinone a concentrazioni solo del 2% 2, 8. Inoltre, è possibile che la concentrazione
indicata nelle confezioni non sempre rispecchi fedelmente la
concentrazione reale contenuta nel prodotto 10.
Oltre all’idrochinone, tra le sostanze ad azione depigmentante si annoverano il mercurio, il fenolo e la resorcina,
il cui impiego attualmente è scoraggiato o addirittura proibito per il rischio di tossicità sistemica 11.
L’ocronosi esogena all’esordio si manifesta con macule
nero-bluastre, asintomatiche, a livello delle regioni malari,
della fronte, le tempie, la parte inferiore delle guance e i lati
del collo. Benché questa dermatosi presenti aspetti clinici e
istologici sovrapponibili all’alcaptonuria, mancano l’interessamento sistemico e le alterazioni urinarie. Dogliotte et
al.12, nel 1979, hanno descritto 3 stadi principali clinicoevolutivi dell’ocronosi esogena: 1) stadio dell’eritema e
modesta pigmentazione; 2) stadio dell’iperpigmentazione e
dei milia colloidi di colorito nerastro; 3) stadio papulo-nodulare con o senza infiammazione.
Istologicamente, il quadro dell’ocronosi esogena da idrochinone è considerato sostanzialmente sovrapponibile a
quello dell’alcaptonuria 8. Nell’ocronosi esogena da idrochinone, tuttavia, la patogenesi dei depositi ocronotici nel
derma non è stata ancora ben definita. È stato dimostrato che
l’idrochinone inibisce l’attività dell’enzima ossidativo dell’acido omogentisinico 13, la cui attività è compromessa
nell’alcaptonuria. Nell’ocronosi esogena, l’applicazione di
idrochinone potrebbe inibire, quindi, tale enzima, con conseguente accumulo di pigmento ocronotico, come si verifica nell’alcaptonuria 14. È stato, inoltre, ipotizzato un ruolo
del melanocita nella patogenesi dell’ocronosi per la comparsa
delle lesioni quasi esclusivamente su cute fotoesposta 15.
Se si considera che l’acido omogentisinico nella cute è presente principalmente nei melanociti, è ragionevole ipotizzare
che la penetrazione di idrochinone nei melanociti produca,
attraverso l’inibizione del relativo enzima ossidativo, un
294
accumulo intracellulare di acido omogentisinico. Con il
tempo, questo fenomeno potrebbe danneggiare le strutture
cellulari con conseguente rilascio di acido omogentisinico
nel derma con formazione di polimeri. L’assenza di pigmento ocronotico in corrispondenza delle aree affette da
vitiligine rinforza il possibile ruolo patogenetico del melanocita 16. Se quest’ipotesi è corretta, dovrebbe essere possibile osservare gli effetti patologici nelle biopsie cutanee di
pazienti affetti da ocronosi esogena da idrochinone. Nel
nostro caso, la presenza di alterazioni dell’interfaccia dermo-epidermica con melanociti vacuolizzati e l’incontinenza del pigmento melanico potrebbero essere l’espressione del
danno diretto dell’idrochinone sul melanocita. A nostra
conoscenza, tali alterazioni non sono state descritte nell’ocronosi di tipo endogeno.
Attualmente, in Italia, l’idrochinone non è più disponibile sul mercato a causa dei possibili effetti tossici a lungo termine. In animali da esperimento, infatti, è stata riscontrata l’insorgenza di adenomi renali e leucemie a indicazione delle
proprietà nefrotossiche e carcinogeniche di tale sostanza 17.
Prodotti alternativi a base di acido azelaico e acido alfalipoico sono, però, disponibili.
L’ocronosi esogena rappresenta un inestetismo cutaneo
cronico la cui correzione è difficoltosa. La sospensione dell’agente causale può portare a miglioramenti 5 e la maggior
parte degli Autori ritiene che la pigmentazione si attenui con
il tempo. In casi sporadici sono stati ottenuti buoni risultati
con l’impiego combinato di dermoabrasione e Laser a CO211
e mediante Laser a rubino («Q-switched ruby laser») 18.
Riassunto
Gli Autori riportano un caso di ocronosi esogena conseguente ad applicazione di una crema contenente idrochinone. La paziente, una donna nigeriana di 42 anni, aveva applicato la crema schiarente al volto e agli arti per un periodo di
circa 5 anni. L’esame obiettivo rivelava la presenza di numerose chiazze di dimensioni variabili da alcuni millimetri a 2
cm circa di colorito grigiastro, distribuite in maniera simmetrica agli zigomi, al naso e, in minor misura, alle guance
e agli arti inferiori. Non vi era coinvolgimento delle mucose. L’esame istologico di una biopsia eseguita su una lesione discromica evidenziava, a livello del derma superficiale
e medio, un collagene focalmente addensato a formare elementi arciformi di colorito giallo-brunastro. L’epidermide
sovrastante mostrava fenomeni di degenerazione vacuolare
dello strato basale, alcuni cheratinociti necrotici e incontinenza melanica. In questo caso, la presenza di alterazioni
dell’interfaccia dermo-epidermica, assenti nella forma endogena di ocronosi, potrebbe essere direttamente legata all’effetto tossico dell’idrochinone sul melanocita, con conseguente accumulo locale di acido omogentisinico e successivo
rilascio del metabolita nel derma e formazione di pigmento
ocronotico.
PAROLE CHIAVE: Ocronosi - Idrochinone - Istopatologia.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
Giugno 2005
LETTERE AL DIRETTORE
Filiform hyperkeratosis of the palms
and soles associated with chronic
obstructive pulmonary disease
M. CORAZZA 1, E. COLOMBO 1, A. MARZOLA 2
A. BORGHI 1, A. VIRGILI 1
1Section of Dermatology, Department of Experimental
and Clinical Medicine, University of Ferrara, Ferrara, Italy
2Section of Anatomopathology, Department of Experimental
Medicine and Diagnostics, University of Ferrara, Ferrara, Italy
[G ITAL DERMATOL VENEREOL 2005;140:0295-7]
Dear Editor,
Figure 2. A column of parakeratosis overlapping an area of agranulosis
(Hematoxylin and eosin staining 10X).
A
73-year-old patient, previously smoker, with a twentyyear history of chronic obstructive pulmonary disease
(COPD) and bronchial asthma, during hospitalization presented asymptomatic, filiform, whitish keratotic lesions on
his palms and soles and the lateral aspect of his fingers and
toes. These lesions presented 2 years before, strictly adhering to the skin, not removable by scratching, very rough to
touch and 1-2 mm in length (Figure 1).
There was no family history of keratinization disorders
Figure 3.—Absence of granular layer and parakeratosis. (Hematoxylin
and eosin staining 20X).
Figure 1. Multiple filiform keratotic lesions localized on the lateral aspect
of the secon finger of the hand.
This paper has been presented as free communication at the 1st Regional Congress of Dermatologists in Emilia-Romagna under the auspices of
SIDEMAST-ADOI, held in Bologna, March 20, 2004.
Vol. 140 - N. 3 3
and there were no other cutaneous, adnexal, or bone alterations.
Histopathological examination showed a distinct column
of parakeratosis overlapping an area of epidermis with agranulosis. No vacuolated cells, dyskeratosis or significant dermal alterations were observed (Figures 2, 3).
Topical treatment with urea 10% cream (2 applications
daily) was not useful and the patient refused any other treatment since he was asymptomatic.
At a 4-year follow-up after diagnosis, the cutaneous alterations are unchanged, COPD is stable and neither malignancies nor other systemic diseases have been detected.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
295
LETTERE AL DIRETTORE
TABLE I.—Classification of filiform hyperkeratoses. Modified from
Zarour et al.2
Type
Histology
Topography
Ia
Ib
IIa
IIb
Parakeratosis
Parakeratosis
Orthokeratosis
Orthokeratosis
Palms and soles
Shoulders, trunk, upper limbs
Palms and soles
Diffuse lesions with sparing of
palms and soles
II
Parakeratosis associated with Palms, soles, axillae, limbs, neck
sweat duct structures
Filiform hyperkeratosis (FH) is a keratinisation disorder of
unknown etiology.1
Zarour et al.2 do not consider FH a unique clinical entity,
but rather a group of cutaneous manifestations characterized
by: a) multiple and circumscribed areas of hyperkeratosis; b)
a column of compact keratotic material solid enough to resist to trauma.
Pending a better understanding of its pathogenesis the
same authors have proposed a classification of FH based on
histological and topographical criteria (Table I).
As observed in our patient, FH is clinically characterized
by filiform keratotic lesions, firmly adherent to the skin,
localized on the palms and soles or diffused in other sites, whitish-coloured, 1 mm diameter. They resemble “music box”
spines.2
The histopathological alterations observed in our patient
are consistent with those reported in the literature: a column
of orthokeratotic or parakeratotic epidermis with hypogranulosis.1
FH is also reported in the literature with many different and
often confounding terms, like punctate keratoderma, punctate porokeratotic keratoderma, porokeratosis punctata palmaris et plantaris, punctate porokeratosis.3 In true porokeratosis, in addition to the parakeratotic column and hypogranulosis, dyskeratosis and/or vacuolated cells and a
lymphohistiocytic infiltrate in the papillary dermis are observed.4 For this reason FH has to be distinguished from true
porokeratosis. The term punctate keratoderma also appears
incorrect. In fact, true punctate keratoderma is characterized
by hyperkeratotic papules without a peculiar filiform appearance and from the histological point of view by simple
hyperkeratosis with underlying acanthosis and minimal
parakeratosis.3
FH has been described in association with malignancies
such as esophageal, renal, rectal and bronchial carcinoma,
lymphoma, melanoma.1, 4, 5 Some authors 6 have hypothesized that FH could represent a genetic marker of predisposition to the development of a tumour, that may be observed
even after many years of latency. Adequate investigation
could prove mandatory for the early detection of underlying
malignancies. In our patient those investigations were negative.
FH has also been described in association with myelofi-
296
brosis, chronic renal failure, Darier’s disease, Crohn’s disease,1 type IV hyperlipoproteinemia.4
Only one case of FH associated with asthma has been
reported;5 nevertheless a causal relationship between these
2 conditions has not been demonstrated.
References
1. Mehta RK, Mallett RB, Green C, Rytina E. Palmar filiform hyperkeratosis (FH) associated with underlying pathology? Clin Exp Dermatol 2002;27:216-9.
2. Zarour H, Grob JJ, Andrac L, Bonerandi JJ. Palmoplantar orthokeratotic filiform hyperkeratosis in a patient with associated Darier’s
disease. Classification of filiform hyperkeratosis. Dermatology
1992;185:205-9.
3. Osman Y, Daly TJ, Don PC. Spiny keratoderma of the palms and
soles. J Am Acad Dermatol 1992;26:879-81.
4. Urbani CE, Moneghini L. Palmar spiny keratoderma associated with
type IV hyperlipoproteinemia. J Eur Acad Dermatol Venereol
1998;10:262-6.
5. Handa Y, Sakakibara A, Araki M, Yamanaka N. Spiny keratoderma of
the palms and soles - report of two cases. Eur J Dermatol 2000;10:
542-5.
6. Rault S, Salmon-Ehr V, Cambie M-P, Armingaud P, Barhoum K, Ploton D et al. [Palmoplantar filiform parakeratotic hyperkeratosis and
digestive adenocarcinoma] Ann Dermatol Venereol 1997;124:707-9.
French.
Address reprint requests to: : M. Corazza, Sezione di Dermatologia,
Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi
di Ferrara, Via Savonarola 9, 44100 Ferrara. E-mail: [email protected].
Ipercheratosi filiforme polmo-plantare
associata a broncopneumopatia cronica
ostruttiva
Egregio Direttore,
U
n paziente di 73 anni, ex fumatore affetto da broncopneumopatia cronica ostruttiva (BPCO) e asma da 20
anni, durante un ricovero per insufficienza respiratoria acuta, presentava in sede palmo-plantare e ai lati delle dita di
mani e piedi lesioni cheratosiche filiformi biancastre, di
lunghezza 1-2 mm, asintomatiche (Figura 1). Le lesioni,
insorte 2 anni prima, erano strettamente adese alla cute e
notevolmente ruvide al tatto. La familiarità era negativa per
disordini della cheratinizzazione e non vi erano altre alterazioni cutanee, annessiali o ossee.
L’esame istopatologico di una lesione mostrava una distinta colonna di paracheratosi che sormontava un’area di epidermide agranulosica. Non si osservavano né cellule vacuolizzate, né discheratosi, né significative alterazioni a livello dermico (Figure 2, 3).
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
Giugno 2005
LETTERE AL DIRETTORE
Gli esami ematochimici non rivelavano alterazioni significative e le indagini volte alla ricerca di altre patologie sistemiche o neoplasie sottostanti risultavano negative.
Il trattamento topico con crema contenente urea 10% (2
applicazioni/die) non si rivelava utile e, vista la totale assenza di sintomi, il paziente rifiutava ogni altra terapia.
A distanza di 4 anni dalla diagnosi il quadro clinico cutaneo
risulta invariato, la BPCO è stabile e non sono state rilevate neoplasie, né altre malattie sistemiche.
L’ipercheratosi filiforme (IF) è un disordine della cheratinizzazione a eziopatogenesi ignota 1. Zarour et al.2 considerano l’IF non come un’unica specifica entità clinica, bensì come un insieme di manifestazioni cutanee caratterizzate da: a) aree multiple e circoscritte di ipercheratosi; b) una
colonna di materiale cheratosico compatto e abbastanza
solido da resistere al trauma. In attesa di una migliore comprensione della sua patogenesi gli stessi Autori hanno proposto una classificazione basata su criteri topografici e istologici (Tabella I).
L’IF è caratterizzata clinicamente, come osservato nel nostro
paziente, da lesioni cheratosiche filiformi, simili alle spine
del tamburo di un carillon, fermamente adese alla cute, di
colorito biancastro e diametro circa 1 mm, localizzate a
livello palmo-plantare o diffuse in altre sedi 2.
Dal punto di vista istopatologico, le alterazioni sono rappresentate da una colonna di epidermide orto- o paracheratosica con ipogranulosi 1.
L’IF viene anche riportata in letteratura come punctate keratoderma, punctate porokeratotic keratoderma, porokeratosis punctata palmaris et plantaris, punctate porokeratosis 3,
denominazioni spesso confondenti e inadeguate, poiché l’ipercheratosi filiforme deve essere distinta dalla vera porocheratosi. In quest’ultima, infatti, oltre alla colonna paracheratosica e all’ipogranulosi, si osservano cellule vacuolizzate e/o discheratosi e un infiltrato linfoistiocitario nel
derma papillare 4. Anche il sinonimo punctate keratoderma
risulta improprio. La vera cheratodermia punctata, infatti, è
caratterizzata da papule ipercheratosiche senza il peculiare
aspetto filiforme e, istologicamente, da semplice ipercheratosi con sottostante acantosi e minima paracheratosi 3.
L’IF è stata descritta in associazione con neoplasie maligne, quali carcinoma esofageo, renale, rettale, bronchiale,
linfoma, melanoma 1, 4, 5. Alcuni Autori 6 sostengono l’ipotesi secondo cui l’IF rappresenterebbe un marker genetico di predisposizione allo sviluppo di tumori, che può verificarsi anche con una latenza di molti anni. Per questo si
rendono necessarie adeguate indagini mirate alla diagnosi
precoce di neoplasie sottostanti. Nel nostro paziente esse
sono risultate negative.
L’IF è stata anche descritta in associazione con mielofibrosi, insufficienza renale cronica, malattia di Darier, morbo di
Crohn 1, iperlipoproteinemia di tipo IV 4.
In letteratura un solo caso di IF è stato precedentemente
riportato in associazione con asma 5; non è stato, tuttavia,
dimostrato un rapporto causa-effetto tra queste 2 condizioni.
Vol. 140 - N. 3
Acquired reactive
perforating collagenosis
in a patient with HIV disease
D. CALISTA, R. ORIOLI,
C. D’ACUNTO, F. ARCANGELI
Dermatology Unit, M. Bufalini Hospital, Cesena, Italy
[G ITAL DERMATOL VENEREOL 2005;140:0297-9]
Dear Editor,
R
eactive perforating collagenosis (RPC) is a rare skin
disorder in which altered collagen bundles of the superficial dermis are extruded through the overlying epidermis.1
RPC is clinically characterized by umbilicated pruritic papules
with a central keratotic plug.2 The extensor surface of the
upper and lower extremities and the trunk are the most frequently involved areas.1, 2 The disease can start at any age.
When it begins in childhood and other cases are present in the
family, an autosomal inheritance has been suggested.2 In
adult patients with no family history, RPC has often been
associated with chronic diseases such as diabetes or kidney
failure.3-5 The course of the disease is variable. Lesions may
regress spontaneously in some weeks, leaving hypopigmented areas and minor scars, or persist chronically for
years.1-5 The clinical differential diagnosis includes Kyrle’s
disease, perforating folliculitis, elastosis perforantis serpiginosa, perforating granuloma annulare and perforating
osteoma.1, 2 We report a patient suffering with AIDS in whom
RPC developed shortly after he started highly active antiretroviral therapy (HAART) which included indinavir as a
protease inhibitor.
A 44-year-old man, diagnosed as having AIDS in 1993,
Figure 1.—Case 1: umbilicated papules with a central keratotic plug of the
extensor aspect of the legs.
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LETTERE AL DIRETTORE
ated with the disease.1, 4 Only 2 cases of RPC in HIV patients
have been reported to date.4, 5
The first, a 38-year-old man, affected by end stage acute
renal insufficiency, was treated with haemodialisys. RPC
lesions, scattered on the trunk, arms, legs and dorsal aspect
of the feet, were probably elicited by pruritus of renal origin.4
The second patient, a 42-year-old man, had in contrast no diabetes mellitus, renal, or hepatic diseases. He was assuming
indinavir, lamivudine and stavudine when RPC lesions developed on his legs. The authors did not report the temporal
relation between starting HAART and the onset of the cutaneous symptoms. Pruritus was believed to be the only possible etiologic factor.5 In our patient, symptoms began shortly after the onset of HAART therapy with indinavir as a protease inhibitor. First he developed pruritic cutaneous xerosis
and cheilitis, both common side effects induced by indinavir, then RPC lesions on the lower extremities. No abnormality of their renal functions or of glycemia was observed
before, during and after HAART therapy.
We hypothesize that in susceptible patients, the occurrence of RPC during HAART may be related to indinavir
which elicits the dermatosis through cutaneous xerosis, itching and subsequent scratching.
References
Figure 2.—Cup shaped depression in the epidermis containing necrotic
debris and a mixed chronic inflammatory infiltrate (H&H stain ×25).
presented with a 6-month history of multiple pruritic ulcerated papules on his lower legs. Lesions onset concurrently with
the onset of a widespread itching cutaneous xerosis, about 3
weeks after a therapy composed of indinavir, stavudine, and
zidovudine had started. On clinical examination both legs presented numerous erythematous, umbilicated, papules, 3-5 mm
in size, with a central adherent keratotic plug (Figure 1). Diffused xerosis, asteatotic dermatitis and cheilitis related to
indinavir were also noted. A biopsy specimen taken from 1
papule was diagnostic for RPC (Figure 2).
The lesions were unsuccessfully treated with topical corticosteroids and tretinoine. As the patient had previously
taken zidovudine and stavudine with no cutaneous problems, cutaneous xerosis induced by indinavir was suspected
as the possible trigger factor; hence it was replaced with nelfinavir. Finally, cutaneous lesions began to regress and completely cleared one year later.
Acquired RPC is a rare dermatosis that usually occurs in
patients suffering from diabetes mellitus or chronic kidney
failure, mostly during haemodialytic treatment.1, 2 Occasionally, hypothyroidism, hyper-parathyroidism, lepromatous leprosy, liver dysfunction, Hodgkin’s disease, or periampullary carcinoma have been described as being associ-
298
1. Faver IR, Daoud MS, Daniel Su WP. Acquired reactive perforating collagenosis. Report of six cases and review of the literature. J Am Acad
Dermatol 1994;30:575-80.
2. Cochran RJ, Tucker SB, Wilks JK. Reactive perforating collagenosis
in diabetes mellitus and renal failure. Cutis 1983:31:55-8.
3. Pedagrosa R, Knobel HJ, Huguet P, Oristell J, Valdes M, Bosch JA.
Reactive perforating collagenosis in Hodgkin’s disease. Am J Dermatopathol 1987;9:41-4.
4. Bank DE, Cohen PR, Khon SR. Reactive perforating collagenosis in
a setting of double disaster: acquired immunodeficiency syndrome and
end-stage renal disease. J Am Acad Dermatol 1989;21:371-4.
5. Rubio FA, Herranz P, Robayana G, Pena JM, Contreras F, Casado
M. Perforating folliculitis: report of a case in an HIV-infected man. J
Am Acad Dermatol 1999;40:300-2.
Address reprint requests to: D. Calista, Unità Operativa di Dermatologia, Ospedale M. Bufalini, viale Ghirotti, 286, 47023 Cesena, Italy.
E-mail: [email protected]
Collagenosi perforante reattiva
in un paziente con malattia da HIV
Egregio Direttore,
L
a collagenosi perforante reattiva (CPR) è una rara dermatosi caratterizzata dalla focale eliminazione transepidermica di fibre collagene del derma papillare 1. L’ipote-
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LETTERE AL DIRETTORE
si ezio-patogenetica più accreditata ipotizza che alla base di
tale malattia vi siano alterazioni di struttura delle fibre collagene che, riconosciute come estranee dal sistema immunitario, sarebbero eliminate attraverso l’epidermide soprastante 2. L’aspetto clinico è contraddistinto da papule o noduli grigiastri, tipicamente ombelicati e con tappo cheratinico
centrale. Le lesioni si localizzano alle superfici estensorie
delle mani, ai gomiti, alle ginocchia e al tronco 1, 2. Il decorso è variabile potendo regredire nel volgere di poche settimane, con esiti pigmentari e piccole cicatrici atrofiche, o persistere per anni 2. Sebbene nella maggior parte dei casi la
CRP si presenti in forma sporadica, sono stati riportati rari
casi di individui affetti nello stesso nucleo familiare, tanto
da far sospettare una possibile predisposizione genetica 3-5.
In età adulta la CPR predilige pazienti affetti da diabete
mellito o da insufficienza renale cronica 1-5. La diagnosi
differenziale si pone con la malattia di Kyrle, le follicoliti
perforanti, l’elastosis perforantis serpiginosa, il granuloma
annulare perforante, l’osteoma perforante e il mollusco contagioso 1, 2.
Viene descritto il caso di un paziente con malattia da HIV
che aveva sviluppato una CPR a distanza di poche settimane dall’inizio di una terapia di combinazione che includeva
indinavir come inibitore delle proteasi.
Il paziente, un soggetto di sesso maschile di 44 anni, affetto da AIDS, giungeva alla nostra osservazione per la comparsa
di xerosi diffusa a tutto l’ambito cutaneo e di numerose lesioni papulari intensamente pruriginose distribuite agli arti inferiori e riferiva che tali manifestazioni erano insorte 3 settimane
dopo l’inizio di una terapia antiretrovirale con indinavir, stavudina, e zidovudina.
All’esame obiettivo dermatologico a carico di entrambi gli
arti inferiori si osservavano una trentina di lesioni papuloombelicate, del diametro variabile da 3 a 5 mm, sormontate da un agglomerato cheratosico, grigiastro e aderente (Figura 1). Cheilite, xerosi diffusa ed eczema asteatosico, noti
effetti collaterali indotti da indinavir, completavano l’obiettività cutanea. L’esame istologico metteva in evidenza lesio-
Vol. 140 - N. 3
ni crateriformi con infiltrato infiammatorio misto e fasci di
fibre collagene che si verticalizzavano attraversando l’epitelio
necrotico sovrastante (Figura 2). Poiché il decorso della
malattia non era stato in alcun modo attenuato da una terapia topica a base di isotretinoina e steroidi e da un successivo ciclo di PUVA terapia, veniva consigliata la sospensione
dell’indinavir, sostituito da un inibitore delle proteasi di classe diversa. Tale provvedimento portava rapidamente alla
riduzione della xerosi e del prurito e al miglioramento dell’obiettività cutanea. La completa risoluzione delle lesioni
papulose avveniva in 1 anno.
La CPR è una rara dermatosi diagnosticata prevalentemente in pazienti affetti da diabete mellito o da insufficienza renale, soprattutto se sottoposti a trattamento dialitico 1, 2.
Occasionalmente la CPR è stata osservata in pazienti affetti da ipo o iperparatiroidismo, malattia di Hansen, epatite
virale, morbo di Hodgkin e carcinomi periampollari 1, 4.
L’associazione CPR e malattia da HIV è stata precedentemente segnalata in soli 2 casi 4, 5. Il primo era un soggetto in
trattamento emodialitico per insufficienza renale con lesioni cutanee localizzate al tronco e agli arti, probabilmente
elicitate dal trattamento conseguente al prurito di origine
renale 4. Il secondo era un paziente di 42 anni, affetto da
diabete mellito che, a distanza di poche settimane dall’inizio
di una terapia antiretrovirale a base di indinavir, lamivudina
e stavudina, aveva sviluppato una follicolite perforante 5.
Anche nel caso presentato la CPR ha avuto esordio a breve
distanza dall’inizio di una terapia antiretrovirale altamente
attiva che conteneva indinavir come inibitore delle proteasi.
La storia clinica metteva in evidenza un rapporto diretto fra
il grattamento indotto dal prurito e la comparsa delle lesioni papulo-ombelicate. Nessuna anormalità della funzione
renale o della glicemia è stata osservata prima, durante e
dopo la terapia di combinazione. Sulla base di tali considerazioni è verosimile ipotizzare che, in pazienti suscettibili la
comparsa di CPR potrebbe essere correlata al riflesso del
grattamento indotto dal prurito provocato, a sua volta, dalla
xerosi cutanea noto effetto indesiderato di indinavir.
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