A Database Analysis of Cutaneous Lupus Erythematosus with the EUSCLE Core Set Questionnaire

Abstract

The aim of this study was to determine whether the Core Set Questionnaire developed recently by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) is a useful tool to evaluate clinical features and therapeutic strategies in cutaneous lupus erythematosus. Disease characteristics were analysed in 50 patients with different subtypes of cutaneous lupus erythematosus from two European centres (Germany and Sweden). Mean age at onset of disease was 42.0 +/- 13.3 years (range: 7-69 years) and this differed significantly between the cutaneous lupus erythematosus subtypes. Moreover, 22 (44.0%) of the patients with cutaneous lupus erythematosus fulfilled four or more of the American College of Rheumatology (ACR) criteria; however, only 7 (14.0%) had severe systemic organ manifestations, such as kidney involvement. The analysis of serological features, such as antinuclear antibodies, revealed further significant differences between the cutaneous lupus erythematosus subtypes. In conclusion, the EUSCLE Core Set Questionnaire provides a useful tool for standardized collection and statistical analysis of data on cutaneous lupus erythematosus in clinical practice.

Full text

Acta Derm Venereol 90
INVESTIGATIVE REPORT
Acta Derm Venereol 2010; 90: 386–394
© 2010 The Authors. doi: 10.2340/00015555-0879
Journal Compilation © 2010 Acta Dermato-Venereologica. ISSN 0001-5555
The aim of this study was to determine whether the Core
Set Questionnaire developed recently by the European
Society of Cutaneous Lupus Erythematosus (EUSCLE)
is a useful tool to evaluate clinical features and therapeu-
tic strategies in cutaneous lupus erythematosus. Disease
characteristics were analysed in 50 patients with diffe-
rent subtypes of cutaneous lupus erythematosus from two
European centres (Germany and Sweden). Mean age at
onset of disease was 42.0 ± 13.3 years (range: 7–69 years)
and this differed signicantly between the cutaneous lu-
pus erythematosus subtypes. Moreover, 22 (44.0%) of
the patients with cutaneous lupus erythematosus fullled
four or more of the American College of Rheumatology
(ACR) criteria; however, only 7 (14.0%) had severe sys-
temic organ manifestations, such as kidney involvement.
The analysis of serological features, such as antinuclear
antibodies, revealed further signicant differences bet-
ween the cutaneous lupus erythematosus subtypes. In
conclusion, the EUSCLE Core Set Questionnaire provi-
des a useful tool for standardized collection and statisti-
cal analysis of data on cutaneous lupus erythematosus in
clinical practice. Key words: lupus erythematosus; ques-
tionnaire; skin; ACR criteria.
(Accepted February 15, 2010.)
Acta Derm Venereol 2010; 90: 386–394.
Annegret Kuhn, Department of Dermatology, University of
Muenster, Von-Esmarch-Strasse 58, DE-48149 Muenster,
Germany. E-mail: kuhnan@uni-muenster.de
The clinical expression of skin lesions in lupus ery-
thematosus (LE) presents with a great variety, and,
consequently, it has been difcult to develop a unifying
concept of the various cutaneous symptoms of the di-
sease. In 1977, Gilliam et al. (1–3) initially proposed a
classication system that divided the skin manifestations
of LE into those that are specic for LE (i.e. LE-specic
skin disease) and those that are not specic for the di-
sease (i.e. LE-non-specic skin disease) by histological
analysis of skin biopsy specimens. There are a number
of distinctive forms of LE-non-specic manifestations,
such as urticarial vasculitis and livedo reticularis, which
are mostly associated with systemic LE (SLE), reecting
potentially internal organ involvement and serious com-
plications (4, 5). The LE-specic manifestations encom-
pass the various subtypes of cutaneous LE (CLE), which
are subdivided into different categories, as dened by
constellations of clinical features, histological changes,
serological abnormalities, and average duration of skin
lesions: acute CLE (ACLE), subacute CLE (SCLE), and
chronic CLE (CCLE). Recently, modication and exten-
sion of the Gilliam classication was suggested, with the
intermittent CLE (ICLE) subtype, including LE tumidus
(LET) as a separate entity of the disease (Duesseldorf
Classication 2004) (6).
In all subtypes of CLE, systemic organ manifestations
can occur during the course of the disease, but exact
population-based data are not currently available in the
literature. Overall, epidemiological analyses have rarely
been performed; it has been estimated that patients with
CLE are two to three times more prevalent than those
with SLE (7). In 2007, Popovic et al. (8) reported the
prevalence of anti-Ro/SSA-positive SCLE patients
in Stockholm County, Sweden, to be 6.2–14.0 per
100,000 persons. Moreover, the European Medicines
Agency (EMEA) recently evaluated CLE as a severe
and rare disease, which exists in fewer than 5 out of
10,000 citizens in the European Union (9). Moreover,
no standardized guidelines exist for the assessment and
treatment of patients with CLE. This results in varying
diagnostic and therapeutic strategies in the different
European centres, which impedes the comparison of
patient data.
In order to facilitate data collection in patients with
CLE and to enable consistent evaluation, comparison,
and statistical analysis throughout Europe, a study group
of the European Society of Cutaneous Lupus Erythe-
matosus (EUSCLE) dened a core set of variables for
the evaluation of patients with CLE, resulting in the
EUSCLE Core Set Questionnaire (10). By collecting
data from CLE patients, the non-prot working group
EUSCLE aims to achieve a general consensus con-
cerning evidence-based clinical standards for disease
assessment and to develop diagnostic and therapeutic
guidelines. The main purpose of the current study was
to evaluate the recently developed EUSCLE Core Set
Questionnaire and the associated database on 50 pa-
tients with different subtypes of CLE from two centres
A Database Analysis of Cutaneous Lupus Erythematosus with the
EUSCLE Core Set Questionnaire
Anna Maria MEUTH1, Susanne AMLER2, Merle HAUST3, Dennis BEIN1, Cristina SAUERLAND2, Wolfgang KÖPCKE2, Gisela
BONSMANN1, Filippa NYBERG4 and Annegret KUHN1*
1Department of Dermatology, 2Department of Medical Informatics and Biomathematics, University of Muenster, Muenster, 3Department of Dermatology,
University of Duesseldorf, Duesseldorf, Germany, and 4Department of Medical Science (Dermatology), Uppsala University, Sweden

387
EUSCLE Core Set Questionnaire analysis
in Germany and Sweden. The results demonstrate that
the EUSCLE Core Set Questionnaire enables consistent
data collection and statistical analysis of the various
clinical features in CLE, providing a useful tool for an
extensive and comparative evaluation of data related
to the disease.
METHODS
Patients
A total of 50 patients (42 females, 8 males) with different
subtypes of CLE was included in the analysis, 40 patients
(32 females, 8 males) from the Department of Dermatology,
University of Duesseldorf, Germany, and 10 female patients from
the Department of Dermatology, Danderyd Hospital, Stockholm,
Sweden. The included CLE patients were representative of
the patient cohort that was treated at the two centres in the
period between July and December 2006. The mean age of
the CLE patients at the time of data collection was 51.9 ± 12.6
years, range 19–73 (Germany, mean ± SD age, 53.0 ± 11.6 years;
Sweden, mean ± SD age, 47.6 ± 15.8 years). Ten patients
(mean ± SD age, 32.8 ± 7.6 years) were ≤ 40 years old and 40
patients (mean ± SD age, 56.7 ± 8.3 years) were > 40 years old.
The age of the male CLE patients ranged from 38 to 67 years
(mean ± SD age; 54.3 ± 11.5 years), whereas the age of the
female patients ranged from 19 to 73 years (mean ± SD age;
51.5 ± 12.8 years).
The diagnosis and classification of CLE were based on clini-
cal and histological criteria, as well as on serological abnor-
malities according to the Duesseldorf Classification 2004 (6).
Patients with the following subtypes of CLE were included in
the study: ACLE (5 females, mean ± SD age; 41.6 ± 15.3 years),
SCLE (11 females; mean ± SD age, 59.0 ± 9.1 years), CCLE
(13 females and 1 male; mean
± SD age, 52.5 ± 12.7 years),
and ICLE (13 females and 7 males; mean ± SD age, 50.2 ± 12.0
years). Sub-classification of CCLE into discoid LE (DLE), LE
panniculitis (LEP), and chilblain LE (CHLE) was performed,
but is only indicated for some clinically relevant aspects. Nine
(18.0%) of the 50 patients presented with two different CLE
subtypes (Table I); the respective subtype that was initially
diagnosed was defined as the main diagnosis in the statistical
analysis. Therefore, the CLE subtype analysis always refers to
the main diagnosis unless otherwise indicated.
The study was approved by the ethics committee of the
University of Duesseldorf (Duesseldorf, Germany) and was
conducted according to the ethics guidelines at the institutions
and the Helsinki Declaration.
EUSCLE Core Set Questionnaire
The EUSCLE Core Set Questionnaire includes various parame-
ters considered to be the most relevant features of CLE, which
were compiled from international literature, clinical praxis, and
the long-term CLE experience of the authors (10). Moreover,
the 11 clinical and laboratory criteria of the American College
of Rheumatology (ACR) for the diagnosis of SLE, which were
established in 1971 (11) and revised in 1982 (12) and 1997 (13),
are listed in the EUSCLE Questionnaire. For the analysis of di-
sease activity and damage, the recently published and validated
disease activity and damage scoring system “Cutaneous Lupus
Erythematosus Disease Area and Severity Index” (CLASI) (14,
15) is also included in the EUSCLE Core Set Questionnaire. The
compilation of parameters for the evaluation of CLE resulted in
the 4-paged EUSCLE Core Set Questionnaire with the following
six sections: (A) Patient, (B) Diagnosis, (C) Skin involvement,
(D) Activity and damage of disease, (E) Laboratory analysis,
and (F) Treatment. The parameters included in the EUSCLE
Core Set Questionnaire are defined precisely in an associated
glossary that was also distributed to the participating centres.
Statistical methods
Data collection and transformation was performed using SPSS
statistical packages version 14.0. A SPSS database was designed
to enable a consistent, detailed statistical analysis of the EUSCLE
Core Set Questionnaire with the nal aim of including a high
number of CLE patients from various centres all over Europe.
For the conformal transmission of the data, each parameter was
assigned a specic name in SPSS, and a standard coding plan
for the numerical values was developed. The EUSCLE Core Set
Questionnaire is based on a nominal scale level. The structure
of the database enables various test application possibilities and
different combinations for comparison. Statistical analysis was
performed using SPSS and SAS version 9.1. The database-driven
analysis was performed primarily with a Fisher’s exact test to
adjust small case numbers. According to the respective question
analysed, a Kruskal-Wallis test, a Mann-Whitney U test, or an
analysis of variance (one-way ANOVA with Scheffé post hoc
test) was applied. p-values < 0.05 were considered signicant.
Means are presented with standard deviations.
RESULTS
Gender and age at onset of disease
In the 50 patients with different subtypes of CLE parti-
cipating in the study, there was a signicant difference
with regard to gender (p = 0.042). Seven (87.5%) of the
8 male patients presented with ICLE and one (12.5%)
presented with CCLE, but none of the male patients
presented with any of the other subtypes, i.e. ACLE
or SCLE. In the female patients, however, all different
CLE subtypes were diagnosed (Fig. 1A). The mean
age at onset of disease (42.0 ± 13.3 years, range 7–69)
did not differ signicantly between male and female
patients; it was slightly higher in the male patients
aged 44.6 ± 12.6 years (range 29–61) compared with
the female patients aged 41.5 ± 13.5 years (range 7–69).
However, concerning the mean age at onset of disease
in the different CLE subtypes, signicant differences
were found between ACLE and SCLE (p = 0.011) and
SCLE and ICLE (p = 0.038) being lowest in ACLE
Table I. Subtypes of cutaneous lupus erythematosus (CLE) occurring
simultaneously in patients. The number of CLE patients is indicated,
highlighting those who presented with particular combinations
of disease subtypes. The main diagnosis (left-hand column) that
was primarily seen in the patients was used for further statistical
analysis
Main diagnosis
Secondary diagnosis
ACLE SCLE CCLE ICLE
ACLE – 1 2 –
SCLE – – 2 –
CCLE 1 – – 1
ICLE 2 – – –
ACLE: acute cutaneous lupus erythematosus; SCLE: subacute cutaneous
lupus erythematosus; CCLE: chronic cutaneous lupus erythematosus;
ICLE: intermittent cutaneous lupus erythematosus.
Acta Derm Venereol 90

388 A. M. Meuth et al.
(28.8 ± 8.6 years, range 17–38) and highest in SCLE
(51.4 ± 9.6 years, range 36–69) (Fig. 1B). In all patients
with ACLE, the mean age at onset of disease was ≤ 40
years, whereas in the other CLE subtypes the mean
age at onset of disease was primarily > 40 years. These
differences were signicant (Fig. 1C).
ACR criteria
Seven patients with the diagnosis of SLE fullled four
or more of the ACR criteria at the time of or prior to
data collection; 15 patients fullled four or more of
the ACR criteria, although they had not initially been
diagnosed with SLE by the attending physicians. Mo-
reover, there was a signicant difference between the
number of patients with ACLE and ICLE who fullled
four or more of the ACR criteria (p = 0.002) (Fig. 2A).
The most frequently fullled ACR criterion in CLE
was photosensitivity, which was present in 42 of the
50 patients (84.0%) (Fig. 2B). Antinuclear antibodies
(ANA) were present in 31 patients (62.0%); discoid
rash, malar rash, immunological disorders, and arthritis
A
ACLE CCLE ICLE
No. of patients (%)
Male
Female
20
40
60
80
100
SCLE
0
{
{
*
0 0
C
ACLE SCLE CCLE ICLE
No. of patients (%)
0
20
40
60
80
100
> 40 years
40 years
**
*
{
{
{
{
0
*
{
{
B
0
10
20
30
40
50
60
ACLE SCLE CCLE ICLE
70
Mean age at onset of disease
**
*
Fig. 1. (A) Male and female patients with
different cutaneous lupus erythematosus
(CLE) subtypes. The percentage of male
(n = 8) and female (n = 42) patients is shown
with respect to each of the CLE subtype. (B)
The mean age at onset in CLE subtypes is
presented with standard deviation for each
CLE subtype. (C) The percentage of patients
with different CLE subtypes is demonstrated
with regard to the age at onset of disease (≤ 40
years or > 40 years). ACLE: acute cutaneous
lupus erythematosus; SCLE: subacute
cutaneous lupus erythematosus; CCLE:
chronic cutaneous lupus erythematosus; ICLE:
intermittent cutaneous lupus erythematosus.
*p < 0.05; **p < 0.01.
A
No. of patients (%)
100
B
C
0
20
40
60
80
100
No. of patients (%)
ACLE
SCLE
CCLE
ICLE
0 0 0
Malar rash Discoid rash Oral ulcers Arthritis
*
**
*
* **
*
**
*
**
** *
0 0 0 0 0
*
Renal
disorder
Neurologic
disorder
Hematologic
disorder
* *
ACLE SCLE ICLE CCLE
<4 ACR
4 ACR
0
20
40
60
80
0
**
{
{
0
10
20
30
40
50
No. of patients (total)
Fig. 2. (A) Presence of four or more of the American
College of Rheumatology (ACR) criteria in different
cutaneous lupus erythematosus (CLE) subtypes. The
percentage of CLE patients with the four subtypes
who fullled < 4 or ≥ 4 of the ACR criteria is presented.
(B) Number of CLE patients who fullled the various
ACR criteria. The 11 ACR criteria are listed with
the respective number of CLE patients who fullled
any of these criteria. (C) Signicant differences of
ACR criteria in CLE subtypes. Each bar indicates
the percentage of patients within the CLE subtypes
who fullled the respective ACR criteria, resulting
in signicant differences. ACLE: acute cutaneous
lupus erythematosus; SCLE: subacute cutaneous
lupus erythematosus; CCLE: chronic cutaneous lupus
erythematosus; ICLE: intermittent cutaneous lupus
erythematosus. *p < 0.05; **p < 0.01.
Acta Derm Venereol 90

389
EUSCLE Core Set Questionnaire analysis
were also frequently observed. The presence of several
ACR criteria, such as malar rash, discoid rash, and
arthritis, differed signicantly between the various
CLE subtypes (Fig. 2C). Other ACR criteria, such as
photosensitivity, serositis, immunological disorder and
antinuclear antibodies, did not show signicant diffe-
rences among the CLE subtypes (Table II).
The presence of two of the 11 ACR criteria varied sig-
nicantly between male and female patients with CLE.
Arthritis appeared signicantly more often in female
patients (p = 0.043), in 16 (38.1%) of 42 patients in
contrast to none of the 8 male patients. Moreover, ANA
were also detected signicantly (p = 0.041) more often
in female patients (29 of 42; 69.0%) compared with 2
of the 8 male patients (25.0%). Overall, the number of
CLE patients who fullled four or more of the ACR
criteria was much higher in female patients (21 of 42;
50.0%) than in male patients (1 of 8; 12.5%), but this
difference was not signicant. In addition, there was a
signicant difference in patients with regard to mean
age at onset of disease ≤ 40 or > 40 years and malar rash
(p = 0.042). Only 6 (21.4%) of the 28 patients with an
age at onset of disease > 40 years presented with a malar
rash, but 11 (50%) of the 22 patients with a mean onset
of disease < 40 years presented with a malar rash.
Polymorphous light eruption and Sjögren’s syndrome
The occurrence of polymorphous light eruption
(PLE) and Sjögren’s syndrome (SS) is evaluated in
the EUSCLE Core Set Questionnaire as concomitant
diseases. The incidence of each disease, however, was
not signicantly different between the CLE subtypes.
Of the 6 patients presenting with PLE, 2 (33.3%) were
diagnosed as SCLE and 2 were diagnosed as ICLE;
one (16.7%) was diagnosed as DLE and one was
diagnosed as LEP. Of the 6 patients with SS, 3 (50.0%)
were diagnosed as SCLE; one (16.7%) as ACLE; one
as DLE; and one as ICLE. In most patients (5 of 6,
83.3%), the onset of PLE was prior to the diagnosis
of LE, whereas SS was not diagnosed in any of the
patients prior to the onset of LE. In three cases, SS was
diagnosed simultaneously with, or secondarily in the
course of the disease.
LE-specic skin lesions
All 8 patients with ACLE lesions presented at the
time of data collection or in the past with the locali-
zed form as malar rash, and none showed any sign of
a generalized manifestation. Of the 12 patients with
SCLE, 8 (66.7%) presented with the annular form and
5 (41.7%) presented with the papulosquamous form,
with one patient (8.3%) displaying both forms. Within
the different subforms of CCLE, all 18 patients were
diagnosed as DLE, mostly (13 of 18, 72.2%) presen-
ting with the localized form; 5 (27.8%) of 18 patients
presented with the disseminated form; one (5.6%) of
the DLE patients additionally had LEP, but none of the
patients with CCLE was diagnosed as
CHLE.
The diagnosis of LE-specic skin lesions was conr-
med by histological analysis of skin biopsy specimens
in all patients, except 2 patients with a buttery rash
consistent with the localized form of ACLE and one
patient with ICLE who was only 7 years old at the time
of rst diagnosis.
LE-non-specic skin lesions
In 19 (38%) of the 50 patients, LE-non-specic skin
lesions had been diagnosed during the course of the
disease. The majority of cases (12, 63.2%) presented
with non-scarring alopecia; 6 of these patients were
diagnosed as CCLE, 4 as SCLE, one as ACLE and one
as ICLE. We observed signicantly less non-scarring
alopecia in patients with ICLE than in patients with
SCLE (p = 0.042) and CCLE (p = 0.012). Raynaud’s
syndrome was the second most frequently diagnosed
LE-non-specic skin manifestation, which was present
in 8 (16.0%) of the patients: 3 with SCLE, 3 with CCLE,
and 2 with ICLE. The other LE-non-specic skin le-
sions included one case each of urticarial vasculitis,
periungual teleangiectasia, livedo reticularis, thrombo-
phlebitis, and calcinosis cutis. Moreover, 5 patients (1
ACLE, 1 SCLE, 2 CCLE, 1 ICLE) were evaluated as
having “other non-specic lesions”, which were not
further specied.
Photosensitivity and photoprovocation test
Of the 50 patients with CLE, 49 (98.0%) presented with
skin lesions in sun-exposed areas; only one patient with
ICLE had lesions exclusively on the back in non-sun-
exposed areas. Photosensitivity by patient’s history was
reported by 37 of the 49 patients (75.5%) with lesions in
sun-exposed areas; however, 12 patients (24.5%) with
lesions in sun-exposed areas denied any photosensiti-
vity. With regard to CLE subtypes, patients with ACLE
and ICLE were most frequently (80.0% and 84.2%, re-
Table II. Distribution of further American College of Rheumatology
(ACR) criteria in cutaneous lupus erythematosus (CLE) subtypes.
The table reveals the presence of the remaining non-signicant ACR
criteria in the 50 patients with the different CLE subtypes
Subtype
Number (%) of patients
Photosensitivity Serositis
Immunological
disorder
Antinuclear
antibody
ACLE 4 (80.0) 1 (20.0) 2 (40.0) 4 (80.0)
SCLE 9 (81.8) 0 (0.0) 4 (36.4) 10 (90.9)
CCLE 12 (85.7) 2 (14.3) 6 (42.9) 8 (57.1)
ICLE 17 (85.0) 0 (0.0) 5 (25.0) 9 (45.0)
ACLE: acute cutaneous lupus erythematosus; SCLE: subacute cutaneous
lupus erythematosus; CCLE: chronic cutaneous lupus erythematosus;
ICLE: intermittent cutaneous lupus erythematosus.
Acta Derm Venereol 90

390 A. M. Meuth et al.
spectively) photosensitive by patient’s history, whereas
patients with CCLE (64.3%) presented least frequently
with photosensitivity by patient’s history.
Phototesting was performed, according to a standar-
dized protocol (16), in 42 of the 50 patients (84.0%)
with CLE. Only one of the 5 patients with ACLE under-
went phototesting, which yielded a negative result. In
the other subtypes, the majority of photoprovocation
test results were positive, ranging from 63.2% in ICLE
to 69.2% in CCLE. In many cases, photoprovocation
test results did not correspond to photosensitivity by
patient’s history; 5 (45.5%) of the 11 patients, who de-
nied any history of photosensitivity, displayed positive
photoprovocation test results. In contrast, 9 (29.0%)
of the 31 patients who reported a positive history of
photosensitivity displayed negative photoprovocation
test results.
Moreover, photoprovocation test results and photo-
sensitivity by patient’s history also differed in patients
with concomitant PLE disease. Although all 6 CLE
patients with associated PLE were photosensitive by
patient’s history, only 2 (50%) of the 4 tested patients
displayed positive photoprovocation test results.
Laboratory analysis
In comparison with all laboratory analyses reported in
the EUCLE Core Set Questionnaire, ANA were most
frequently found to be positive (with a titre of > 1:160
using HEp-2 cells), in more than half of the patient
cohort (29 (58.0%) of the CLE patients) (Table III).
The presence of specic antibodies, such as anti-Ro/
SSA, anti-La/SSB and anti-dsDNA antibodies, diffe-
red signicantly among the CLE subtypes, while the
differences regarding ANA were remarkable, but not
signicant (Fig. 3). Thirteen (28.9%) of the 45 tested
patients were positive for anti-Ro/SSA and 10 (22.2%)
were positive for anti-La/SSB antibodies. If one of
these two antibodies was positive in a CLE patient, the
other one was also positive in most cases: 8 (17.8%) of
the 45 tested patients were positive for both anti-Ro/
SSA and anti-La/SSB antibodies, representing 61.5%
of the patients with anti-Ro/SSA antibodies and 80.0%
of the patients with anti-La/SSB antibodies.
Anti-Sm antibodies were not positive in any of the
37 tested patients, and similarly anti-histone antibodies
were not positive in any of the 36 analysed patients. The
erythrocyte sedimentation rate (ESR) and the C-reactive
protein (CRP) were found to be increased in 9 (21.4%)
of 42 tested patients and in 10 (25.0%) of 40 tested pa-
tients, respectively. Of the complement factors, C3 was
most often found to be decreased (in 8 (19.0%) of 42
tested patients), whereas C4 was decreased in 4 (9.5%)
of 42 tested patients. C1q was found to be decreased
in only one (4.2%) patient; however, only 24 patients
were tested. Anti-dsDNA antibodies were positive in 8
(17.0%) of 47 tested patients. Anti-cardiolipin antibo-
dies (IgG) were positive in only 2 (5.9%) of 34 tested
patients, and anti-cardiolipin antibodies (IgM) were
positive in 3 (8.8%) of 34 tested patients (Table III).
Leukopenia was detected in 5 (11.4%) of 44 tested pa-
tients and proteinuria in 4 (9.1%) of 44 tested patients.
Signicance was found concerning the age at onset of
disease and the current presence of proteinuria, sug-
gesting that proteinuria correlated negatively with the
age at onset of disease points to a greater chance that
patients with an age at onset of disease ≤ 40 years will
be more likely to exhibit renal involvement (p = 0.018).
Of the 44 CLE patients for which we analysed urine for
the presence of albumin, 4 (9.1%) were diagnosed as
having proteinuria; interestingly, all of them presented
with a mean age at onset of disease ≤ 40 years.
Treatment
Forty-seven (94.0%) of the 50 CLE patients had applied
sunscreen at the time of the study or at some time in
the past. In 36 (76.6%) of the 47 patients, sunscreens
were recorded as being successful in prevention of
skin lesions. In 2 (4.3%) CLE patients, sunscreens
were evaluated as not being successful; the success of
prevention was unknown in the remaining 9 (19.2%)
0
20
40
60
80
100
No. of patients (%)
0
* *
*
*
**
**
* * **
ACLE SCLE CCLE ICLE
Fig. 3. Autoantibodies in different cutaneous lupus erythematosus (CLE)
subtypes. Bars represent the percentage of patients with positive antibodies
including anti-Ro/SSA, anti-La/SSB, and anti-dsDNA antibodies within the
patients of the respective CLE subtype. Differentiation of antibodies was
primarily performed if ANA were positive; therefore, not all patients were
evaluated for anti-dsDNA and anti-Ro/SSA and anti-La/SSB antibodies.
Numbers of tested patients for each antibody are indicated. Ab: antibodies;
ACLE: acute cutaneous lupus erythematosus; ANA: antinuclear antibodies;
SCLE: subacute cutaneous lupus erythematosus; CCLE: chronic cutaneous
lupus erythematosus; ICLE: intermittent cutaneous lupus erythematosus.
*p < 0.05; **p < 0.01.
Acta Derm Venereol 90

391
EUSCLE Core Set Questionnaire analysis
patients. Application of topical glucocorticosteroids
was evaluated as successful in 26 (56.5%) of 46 CLE
patients; however, there was also a comparatively
high number of patients (10 (21.7%)) in whom the
treatment did not show any success. In the remaining
10 (21.7%) patients with CLE, the success of topical
glucocorticosteroids was unknown. Topical calcineurin
inhibitors had been applied at the time of the study or
at some time in the past by 22 CLE patients (44.0%);
in 13 (59.1%) of these patients, the agents were also
recorded as successful.
Overall, systemic treatment was applied in 33 (66.0%)
of the 50 patients included in the EUSCLE Core Set
Questionnaire. In contrast to the other CLE subtypes,
all patients with ACLE received systemic agents due to
the frequent involvement of internal organs. Systemic
glucocorticosteroids were recorded as a successful treat-
ment in 12 (80.0%) of 15 treated patients and as not
successful in one patient with CLE. Of the antimalarial
agents, chloroquine showed the highest success rate,
with 19 (86.4%) of 22 patients being recorded as treated
successfully; treatment failed in only one patient with
DLE. Treatment with hydroxychloroquine was rated as
successful in 11 (68.8%) of 16 and not successful in 4
(25.0%) of the CLE patients. In one patient, quinacrine
was applied in addition to chloroquine, but the treatment
did not prove successful. This might be due to the fact
that the patient was a regular smoker. Of 4 CLE patients
who received systemic retinoids, treatment was evalua-
ted as successful in 2 patients and one patient showed
no response. Other treatments recorded in the EUSCLE
Core Set Questionnaire, e.g. thalidomide, were applied
only in a very low number or not applied in any of the
participating patients.
DISCUSSION
In this rst retrospective analysis, we tested the feasibi-
lity and validity of the EUSCLE Core Set Questionnaire
in two centres and found signicant differences with re-
gard to gender and mean age at onset of disease among
the different subtypes of CLE. All patients with ACLE
participating in this study were female and presented
with a mean age ≤ 40 years at onset of disease. This
might be due to the fact that ACLE usually occurs in
association with SLE, preceding the onset of a multi-
system disease (17). In most studies, the percentage
of females with SLE ranges from 78% to 96%, with a
female:male ratio of approximately 10:1 (18). More-
over, the symptoms of patients with SLE appear bet-
ween the ages of 15 and 40 years, with a mean age at
onset of disease of 29–32 years. In contrast to ACLE,
the other subtypes of CLE have been shown to appear at
a later age and the male:female ratio has been reported
to vary between 1:3 and 1:6 in SCLE and CCLE patients
(7). ICLE has been reported to be equally frequent in
both groups (19); however, a systematic epidemiologi-
cal analysis of the various CLE subtypes has not been
performed. In a recent population-based study from
Minnesota, USA, the overall male:female ratio of CLE
was 1:1.79 between 1965 and 2005 (20).
The ACR criteria include 11 clinical and laboratory
features and are the only universally accepted criteria
for the classication of SLE, providing some degree of
uniformity to the patient populations of clinical studies
Table III. Laboratory analysis in patients with cutaneous lupus
erythematosus (CLE).
Positive
patients (%)
Positive patients,
number/total tested
patients
ANA (HEp-2) 58.0 29/50
Anti-Ro/SSA Ab 28.9 13/45
Anti-La/SSB Ab 22.2 10/45
Anti-cardiolipin (IgG) Ab 5.9 2/34
Anti-cardiolipin (IgM) Ab 8.8 3/34
Anti-dsDNA Ab 17.0 8/47
C3 (decreased) 19.0 8/42
C4 (decreased) 9.5 4/42
C1q (decreased) 4.2 1/24
ESR (increased) 21.4 9/42
CRP (increased) 25.0 10/40
Leukopenia 11.4 5/44
Proteinuria 9.1 4/44
ANA: antinuclear antibodies; ESR: erythrocyte sedimentation rate; CRP:
C-reactive protein.
Table IV. Ranking of the most frequently applied treatments in cutaneous lupus erythematosus (CLE) subtypes. Treatments which were
applied in CLE subtypes at the time of the study or ever in the past are listed, ranked according to the number of patients in whom they
have been applied. Steroids refer to glucocorticosteroids
ACLE
Applied
n (%) SCLE
Applied
n (%) CCLE
Applied
n (%) ICLE
Applied
n (%)
Topical steroids 5 (100.0) Sunscreens 10 (90.9) Sunscreens 14 (100.0) Sunscreens 19 (95.0)
Chloroquine 4 (80.0) Topical steroids 10 (90.9) Topical steroids 14 (100) Topical steroids 17 (85.0)
Sunscreens 4 (80.0) Chloroquine 6 (54.5) Calcineurin inhibitors 10 (71.4 Calcineurin inhibitors 8 (40.0)
Systemic steroids 3 (60.0) Systemic steroids 4 (36.4) Chloroquine 6 (42.9) Hydroxychloroquine 8 (40.0)
Retinoids 2 (40.0) Calcineurin inhibitors 4 (36.4) Hydroxychloroquine 6 (42.9) Chloroquine 6 (30.0)
Methotrexate 2 (40.0) Hydroxychloroquine 1 (9.1) Systemic steroids 4 (28.6) Systemic steroids 4 (20.0)
ACLE: acute cutaneous lupus erythematosus; SCLE: subacute cutaneous lupus erythematosus; CCLE: chronic cutaneous lupus erythematosus; ICLE:
intermittent cutaneous lupus erythematosus.
Acta Derm Venereol 90

392 A. M. Meuth et al.
(11–13). In the present study, 22 (44.0%) of the 50 CLE
patients fullled 4 or more of the ACR criteria for the
classication of SLE; only 7 (14.0%) of them had severe
systemic organ manifestations, such as kidney involve-
ment. The proportion of patients with ACLE who full-
led four or more of the ACR criteria was signicantly
greater than among patients with ICLE. Malar rash and
arthritis were signicantly more frequent in patients
with ACLE than in the other CLE subtypes. However,
only a low number of ACLE patients are included
in the present study, and thus statistical analysis and
comparison among the different disease subtypes were
limited in some aspects. Discoid rash was obviously
present in all DLE patients in contrast to other subtypes
of CLE, such as ACLE and SCLE, unless there is a se-
condary diagnosis of DLE. These data suggest that the
fullment of specic ACR criteria is dependent on the
disease subtype, and thus patients with a “malar rash”
(ACLE) or a “discoid rash” (DLE) may more frequently
be classied as SLE according to the ACR criteria than
patients with other CLE subtypes.
Moreover, Albrecht et al. (21) recently criticized that
“malar rash” is often indistinguishable from photosen-
sitivity, and therefore these criteria are not indepen-
dent. “Photosensitivity” is poorly dened in the ACR
criteria as “a result of an unusual reaction to sunlight
by patient’s history or physician’s observation” (12).
In 1986, phototesting with different wavelengths was
developed better to dene sensitivity to ultraviolet (UV)
light in patients with a photosensitive form of CLE (22).
Meanwhile, a standardized protocol for phototesting has
been developed for patients with CLE by considering
multiple factors such as light source, test area, dose of
UV exposure, and frequency of UV irradiation (16).
Interestingly, the history of photosensitivity does not
necessarily predict a positive phototesting result. In the
present study, 45.5% of the CLE patients who denied
any effect of sun exposure on their disease showed
a positive reaction to UVA and/or UVB radiation in
phototesting. This might be due to the latency period of
developing skin lesions after UV exposure in CLE and
the difculty for the patients to realize a relationship
between sun exposure and exacerbation of their disease
(16). Altogether, the ACR criteria are unspecic or as-
sign too much weight to the skin as one expression of a
multi-organ disease (21, 23). As a consequence, patients
without severe systemic involvement are frequently
classied as SLE according to the ACR criteria.
ANA evaluated with HEp-2 cells proved to be reliable
and important indicators of the disease as they were
positive in 58% of the CLE patients. The high propor-
tion (100%) of positive ANA (with a titre of > 1:160) in
ACLE patients compared with the other CLE subtypes
can be explained by the high association of ACLE and
systemic organ involvement. Moreover, anti-dsDNA
antibodies, anti-Ro/SSA and anti-La/SSB antibodies
were also positive in all tested ACLE patients and
revealed further signicant differences between the
various CLE subtypes. In ICLE patients, ANA were
detected in only a small number of patients, which is in
agreement with the literature (19, 24). Of the comple-
ment factors, C3 was most often found to be decreased
(in 8 (19.1%) of 42 tested patients), whereas C4 was
decreased in 4 (9.5%) of 42 tested patients. Further
laboratory parameters, such as C1q, ESR, and CRF, as
well as leucopaenia and proteinuria, were analysed by
the EUSCLE Core Set Questionnaire; however, only
single patients showed pathological results and no sig-
nicant differences were detected between the various
CLE subtypes.
The analysis of treatment strategies in the present
study resulted in an overview of the frequency of thera-
peutic strategies, which were applied in CLE patients;
the respective success rates were also evaluated. Most
(94.0%) of the 50 patients (distributed among all the
different subtypes of CLE) listed sunscreen application
as the most frequently applied treatment. Sunscreens
were further recorded as being successful in prevention
of skin lesions in 76.6% of the patients; therefore, sun-
screens were the most successfully applied preventive
treatment overall. In other studies, it has been shown that
consistent sunscreen photoprotection in patients with
SLE is associated with signicantly better clinical out-
come, such as less frequent renal involvement and a de-
creased need for immunosuppressive treatment (25, 26).
Therefore, it is very important to provide instructions
concerning methods of protection from sunlight and
articial sources of UV radiation (27). Consistent sun
protection can be provided by photoresistant clothing
and applying sunscreens with highly potent chemical or
physical UVA- and UVB-protective lters (28). These
substances should be applied in sufcient amounts (~2
mg/cm
2
) and with a high protection factor (SPF 50) at
least 15–30 min before sun exposure in order to avoid
induction and exacerbation of cutaneous lesions (29).
Topical glucocorticosteroids have proven to be a very
effective treatment for skin lesions in all subtypes of
CLE, reducing symptoms such as redness and scaling
(30). In the present study, the most frequently successful
treatment was topical glucocorticosteroids, yielding
successful results in 56.5% of patients. Due to the well-
known local side-effects (e.g. atrophy, telangiectasia,
dyspigmentation), treatment with topical glucocortico-
steroids is usually limited and preferably intermittent.
Application twice daily for a few days, followed by a
reduction in the frequency of application (with the in-
terruption of treatment lasting a few weeks), may help
to minimize the risks of local side-effects; however,
this practice might also limit the efcacy. Moreover,
recent reports have demonstrated the efcacy of topical
calcineurin inhibitors in CLE, which down-regulate T-
cell activity by inhibiting the calcineurin phosphatase
Acta Derm Venereol 90

393
EUSCLE Core Set Questionnaire analysis
responsible for dephosphorylation of the nuclear factor
in activated T cells (31). In the present study, tacrolimus
and pimecrolimus ointment were applied in 44% of the
patients. In 59.1% of the CLE patients, these topical
agents were reported as being a successful and therefore
promising treatment.
The application of systemic agents becomes necessary
to alleviate and prevent the development of widespread
skin lesions and life-threatening symptoms in CLE pa-
tients. However, only a few randomized, double-blind,
placebo-controlled, multicentre trials are available and
topical and systemic agents are used “off-label” in most
cases (32, 33). In the present study, we demonstrated
that antimalarial agents were the most frequently applied
and also the most effective systemic drugs in CLE. The
value of the study is limited by its small sample size;
however, with the inclusion of more patients in future
studies, the analysis of the EUSCLE Core Set Ques-
tionnaire might serve to improve therapeutic strategies
for the different CLE subtypes.
In summary, this study suggests that the EUSCLE
Core Set Questionnaire is a useful tool to provide an ex-
pedient compilation of parameters for a comprehensive
collection and evaluation of clinical data of the different
CLE subtypes from various centres. Furthermore, it
provides a basis for the development of standardized
diagnostic and therapeutic guidelines to improve the
outcome of patients with CLE. For example, the nding
that proteinuria correlated negatively with the age at
onset of disease points to a greater chance that patients
with an age at onset of disease ≤ 40 years will be more
likely to exhibit renal involvement. This may imply that
CLE patients with an age at onset of disease ≤ 40 years
should be followed with special attention regarding the
potential development of proteinuria. Future and follow-
up studies with a higher number of patients from several
centres throughout Europe will support the analysis of
further prognostic clinical and laboratory parameters
and the improvement of therapeutic strategies for pa-
tients with CLE.
ACKNOWLEDGEMENTS
This work was supported partly by Actelion Pharmaceutical Ltd,
Freiburg, Germany, and by a Heisenberg Scholarship from the
German Research Foundation to AK (KU 1559/1-2).
The authors declare no conflicts of interest.
REFERENCES
Gilliam JN. The cutaneous signs of lupus erythematosus. 1.
Cont Educ Fam Phys 1977; 6: 34–70.
Gilliam JN, Sontheimer RD. Distinctive cutaneous subsets 2.
in the spectrum of lupus erythematosus. J Am Acad Der-
matol 1981; 4: 471–475.
Gilliam JN, Sontheimer RD. Skin manifestations of SLE. 3.
Clin Rheum Dis 1982; 8: 207–218.
Provost TT. Nonspecic cutaneous manifestations of syste-4.
mic lupus erythematosus. In: Kuhn A, Lehmann P, Ruzicka
T, editors. Cutaneous lupus erythematosus. Heidelberg:
Springer, 2004: p. 93–106.
Costner MI, Sontheimer RD, Provost TT. Lupus erythe-5.
matosus. In: Sontheimer RD, Provost TT, editors. Cuta-
neous manifestations of rheumatic diseases. Philadelphia:
Williams & Wilkins, 2003: p. 15–64.
Kuhn A, Ruzicka T. Classication of cutaneous lupus er-6.
ythematosus. In: Kuhn A, Lehmann P, Ruzicka T, editors.
Cutaneous lupus erythematosus. Heidelberg: Springer,
2004: p. 53–58.
Tebbe B, Orfanos CE. Epidemiology and socioeconomic 7.
impact of skin disease in lupus erythematosus. Lupus 1997;
6: 96–104.
Popovic K, Nyberg F, Wahren-Herlenius M. A serology-8.
based approach combined with clinical examination of
125 Ro/SSA-positive patients to define incidence and
prevalence of subacute cutaneous lupus erythematosus.
Arthritis Rheum 2007; 56: 255–264.
The European Medicines Agency. The EMEA recommends 9.
the drug candidate ASF-1096 for orphan drug status. Press
Release, Astion, 2007.
Kuhn A, Kuehn E, Meuth AM, Haust M, Nyberg F, Ruzicka 10.
T, et al. Development of a core set questionnaire for the
evaluation of cutaneous lupus erythematosus. Autoimmun
Rev 2009; 8: 702–712.
Cohen AS, Reynolds WE, Franklin EC, Kulka JP, Ropes 11.
MW, Shulman LE, et al. Preliminary criteria for the clas-
sication of systemic lupus erythematosus. Bull Rheum
Dis 1971; 21: 643–648.
Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Roth-12.
eld NF, et al. The 1982 revised criteria for the classication
of systemic lupus erythematosus. Arthritis Rheum 1982;
25: 1271–1277.
Hochberg MC. Updating the American College of Rheu-13.
matology revised criteria for the classication of systemic
lupus erythematosus. Arthritis Rheum 1997; 40: 1725.
Albrecht J, Taylor L, Berlin JA, Dulay S, Ang G, Fakharza-14.
deh S, et al. The CLASI (Cutaneous Lupus Erythematosus
Disease Area and Severity Index): an outcome instrument
for cutaneous lupus erythematosus. J Invest Dermatol 2005;
125: 889–894.
Albrecht J, Werth VP. Development of the CLASI as an 15.
outcome instrument for cutaneous lupus erythematosus.
Dermatol Ther 2007; 20: 93–101.
Kuhn A, Sonntag M, Richter-Hintz D, Oslislo C, Megahed 16.
M, Ruzicka T, et al. Phototesting in lupus erythematosus: a
15-year experience. J Am Acad Dermatol 2001; 45: 86–95.
Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, 17.
Lavilla P, et al. Systemic lupus erythematosus: clinical and
immunologic patterns of disease expression in a cohort of
1,000 patients. The European Working Party on Systemic
Lupus Erythematosus. Medicine (Baltimore) 1993; 72:
113–124.
Jimenez S, Cervera R, Ingelmo M, Font J. The epidemiology 18.
of cutaneous lupus erythematosus. In: Kuhn A, Lehmann P,
Ruzicka T, editors. Cutaneous lupus erythematosus. Berlin:
Springer-Verlag, 2004: p. 45–52.
Kuhn A, Richter-Hintz D, Oslislo C, Ruzicka T, Megahed 19.
M, Lehmann P. Lupus erythematosus tumidus – a neglec-
ted subset of cutaneous Lupus erythematosus: report of 40
cases. Arch Dermatol 2000; 136: 1033–1041.
Durosaro O, Davis MD, Reed KB, Rohlinger AL. Incidence 20.
of cutaneous lupus erythematosus, 1965–2005: a popula-
tion-based study. Arch Dermatol 2009; 145: 249–253.
Albrecht J, Berlin JA, Braverman IM, Callen JP, Connolly 21.
Acta Derm Venereol 90

394 A. M. Meuth et al.
MK, Costner MI, et al. Dermatology position paper on
the revision of the 1982 ACR criteria for systemic lupus
erythematosus. Lupus 2004; 13: 839–849.
Lehmann P, Hölzle E, von Kries R, Plewig G. Diagnostic 22.
procedures on patients with Photodermatoses. Zentralblatt
Haut- und Geschlechtskrankheiten 1986; 152: 667–682.
Sontheimer RD. The lexicon of cutaneous lupus erythemato-23.
sus – a review and personal perspective on the nomenclature
and classication of the cutaneous manifestations of lupus
erythematosus. Lupus 1997; 6: 84–95.
Alexiades-Armenakas MR, Baldassano M, Bince B, Werth 24.
V, Bystryn JC, Kamino H, et al. Tumid lupus erythemato-
sus: criteria for classication with immunohistochemical
analysis. Arthritis Rheum 2003; 49: 494–500.
Vila LM, Mayor AM, Valentin AH, Rodriguez SI, Reyes 25.
ML, Acosta E, et al. Association of sunlight exposure and
photoprotection measures with clinical outcome in systemic
lupus erythematosus. P R Health Sci J 1999; 18: 89–94.
Schmidt E, Tony HP, Brocker EB, Kneitz C. Sun-induced 26.
life-threatening lupus nephritis. Ann N Y Acad Sci 2007;
1108: 35–40.
Kuhn A, Beissert S. Photosensitivity in lupus erythemato-27.
sus. Autoimmunity 2005; 38: 519–529.
Herzinger T, Plewig G, Rocken M. Use of sunscreens to 28.
protect against ultraviolet-induced lupus erythematosus.
Arthritis Rheum 2004; 50: 3045–3046.
Faurschou A, Wulf HC. The relation between sun protec-29.
tion factor and amount of suncreen applied in vivo. Br J
Dermatol 2007; 156: 716–719.
Lehmann P. Topical treatment of cutaneous lupus ery-30.
thematosus. In: Kuhn A, Lehmann P, Ruzicka T, editors.
Cutaneous lupus erythematosus. Berlin: Springer, 2004:
p. 337–345.
Sardy M, Ruzicka T, Kuhn A. Topical calcineurin inhibi-31.
tors in cutaneous lupus erythematosus. Arch Dermatol Res
2009; 301: 93–98.
Heath M, Raugi GJ. Evidence-based evaluation of immuno-32.
modulatory therapy for the cutaneous manifestations of
lupus. Adv Dermatol 2004; 20: 257–291.
Wenzel J, Bieber T, Uerlich M, Tuting T. Systemic treatment 33.
of cutaneous lupus erythematosus. J Dtsch Dermatol Ges
2003; 1: 694–704.
Acta Derm Venereol 90