- Email: [email protected]
Phototesting in lupus erythematosus: A 15-year experience
Phototesting in lupus erythematosus: A 15-year experience Annegret Kuhn, MD, Monika Sonntag, MD, Dagmar Richter-Hintz, MD, Claudia Oslislo, MD, Mosaad Megahed, MD, Thomas Ruzicka, MD, and Percy Lehmann, MD Düsseldorf, Germany It has long been observed that sun exposure can induce or exacerbate skin lesions in patients with certain forms of lupus erythematosus. Despite the frequency of photosensitivity in these patients, the mechanism by which ultraviolet radiation alters the pathogenic course of this disease remains poorly understood. After development of standardized test methods, our group demonstrated in 1986 that skin lesions in patients with lupus erythematosus can be experimentally reproduced by UVA and UVB irradiation. In the following years, phototesting has received much attention as a valid model to study photosensitivity of different forms of lupus erythematosus and the pathogenetic mechanism of this disease. Further investigations have also made it possible to find genetic and immunologic factors associated with photosensitivity and have helped to identify the pathophysiologic steps involved in the induction of such skin lesions. We present phototesting results and clinical correlations of more than 400 patients with different forms of lupus erythematosus and discuss the recent advances in provocative phototesting. (J Am Acad Dermatol 2001; 45:86-95.)
T
he original concept of photosensitivity in lupus erythematosus (LE) was based on observations made since the beginning of the 19th century. Many articles in the literature had documented that in all forms of LE, cutaneous manifestations are found predominantly on sun-exposed areas, such as the face, V area of the neck, and extensor aspects of the arms, and that exposure to sunlight can induce new skin eruptions, exacerbate existing lesions, cause progression of the disease to non-UV-exposed areas, or induce systemic activity.1-3 However, the incidence of such photosensitivity varied greatly in different studies; therefore, since 1965, reproduction of skin lesions by exposure to UV radiation (UVR) with specific test protocols has been reported.4 In the following years, photosensitivity became a well-established factor in the pathogenesis of LE in clinical and experimental settings and was included as a discriminating factor in the revised cri-
From the Department of Dermatology, Heinrich-Heine-University. Supported by a Lise-Meitner scholarship and a research grant of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany (to A. Kuhn). Accepted for publication Jan 16, 2001. Reprint requests: Annegret Kuhn, MD, Institute of Cell Biology, ZMBE, Westfälische Wilhelms-University, Von-Esmarch-Strasse 56, D-48149 Münster, Germany. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/1/114589 doi:10.1067/mjd.2001.114589
86
teria of the American Rheumatism Association (ARA) for the classification of systemic LE (SLE).5 Results of earlier studies of experimental photoprovocation indicated that characteristic skin lesions of LE could be induced by repeatedly delivering high doses of UVB to the same test site.6,7 In 1986, our group8 demonstrated that the action spectrum of LE reaches into the long-wave UVA region, and, in the following years, a total of 128 patients were investigated.9 Characteristic skin lesions clinically and histologically compatible with LE were experimentally induced by UVA or UVB irradiation in 43% of patients. A practical consequence of UVA sensitivity is that patients with LE are not adequately protected by glass covers or by conventional sunscreens, which mostly absorb UVA poorly. Moreover, high-intensity UVA sources in tanning salons might be dangerous for these patients.10,11 In the ensuing 15 years, this testing regimen has received much attention because photoprovocation is an optimal way to evaluate photosensitivity. Furthermore, the capacity of UVA and UVB irradiation to reproduce LE skin lesions is an ideal model for several experimental approaches, which allow the study of inflammatory and immunologic events that take place before and during lesion formation (for review see Sontheimer12). In addition, phototesting has proved to be useful in further characterizing a highly photosensitive form of cutaneous LE (CLE), lupus erythematosus tumidus (LET).13 Therefore we were interested to impart the informa-
Kuhn et al 87
J AM ACAD DERMATOL VOLUME 45, NUMBER 1
Table I. Demographic data and threshold doses for MED, IPD, and MTD of patients included in the study Threshold doses
Disease
LE DLE (n = 94) LET (n = 70) SCLE (n = 81) CLE* (n = 133) SLE (n = 27) Total (n = 405) Controls PLE (n = 340) Others† (n = 200) Total (n = 540)
Age (y) mean ± SD
Sex M/F (No.)
MED-UVB (mJ/cm2) mean ± SD
IPD (J/cm2) mean ± SD
MTD (J/cm2) mean ± SD
42.7 ± 14.6 42.5 ± 14.6 42.5 ± 14.6 42.5 ± 15.8 42.2 ± 14.6 42.6 ± 14.6
33/61 30/40 16/65 54/79 6/21 139/266
102.5 ± 39.7 106.9 ± 36.1 96.4 ± 37.3 94.7 ± 32.3 92.7 ± 31.6 99.5 ± 36.1
38.0 ± 24.8 43.9 ± 20.8 40.4 ± 19.2 33.8 ± 20.9 40.9 ± 24.3 38.8 ± 21.9
46.7 ± 22.4 52.0 ± 21.9 52.7 ± 23.8 45.7 ± 22.0 46.8 ± 21.1 48.8 ± 22.5
36.9 ± 14.3 47.0 ± 17.2 40.7 ± 16.2
75/265 71/129 146/394
102.5 ± 38.1 92.4 ± 39.6 97.4 ± 39.2
32.7 ± 19.3 42.3 ± 22.7 36.4 ± 21.2
44.9 ± 21.9 52.7 ± 22.4 47.9 ± 22.4
CLE, Cutaneous lupus erythematosus; DLE, discoid lupus erythematosus; LET, lupus erythematosus tumidus; PLE, polymorphous light eruption; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus. *Including various forms of CLE such as hypertrophic lupus erythematosus, lupus erythematosus profundus, and chilblain lupus erythematosus. †Including reticular erythematous mucinosis, lymphocytic infiltration Jessner-Kanof, pseudolymphoma, chronic actinic dermatitis, rosacea, urticaria, atopic eczema, psoriasis, dermatomyositis, and pemphigoid.
tion obtained with this phototesting regimen on the occasion of its 15th “anniversary.” To accomplish this goal, we report on our experience with more than 400 patients with different forms of LE who underwent phototesting in our department since 1990. The protocol for provocative phototesting has been optimized by taking into account multiple factors, such as light source, test area of the irradiated skin, site of irradiation, dose of UV exposure, frequency of irradiation, and time needed to induce lesions. Furthermore, because the profound effects of UVR on the cutaneous immune response have been studied extensively in the past few years, we will also discuss the potential function of UVR on the induction of CLE and the potential interplay of specific autoantibodies in concert with UVR in these patients.
PATIENTS, MATERIAL, AND METHODS Patients Photoprovocation tests were performed in 405 white patients (139 men [34%] and 266 women [66%]) with different forms of LE seen at the Department of Dermatology, Heinrich-Heine-University, Düsseldorf, Germany (Table I). The study included 94 patients with discoid LE (DLE); 70 with LET; 81 with subacute CLE (SCLE); 133 with various other forms of CLE, such as LE profundus, hypertrophic/verrucous LE, and chilblain LE; and 27 with SLE. Diagnosis of the forms of CLE was based on clinical and histopathologic findings, and diagnosis of SLE was made when at least 4 of the revised SLE criteria of the ARA were present.5 The
mean age of patients with LE was 42.6 ± 14.6 (± SD) years (range, 5.0-86.0 years), showing no significant difference with respect to the different clinical subtypes. None of the patients received systemic medication for their skin disease at the time of photoprovocation, and all patients underwent medical history, physical examination, and routine blood analysis. For control purposes, 540 patients (146 men [27%] and 394 women [73%]) with skin diseases other than LE were also studied (mean age, 40.7 ± 16.2 years; range, 3.0-83.0 years) (Table I). The investigations were approved by the local ethics committee. Phototesting procedure The light sources used included a high-pressure metal halide lamp (330-460 nm, UVASUN 3000, Mutzhas, Munich, Germany; or 340-440 nm, UVA1Sellas 2000, Sellas, Medizinische Geräte, Gevelsberg, Germany) for UVA phototesting and a UV-800 unit lamp with fluorescent bulbs (285-350 nm; Philipps TL 20 W/12; Waldmann, Villingen/Schwenningen, Germany) for UVB phototesting. Irradiation output was monitored by means of a UV radiometer (UVAMETER, Mutzhas) and a UV spectrometer (Waldmann). Minimal erythema dose, immediate pigment darkening, and minimal tanning dose Minimal erythema dose (MED), threshold dose for immediate pigment darkening (IPD), and minimal tanning dose (MTD) were determined according
88 Kuhn et al
J AM ACAD DERMATOL JULY 2001
A
C
B
Fig 1. Positive photoprovocation test reactions on the back of patients with different subsets of lupus erythematosus. Appearance of characteristic skin lesions 1 week after UVA irradiation (A), after UVB irradiation in DLE (B), and 1 week after combined UVA and UVB irradiation in LET (C).
Table II. Results of provocative phototesting in lupus erythematosus Positive phototesting results/tested patients, No. (%) Diagnosis
DLE (n = 74) LET (n = 62) SCLE (n = 63) CLE* (n = 104) SLE (n = 20) Total (n = 323)
Total
UVA
UVB
UVA + UVB
33/74 (45) 47/62 (76) 40/63 (63) 43/104 (41) 12/20 (60)
16/74 (22) 32/62 (52) 26/63 (41) 26/104 (25) 10/20 (50)
27/74 (36) 31/62 (50) 33/63 (52) 34/104 (33) 12/20 (60)
5/10 (50) 18/27 (67) 3/6 (50) 1/7 (14) 1/3 (33)
175/323 (54)
110/323 (34)
137/323 (42)
28/53 (53)
*Including various forms of CLE such as hypertrophic lupus erythematosus, lupus erythematosus profundus, and chilblain lupus erythematosus.
to standard procedures.8,14,15 Test reactions were read immediately and 24 hours after irradiation. Provocative phototesting For provocative phototesting, areas (4 × 5 cm) of uninvolved skin on the upper back or extensor aspects of the arms were irradiated with single doses of UVA (100 J/cm2) or UVB (1.5 MED), respectively, daily for 3 consecutive days. Test areas were evaluated until specific lesions appeared for up to 4 weeks after the last irradiation. Controls were provoked according to this protocol. Selection and preparation of biopsy specimens Skin biopsy specimens were taken from primary lesions of all patients with untreated LE and from
pathologic provocation reaction sites after UVA or UVB irradiation. Tissues were fixed, embedded, and stained with hematoxylin-eosin for routine histologic evaluation or immediately frozen and stored at –80°C for direct immunofluorescence studies. Criteria for positive provocation tests Criteria for a positive provocative phototest result required that (1) the induced lesions clinically resembled LE, (2) the histopathologic findings were compatible with LE, and (3) the skin lesions developed slowly and persisted for several days or weeks. Serologic evaluations Antinuclear antibodies (ANAs) were assayed by a standard indirect immunofluorescence technique with
Kuhn et al 89
J AM ACAD DERMATOL VOLUME 45, NUMBER 1
Fig 2. Time course of induction of skin lesions after photoprovocation in patients with polymorphous light eruption (PLE, n = 110) and lupus erythematosus (LE, n = 175).
commercially available HEp-2 cells (Bio-Rad SDP GmbH, Freiburg, Germany). With this assay technique, serum ANA titers greater than 1:160 are abnormal compared with those of healthy controls, and anti-Ro(SS-A) and anti-La(SS-B) antibodies were determined by standardized enzyme-linked immunosorbent assays (ELISA; DPC Biermann, Bad Nauheim, Germany).
Table III. Relation between provocative phototest reaction and medical history of photosensitivity in lupus erythematosus
History of photosensitivity
Positive
Negative
Statistical analysis For testing associations with clinical data, the MannWhitney test was performed, and for testing associations between photoprovocation results and autoantibodies or photosensitivity, the χ2 test was performed to determine statistical significance. Confidence intervals were determined at 95%, and P values less than .05 were considered statistically significant.
Positive (n = 94) Negative (n = 71)
58 (62) 41 (58)
36 (38) 30 (42)
RESULTS Erythematous and pigmentary reactions The MED-UVB in 405 patients with different forms of LE was 99.5 ± 36.1 mJ/cm2, compared with 97.4 ± 39.2 mJ/cm2 in 540 patients in the control group (Table I). For UVA, the IPD threshold dose was 38.8 ± 21.9 J/cm2 and the MTD was 48.8 ± 22.5 J/cm2 in patients with LE compared with 36.4 ± 21.2 J/cm2 and 47.9 ± 22.4 J/cm2, respectively, in the control group. Statistical analysis revealed no significant differences in the time course with respect to the different clinical subtypes of LE or between these patients and the control group. Results of 15 years of provocative phototesting All 405 patients with different forms of LE underwent the phototesting procedure; however, ques-
Provocative phototest reaction, No. (%)
tionable results were found in 33 patients (8%), and 49 (12%) were not available for follow-up. Experimental reproduction of skin lesions was successful with UVA and/or UVB irradiation (Fig 1) and results from the remaining 323 patients with LE are presented in Table II. Altogether, skin lesions characteristic for LE were observed in 175 (54%) of 323 patients; 137 patients (42%) reacted to UVB irradiation only, and 110 (34%) to UVA irradiation only. Fifty-three patients were tested with combined UVA and UVB irradiation, and 28 of these patients (53%) displayed characteristic skin lesions. Patients with LET showed the highest frequency of positive phototest reactions, and, in our study, experimental phototesting revealed characteristic skin lesions in 47 (76%) of 62 patients with LET. Furthermore, skin lesions characteristic of LE were induced in 40 (63%) of 63 patients with SCLE, in 12 (60%) of 20 patients with SLE, and in 33 (45%) of 74 patients with DLE. Approximately 60% of patients were aware of an adverse effect of sunlight on their disease, and 62% showed pathologic test reactions (Table III). Patho-
90 Kuhn et al
J AM ACAD DERMATOL JULY 2001
Fig 3. Correlation between positive photoprovocation test reactions and antinuclear antibodies (ANAs), anti-Ro(SS-A) antibodies, and anti-La(SS-B) antibodies in patients with different forms of LE.
logic test reactions were also induced in 58% of patients who denied any effect of sun exposure on their disease. The onset of positive phototest reactions in LE was significantly slower and persisted longer than reactions in controls with other photodermatoses, such as polymorphous light eruption (Fig 2). In general, pathologic reactions in patients with LE appeared within 1 week (range, 1 day to 3 weeks) after irradiation and lasted for approximately 1 week to 2 months. Statistical analysis revealed no significant differences with respect to the different clinical subtypes of LE. In some cases, hypopigmentation or hyperpigmentation occurred in the test areas that persisted for several weeks after UV exposure. Histopathologic findings of UV-induced skin lesions The experimentally induced skin lesions produced by UVA and UVB showed histopathologically no significant differences compared with primary lesions of the different LE subtypes. Even in early lesions of DLE, epidermal changes such as hyperkeratosis and follicular plugging are present and might be accompanied by a thinned epidermis. Furthemore, in early lesions of DLE lymphocytes are arranged around the superficial plexus only, whereas
in later lesions, they are present around venules of superficial and deep plexuses. Fully developed lesions of DLE are marked by vacuolar alteration of the dermoepidermal junction and, in some cases, by a thickened basement membrane zone. Interstitial mucin deposits in variable amounts might be present. Lesions of SCLE have generally less hyperkeratosis and follicular plugging, and the epidermis is atrophic and displays vacuolar degeneration at the dermoepidermal junction. The sparse infiltrate is usually confined to the papillary dermis and consists of lymphocytes, and interstitial mucin deposits are also present. In LET, the epidermis is normal or slightly acanthotic and changes at the dermoepidermal junction are not found. Abundant mucin deposits are prominent in all patients. There is a perivascular and periadnexal superficial or deep lymphocytic infiltrate and, in some cases, scattered neutrophils are seen. The density of the infiltrate differs from slight to moderate. Direct immunofluorescence of UV-induced skin lesions In accordance with our previous findings, none of the UV-induced lesions showed immunoglobulin deposits at the dermoepidermal junction or around vessels.9,16,17
Kuhn et al 91
J AM ACAD DERMATOL VOLUME 45, NUMBER 1
Table IV. Phototesting in lupus erythematosus: Review of the literature since 1986 Positive phototest reactions in different subtypes of LE
Year
Authors
Tested patients/ Total No.
DLE
LET
SCLE
SLE
1986
Lehmann et al8
27/67 (40%)
40%
–
90%
10%
1989
Wolska et al18
49/202 (24%)
16%
–
63%
24%
1989 1990
Van Weelden et al19 Lehmann et al9
20/24 (83%) 55/128 (43%)
78% 42%
– –
88% 64%
86% 25%
1991
Beutner et al20
90/115 (78%)
60%
–
100%
74%
1993
Kind et al17
81/150 (54%)
36%
81%
63%
35%
1993
Nived et al21
6/23 (26%)
–
–
–
26%
1997
Walchner et al22
29/68 (43%)
39%
–
50%
40%
1997
Hasan et al23
46/67 (69%)
64%
–
100%
70%
1999
Leenutaphong and Boonchai24
6/15 (40%)
44%
–
–
33%
Association of autoantibodies with positive phototesting results Laboratory tests revealed ANAs with titers greater than 1:160 in 58 patients with LE (23%), and 61 (25%) of 248 tested patients showed a borderline result with titers of 1:160. The ANA fluorescence pattern was finely speckled or homogenous. AntiRo(SS-A) antibodies were detected in 39 patients (16%), and anti-La(SS-B) antibodies in 24 (10%). Interestingly, patients with a pathologic reaction to the UV provocation test revealed anti-Ro(SS-A) or anti-La(SS-B) antibodies more often than those with a negative phototest reaction; however, this was dependent on the clinical subtype of LE and was not statistically significant (Fig 3).
DISCUSSION In 1986, our group8 established standardized methods for testing photosensitive diseases, and, moreover, we showed that the action spectrum of LE included UVA in addition to UVB.9,17 Further studies by other groups followed, confirming that skin lesions in this disease might also occur after UVA irradiation (Table IV).18-24 During the past 15 years, protocols for phototesting in LE have been optimized by taking into account multiple factors (Table V). Nonlesional, non-sun-exposed areas of the upper back or extensor aspects of the arms were used for performance of the phototest reactions because other parts of the skin
Comment
First description of positive reactions after UVA irradiation Reproduction of skin lesions after single exposure of UVR Phototesting with visible light Induction of skin lesions with UVA and UVB irradiation Association between anti-Ro(SS-A) antibodies and systemic involvement Histologic studies of early and late UV-induced skin lesions More pronouncement of reactions to long-wave UVA light Overview on phototesting and photoprotection Comparison of photosensitivity and photoprovocation results Phototesting in Asian patients
might not react to the same extent, probably because of some kind of local predisposition of unknown nature other than UVR, such as thickness of the stratum corneum, vascularization, presence of antigens, or distribution of antigen-presenting cells.22 Furthermore, it is important to use a defined test area that should be sufficiently large to provide reactions. Onset of LE skin lesions is characterized by a latency of several days to 3 weeks, and they might persist in some patients for several months. For this reason, it might be difficult for patients to recognize the association between sun exposure and induction of lesions. Although provocation of a systemic disease in patients with SLE has not been observed, these patients should be watched carefully. During the past 15 years, photoprovocation test reactions have been evaluated in more than 400 patients with different forms of LE, and pathologic reactions were induced in 54%. In addition to our previous studies, combined UVA and UVB irradiation has been performed in the past few years, and, interestingly, most patients were provoked by this kind of testing regimen (Table II). It has been confirmed that the development of positive phototest reactions in patients with LE is considerably slower and that lesions persist longer than in other photodermatoses, such as polymorphous light eruption (Fig 2). Furthermore, there are substantial differences in clinical subsets with regard to response to UVR.
92 Kuhn et al
J AM ACAD DERMATOL JULY 2001
Table V. What have we learned about phototesting in lupus erythematosus in the past 15 years? Criteria
Test site Size of test field Pretesting
Dosage Evaluation Light sources
Pretreatment
Results
Comments
Non-sun-exposed, unaffected areas of the upper back or extensor aspects of arms Defined test areas should be sufficiently large to provide reactions (4 × 5 cm) MED, IPD, MTD
100 J/cm2 UVA and/or 1.5 MED-UVB on 3 consecutive d 24, 48, 72 h up to 4 wk after last irradiation UVA: UVASUN 3000 (330-460 nm), Mutzhas or UVA1 Sellas 2000 (340-440 nm), Sellas UVB: UV-800 with fluorescent bulbs, Philipps TL 20 W/12 (285-350 nm), Waldmann No pretreatment
Medication
If possible, no systemic medication for skin disease
Photosensitivity
Phototesting results are not always associated with photosensitivity
Criteria for positive photoprovocation
• Induced skin lesions clinically resemble LE • Skin lesions appear slowly over several days or weeks • Skin lesions persist up to several months • Clinical diagnosis is confirmed by histology UVA and UVB: 53% UVB: 42% UVA 34% LET: 76% SCLE: 63% DLE: 45% SLE: 60% Persistence of hyperpigmentation and hypopigmentation for several months after irradiation Exacerbation of cutaneous lesions in a few patients, no provocation of systemic disease in our studies
Results of phototesting (different wavelength) Results of phototesting (different LE subtypes) Local side effects
Induction of disease
Antibodies
Significant association between positive phototest results and anti-Ro(SS-A) or anti-La(SS-A) antibodies
Patients with LET had been found to be more photosensitive than patients with SCLE, and because LET has rarely been documented in the literature and is often difficult to differentiate from other photodermatoses, such as polymorphous light eruption,
Other parts of the skin might not react to the same extent Too small test areas or test areas different in size might not show reproducible results Testing of the MED is necessary to make data comparable; a prolonged erythematous response was not a conspicuous feature in our studies Single UV exposure is unlikely to induce positive reactions in all possible patients Follow-up shorter than 3 wk might miss positive provocative phototest results in some patients Different light sources with a different action spectrum can result in different numbers of positive phototests Any topical or systemic pretreatment might affect the phototesting procedure Systemic medication, such as antimalarial agents, corticosteroids, and immunosuppressive drugs might lead to false-negative results It might be difficult for patients to recognize the association between sun exposure and induction of skin lesions Positive phototest reactions are considerably slower and persist longer than other photodermatoses, such as polymorphous light eruption, persistent light reaction, photoallergy, hydroa vacciniforme, and solar urticaria Differences in phototest results are found because of different protocols and age of patients at onset of disease Differences in phototest results are found because of different protocols; LET patients are more photosensitive than SCLE patients Patients should be reminded of these possible side effects because they might lead to cosmetic problems Follow-up of SLE patients after phototesting is very important because reports in the literature describe exacerbation of systemic disease under phototesting Positive photoprovocation results in Ro(SS-A)and La(SS-B)-positive patients strengthen the role of these autoantigens in the pathomechanism of UV-induced LE skin lesions
this phototesting model proved to be useful in further characterizing this chronic form of CLE.13 Results of reported phototesting in patients with LE often differ between various groups because there are numerous technical differences between
Kuhn et al 93
J AM ACAD DERMATOL VOLUME 45, NUMBER 1
Table VI. Reported photosensitivity and provocative phototest reactions in different subsets of LE Diagnosis
DLE LET SCLE SLE
Reported photosensitivity5,13,20,22,26-52
Positive photoprovocation8,9,13,17-24
25%-90% 43%-50% 27%-100% 6%-94%
10%-64% 70%-81% 50%-100% 25%-85%
the studies that could explain the different findings (Table VI).8,9,13,17-24 Varying factors are light source, energy dose, wavelength, time points of provocation and evaluation, and location and size of test area. Most studies were conducted in white patients; however, there is one recent article on phototesting in 15 Asian patients with LE.24 Using exactly the same test protocol as our group, the incidence of positive phototest reactions in these patients seemed to be similar to or a little lower than that in white patients; there was also no correlation between a positive history of UV sensitivity and phototest reactions. Furthermore, classification of positive test results might be difficult in some patients because persistent erythema can occur, which is even hard to interpret histologically. It is also unclear why skin lesions cannot always be reproduced under the same conditions several months after the initial phototest and why phototesting results are not positive in all patients with LE who are tested, providing indirect evidence for variant factors in the pathophysiology of LE.25 A history of photosensitivity in patients with LE does not necessarily predict positive reactions on phototesting, and results of reported photosensitivity often differ between various groups (Table VI).5,13,22,26-52 This might be because skin lesions after UVR do not appear rapidly after sun exposure and, therefore, a relationship between sun exposure and exacerbation of LE does not seem obvious to the patient. An additional factor might be the age at onset of disease, as observed by Walchner, Messer, and Kind,22 who demonstrated that mainly patients younger than 40 years reported photosensitivity. Furthermore, the occurrence of photosensitivity varies between different types of LE, and some ethnic groups such as African blacks seem to be less photosensitive than others.36,40,42,45,46,49 Nevertheless, the term photosensitivity (skin rash as a result of unusual reaction to sunlight by patient history or physician observation) is poorly defined,53 although it is listed as one of the ARA criteria for the classification of SLE.5 In 1996, a high discrepancy between a personal history of photosensitivity and a decreased MED was documented by Doria et al,29 concluding
that the use of photosensitivity as a classification criterion for SLE remains questionable, at least when it is assessed according to the ARA criteria. In general, results of histopathologic and immunopathologic examination of UV-induced LE lesions are similar to the findings of spontaneously occurring primary skin lesions, but can give further insight into the earliest pathologic events in CLE lesions. Kind, Lehmann, and Plewig17 demonstrated that histopathologic examination of early UV-induced lesions (up to 10 days) in patients with CLE and SLE shows nonspecific changes such as superficial perivascular lymphocytic infiltration. On the other hand, late UV-induced lesions (more than 10 days) were characterized by parakeratosis, few necrotic basal keratinocytes, and vacuolar degeneration of the dermoepidermal zone. Furthermore, under experimental conditions the appearance of immunoglobulins in UV-induced LE lesions has been reported as a late phenomenon, and in our study, direct immunofluorescence findings were negative in all skin lesions investigated up to 3 weeks after UV exposure. This is in accordance with the findings of Cripps and Rankin,7 who detected the first immunoglobulin deposits 6 weeks after irradiation and mainly along the basement membrane. In contrast, Velthuis et al54 demonstrated that in UV-induced lesions of patients with LE, immunohistochemical changes can be induced similar to those in spontaneously evolved lesions. Furthermore, Nyberg, Skoglund, and Stephansson55 observed that in experimentally UV-induced lesions of patients with LE, dustlike particles, a specific fine-speckled, epidermalsubepidermal direct immunofluorescence staining pattern, can be detected within 2 weeks after UV exposure. A potential interplay of UVR with specific autoantibodies, particularly anti-Ro(SS-A) and anti-La(SS-B) antibodies, has been previously reported, and in different subtypes of LE, such as SCLE and neonatal LE, photosensitivity has been found to be strongly associated with the presence of such antibodies (for review see Lee and Farris53). Our observation strengthens the involvement of these autoantibodies in the pathogenetic mechanism of UV-induced skin lesions (Fig 3). Results of an early study by LeFeber et al56 indicated
94 Kuhn et al
that UVR of cultured keratinocytes led to increased IgG binding to the cell surface of keratinocytes; several years later, Norris57 noted increased antibody binding as a result of in vivo UVR to human skin. Golan et al58 independently observed UV-induced binding of antibodies from Ro(SS-A)-positive sera to a small percentage of cultured keratinocytes. Nevertheless, the strongest evidence supporting the possibility that these antibodies are involved in the pathogenesis of LE comes from patients with neonatal LE.59 These infants have maternally acquired anti-Ro(SS-A) antibodies and experience SCLE-like skin lesions, and because these antibodies are cleared from the infants’ circulation several months after birth, the skin lesions resolve spontaneously.60 In DLE, the association of skin disease with antibodies is much less clear, and, in previous studies, a clear association between the presence of anti-Ro(SS-A) antibodies and the clinical finding of photosensitivity was not found.53 However, because similar levels of anti-Ro(SS-A) antibodies are seen in other disorders such as Sjögren’s syndrome that are not usually associated with specific LE lesions, other factors must be involved in the production of LE inflammation. Results published to date suggest that UVR is of major importance in the induction of skin lesions in patients with different forms of LE, in particular LET and SCLE; however, the pathogenetic mechanisms of UV-induced lesions have not been fully elucidated. In the past 15 years, we have shown that phototesting with UVA and UVB irradiation is an optimal model to analyze the steps involved in the induction of such skin lesions because it allows the study of events that take place proximate to lesion formation. Therefore we are confident that provocative phototesting with standardized protocols will help to identify the pathogenesis of this disease in the future. REFERENCES 1. Pusey WA. Attacks of lupus erythematosus following exposure to sunlight or other weather factors. Arch Dermatol Syphil 1915;33:388. 2. Macleod JMH. Lupus erythematosus: some observations on its etiology. Arch Dermatol Syphil 1924;9:1-12. 3. Freund H. Inwiefern ist der Lupus erythematodes von allgemeinen Faktoren abhängig? Dermatol Wochenschr 1929;89: 1939-46. 4. Epstein JH, Tuffanelli DL, Dubois EL. Light sensitivity and lupus erythematosus. Arch Dermatol 1965;91:483-5. 5. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271-7. 6. Freeman RG, Knox JM, Owens DW. Cutaneous lesions of lupus erythematosus induced by monochromatic light. Arch Dermatol 1969;100:677-82. 7. Cripps DJ, Rankin J. Action spectra of lupus erythematosus and experimental immunofluorescence. Arch Dermatol 1973;107: 563-7.
J AM ACAD DERMATOL JULY 2001
8. Lehmann P, Hölzle E, v. Kries R, Plewig G. Lichtdiagnostische Verfahren bei Patienten mit Verdacht auf Photodermatosen. Zbl Haut- und Geschl-Kr 1986;152:667-82. 9. Lehmann P, Hölzle E, Kind P, Goerz G, Plewig G. Experimental reproduction of skin lesions in lupus erythematosus. J Am Acad Dermatol 1990;22:181-7. 10. Stern RS, Docken W. An exacerbation of SLE after visiting a tanning salon. JAMA 1986;255:3120. 11. Tronnier H, Petri H, Pierchalla P. UV-provozierte bullöse Hautveränderungen bei systemischem Lupus erythematodes. Z Hautkr 1988;154: 616-7. 12. Sontheimer RD. Photoimmunology of lupus erythematosus and dermatomyositis: a speculative review. Photochem Photobiol 1996;63:583-94. 13. Kuhn A, Richter-Hintz D, Oslislo C, Ruzicka T, Megahed M, Lehmann P. Lupus erythematosus tumidus: a neglected subset of cutaneous lupus erythematosus—report of 40 patients. Arch Dermatol 2000;136:1033-41. 14. Hölzle E, Plewig G, Lehmann P. Photodermatoses: diagnostic procedures and their interpretation. Photodermatology 1987;4: 109-14. 15. Lehmann P. Photodiagnostische Testverfahren. In: Macher E, Kolde G, Bröcker EB, editors. Jahrbuch der Dermatologie 1992/1993. Zülpich, Germany: Biermann Verlag; 1992. p. 81-100. 16. Kind P, Lehmann P. Photobiologie des Lupus erythematodes. Hautarzt 1990;41:66-71. 17. Kind P, Lehmann P, Plewig G. Phototesting in lupus erythematosus. J Invest Dermatol 1993;100:53S-7S. 18. Van Weelden H, Velthuis PJ, Baart de la Faille H. Light-induced skin lesions in lupus erythematosus: photobiological studies. Arch Dermatol Res 1989;281:470-4. 19. Wolska H, Blazczyk M, Jablonska S. Phototests in patients with various forms of lupus erythematosus. Int J Dermatol 1989;28: 98-103. 20. Beutner EH, Blaszczyk M, Jablonska S, Chorzelski TP, Kumar V, Wolska H. Studies on criteria of the European Academy of Dermatology and Venerology for the classification of cutaneous lupus erythematosus, I. Selection of clinical groups and study factors. Int J Dermatol 1991;30:411-7. 21. Nived O, Johansen PB, Sturfelt G. Standardized ultraviolet-A exposure provokes skin reaction in systemic lupus erythematosus. Lupus 1993;2:247-50. 22. Walchner M, Messer G, Kind P. Phototesting and photoprotection in LE. Lupus 1997;6:167-74. 23. Hasan T, Nyberg F, Stephansson E, Puska P, Hakkinen M, Sarna S, et al. Photosensitivity in lupus erythematosus, UV photoprovocation results compared with history of photosensitivity and clinical findings. Br J Dermatol 1997;136:699-705. 24. Leenutaphong V, Boonchai W. Phototesting in oriental patients with lupus erythematosus. Photodermatol Photoimmunol Photomed 1999;15:7-12. 25. Higuchi D, Ogura Y, Watanabe H, Takiuchi I. Experimental production of DLE lesion with a single exposure to UVB (2.7 MEDs) radiation. J Dermatol 1991;18:545-8. 26. Callen JP. Discoid lupus erythematosus: variants and clinical associations. Clin Dermatol 1985;3:49-57. 27. Callen JP, Klein J. Subacute cutaneous lupus erythematosus: clinical, serologic, immunogenetic, and therapeutic considerations in seventy-two patients. Arthritis Rheum 1988;31:100713. 28. Drosos AA, Dimou GS, Siamopoulou-Mavridou A, Hatzis J, Moutsopoulos HM. Subacute cutaneous lupus erythematosus in Greece: a clinical, serological, and genetic study. Ann Med Interne 1990;141:421-4. 29. Doria A, Biasinutto C, Ghirardello A, Sartori E, Rondinone R,
J AM ACAD DERMATOL VOLUME 45, NUMBER 1
30. 31.
32.
33.
34. 35.
36.
37.
38.
39.
40.
41.
42.
43.
44. 45.
Piccoli A, et al. Photosensitivity in systemic lupus erythematosus: laboratory testing of ARA/ACR definition. Lupus 1996;5: 263-8. Dubois EL, editor. Lupus erythematosus. 2nd ed. Los Angeles: University of Southern California Press; 1974. Grigor R, Edmonds J, Lewkonia R, Bresnihan B, Hughes GRV. Systemic lupus erythematosus: a prospective analysis. Ann Rheum Dis 1978;37:121-8. Harvey AM, Shulman LE, Tumulty PA, Conley CL, Schoenrich EH. Systemic lupus erythematosus: review of the literature and clinical analysis of 138 cases. Medicine 1954;33:291-437. Herrero C, Bielsa I, Font J, Lozano F, Ercilla G, Lecha M, et al. Subacute cutaneous lupus erythematosus: clinicopathologic findings in thirteen cases. J Am Acad Dermatol 1988;19:105762. Hymes SR, Russell TJ, Jordon RE. The anti-Ro antibody system. Int J Dermatol 1986;25:1-7. Lee PL, Urowitz MB, Bookman AM, Koehler BE, Smythe HA, Gordon DA, et al. Systemic lupus erythematosus: a review of 110 cases with reference to nephritis, the nervous system, infections, aseptic necrosis and prognosis. Q J Med 1977;46:132. Mody GM, Parag KB, Nathoo BC, Pudifin DJ, Duursma J, Seedat YK. High mortality with systemic lupus erythematosus in hospitalized African blacks. Br J Rheumatol 1994;33:1151-3. Mond CB, Peterson MG, Rothfield NF. Correlation of anti-Ro antibody with photosensitivity rash in systemic lupus erythematosus patients. Arthritis Rheum 1989;32:202-4. O’Loughlin S, Schroeter AL, Jordon RE. A study of lupus erythematosus with particular reference to generalized discoid lupus. Br J Dermatol 1978;99:1-11. Pande I, Sekharan NG, Kailash S, Uppal SS, Singh RR, Kumar A, et al. Analysis of clinical and laboratory profile in Indian childhood systemic lupus erythematosus and its comparison with SLE in adults. Lupus 1993;2:83-7. Petri M, Perez-Gutthann S, Craig Longenecker J, Hochberg M. Morbidity of systemic lupus erythematosus: role of race and socioeconomic status. Am J Med 1992;91:345-53. Pistiner M, Wallace DJ, Nessim S, Metzger AL, Klinenberg JR. Lupus erythematosus in the 1980s: a survey of 570 patients. Semin Arthritis Rheum 1991;21:55-64. Shou-yi S, Shu-fang F, Kang-huang L, Li Fang, Ke-fei K. Clinical study of 30 cases of subacute cutaneous lupus erythematosus. Chin Med J 1987;100:45-8. Sontheimer RD, Thomas JR, Gilliam JN. Subacute cutaneous lupus erythematosus: a cutaneous marker for a distinct lupus erythematosus subset. Arch Dermatol 1979;115:1409-15. Sontheimer RD. Subacute cutaneous lupus erythematosus: a decade’s perspective. Med Clin North Am 1989;73:1073-90. Sutej PG, Gear AJ, Morrison RC,Tikly M, de Beer M, Dos Santos L, et al.Photosensitivity and anti-Ro (SS-A) antibodies in black patients with systemic lupus erythematosus (SLE). Br J Rheumatol 1989; 28:321-4.
Kuhn et al 95
46. Taylor HG, Stein CM. Systemic lupus erythematosus in Zimbabwe. Ann Rheum Dis 1986;45:645-8. 47. Tuffanelli DL, Dubois EL. Cutaneous manifestations of systemic lupus erythematosus. Arch Dermatol 1964;90:377-86. 48. Vila LM, Mayor AM, Valentin AH, Rodriguez SI, Reyes 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. 49. Ward MM, Studenski S. Clinical manifestations of systemic lupus erythematosus: identification of racial and socioeconomic influences. Arch Intern Med 1990;150:849-53. 50. Wilson WA, Hughes GR. Rheumatic disease in Jamaica. Ann Rheum Dis 1979;38:320-5. 51. Wilson WA, Scopelitis E, Michalski JP. Association of HLA-DR7 with both antibody to SSA(Ro) and disease susceptibility in blacks with systemic lupus erythematosus. J Rheumatol 1984; 11:653-7. 52. Wysenbeek AJ, Block DA, Fries JF. Prevalence and expression of photosensitivity in systemic lupus erythematosus. Ann Rheum Dis 1989;48:461-3. 53. Lee LA, Farris AD. Photosensitivity diseases: cutaneous lupus erythematosus. J Invest Dermatol Symp Proc 1999;4:73-8. 54. Velthuis PJ, van Weelden H, van Wichen D, Baart de la Faille H. Immunohistopathology of light-induced skin lesions in lupus erythematosus. Acta Derm Venereol 1990;70:93-8. 55. Nyberg F, Skoglund C, Stephansson E. Early detection of epidermal dust-like particles in experimentally UV-induced lesions in patients with photosensitivity and lupus erythematosus. Acta Derm Venereol 1998;78:177-9. 56. LeFeber WP, Norris DA, Ryan RS, Huff JC, Lee LA, Kubo M. Ultraviolet light induces binding of antibodies to selected nuclear antigens on cultured keratinocytes. J Clin Invest 1984; 74:1545-51. 57. Norris DA. Pathomechanisms of photosensitive lupus erythematosus. J Invest Dermatol 1993;100:58S-68S. 58. Golan TD, Elkon KB, Gharavi AE, Krueger JG. Enhanced membrane binding of autoantibodies to cultured keratinocytes of systemic lupus erythematosus patients after ultraviolet B/ultraviolet A irradiation. J Clin Invest 1992;90:1067-76. 59. Lee LA. Neonatal lupus erythematosus. J Invest Dermatol 1993; 100:9S-13S. 60. Lee LA, Gaither JK, Coulter SN, Norris DA, Harley JB. Pattern of cutaneous immunoglobin G deposition in subacute cutaneous lupus erythematosus is reproduced by infusing purified anti-Ro (SSA) autoantibodies into human skin-graft mice. J Clin Invest 1989;83:1556-62.
T
he original concept of photosensitivity in lupus erythematosus (LE) was based on observations made since the beginning of the 19th century. Many articles in the literature had documented that in all forms of LE, cutaneous manifestations are found predominantly on sun-exposed areas, such as the face, V area of the neck, and extensor aspects of the arms, and that exposure to sunlight can induce new skin eruptions, exacerbate existing lesions, cause progression of the disease to non-UV-exposed areas, or induce systemic activity.1-3 However, the incidence of such photosensitivity varied greatly in different studies; therefore, since 1965, reproduction of skin lesions by exposure to UV radiation (UVR) with specific test protocols has been reported.4 In the following years, photosensitivity became a well-established factor in the pathogenesis of LE in clinical and experimental settings and was included as a discriminating factor in the revised cri-
From the Department of Dermatology, Heinrich-Heine-University. Supported by a Lise-Meitner scholarship and a research grant of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany (to A. Kuhn). Accepted for publication Jan 16, 2001. Reprint requests: Annegret Kuhn, MD, Institute of Cell Biology, ZMBE, Westfälische Wilhelms-University, Von-Esmarch-Strasse 56, D-48149 Münster, Germany. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/1/114589 doi:10.1067/mjd.2001.114589
86
teria of the American Rheumatism Association (ARA) for the classification of systemic LE (SLE).5 Results of earlier studies of experimental photoprovocation indicated that characteristic skin lesions of LE could be induced by repeatedly delivering high doses of UVB to the same test site.6,7 In 1986, our group8 demonstrated that the action spectrum of LE reaches into the long-wave UVA region, and, in the following years, a total of 128 patients were investigated.9 Characteristic skin lesions clinically and histologically compatible with LE were experimentally induced by UVA or UVB irradiation in 43% of patients. A practical consequence of UVA sensitivity is that patients with LE are not adequately protected by glass covers or by conventional sunscreens, which mostly absorb UVA poorly. Moreover, high-intensity UVA sources in tanning salons might be dangerous for these patients.10,11 In the ensuing 15 years, this testing regimen has received much attention because photoprovocation is an optimal way to evaluate photosensitivity. Furthermore, the capacity of UVA and UVB irradiation to reproduce LE skin lesions is an ideal model for several experimental approaches, which allow the study of inflammatory and immunologic events that take place before and during lesion formation (for review see Sontheimer12). In addition, phototesting has proved to be useful in further characterizing a highly photosensitive form of cutaneous LE (CLE), lupus erythematosus tumidus (LET).13 Therefore we were interested to impart the informa-
Kuhn et al 87
J AM ACAD DERMATOL VOLUME 45, NUMBER 1
Table I. Demographic data and threshold doses for MED, IPD, and MTD of patients included in the study Threshold doses
Disease
LE DLE (n = 94) LET (n = 70) SCLE (n = 81) CLE* (n = 133) SLE (n = 27) Total (n = 405) Controls PLE (n = 340) Others† (n = 200) Total (n = 540)
Age (y) mean ± SD
Sex M/F (No.)
MED-UVB (mJ/cm2) mean ± SD
IPD (J/cm2) mean ± SD
MTD (J/cm2) mean ± SD
42.7 ± 14.6 42.5 ± 14.6 42.5 ± 14.6 42.5 ± 15.8 42.2 ± 14.6 42.6 ± 14.6
33/61 30/40 16/65 54/79 6/21 139/266
102.5 ± 39.7 106.9 ± 36.1 96.4 ± 37.3 94.7 ± 32.3 92.7 ± 31.6 99.5 ± 36.1
38.0 ± 24.8 43.9 ± 20.8 40.4 ± 19.2 33.8 ± 20.9 40.9 ± 24.3 38.8 ± 21.9
46.7 ± 22.4 52.0 ± 21.9 52.7 ± 23.8 45.7 ± 22.0 46.8 ± 21.1 48.8 ± 22.5
36.9 ± 14.3 47.0 ± 17.2 40.7 ± 16.2
75/265 71/129 146/394
102.5 ± 38.1 92.4 ± 39.6 97.4 ± 39.2
32.7 ± 19.3 42.3 ± 22.7 36.4 ± 21.2
44.9 ± 21.9 52.7 ± 22.4 47.9 ± 22.4
CLE, Cutaneous lupus erythematosus; DLE, discoid lupus erythematosus; LET, lupus erythematosus tumidus; PLE, polymorphous light eruption; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus. *Including various forms of CLE such as hypertrophic lupus erythematosus, lupus erythematosus profundus, and chilblain lupus erythematosus. †Including reticular erythematous mucinosis, lymphocytic infiltration Jessner-Kanof, pseudolymphoma, chronic actinic dermatitis, rosacea, urticaria, atopic eczema, psoriasis, dermatomyositis, and pemphigoid.
tion obtained with this phototesting regimen on the occasion of its 15th “anniversary.” To accomplish this goal, we report on our experience with more than 400 patients with different forms of LE who underwent phototesting in our department since 1990. The protocol for provocative phototesting has been optimized by taking into account multiple factors, such as light source, test area of the irradiated skin, site of irradiation, dose of UV exposure, frequency of irradiation, and time needed to induce lesions. Furthermore, because the profound effects of UVR on the cutaneous immune response have been studied extensively in the past few years, we will also discuss the potential function of UVR on the induction of CLE and the potential interplay of specific autoantibodies in concert with UVR in these patients.
PATIENTS, MATERIAL, AND METHODS Patients Photoprovocation tests were performed in 405 white patients (139 men [34%] and 266 women [66%]) with different forms of LE seen at the Department of Dermatology, Heinrich-Heine-University, Düsseldorf, Germany (Table I). The study included 94 patients with discoid LE (DLE); 70 with LET; 81 with subacute CLE (SCLE); 133 with various other forms of CLE, such as LE profundus, hypertrophic/verrucous LE, and chilblain LE; and 27 with SLE. Diagnosis of the forms of CLE was based on clinical and histopathologic findings, and diagnosis of SLE was made when at least 4 of the revised SLE criteria of the ARA were present.5 The
mean age of patients with LE was 42.6 ± 14.6 (± SD) years (range, 5.0-86.0 years), showing no significant difference with respect to the different clinical subtypes. None of the patients received systemic medication for their skin disease at the time of photoprovocation, and all patients underwent medical history, physical examination, and routine blood analysis. For control purposes, 540 patients (146 men [27%] and 394 women [73%]) with skin diseases other than LE were also studied (mean age, 40.7 ± 16.2 years; range, 3.0-83.0 years) (Table I). The investigations were approved by the local ethics committee. Phototesting procedure The light sources used included a high-pressure metal halide lamp (330-460 nm, UVASUN 3000, Mutzhas, Munich, Germany; or 340-440 nm, UVA1Sellas 2000, Sellas, Medizinische Geräte, Gevelsberg, Germany) for UVA phototesting and a UV-800 unit lamp with fluorescent bulbs (285-350 nm; Philipps TL 20 W/12; Waldmann, Villingen/Schwenningen, Germany) for UVB phototesting. Irradiation output was monitored by means of a UV radiometer (UVAMETER, Mutzhas) and a UV spectrometer (Waldmann). Minimal erythema dose, immediate pigment darkening, and minimal tanning dose Minimal erythema dose (MED), threshold dose for immediate pigment darkening (IPD), and minimal tanning dose (MTD) were determined according
88 Kuhn et al
J AM ACAD DERMATOL JULY 2001
A
C
B
Fig 1. Positive photoprovocation test reactions on the back of patients with different subsets of lupus erythematosus. Appearance of characteristic skin lesions 1 week after UVA irradiation (A), after UVB irradiation in DLE (B), and 1 week after combined UVA and UVB irradiation in LET (C).
Table II. Results of provocative phototesting in lupus erythematosus Positive phototesting results/tested patients, No. (%) Diagnosis
DLE (n = 74) LET (n = 62) SCLE (n = 63) CLE* (n = 104) SLE (n = 20) Total (n = 323)
Total
UVA
UVB
UVA + UVB
33/74 (45) 47/62 (76) 40/63 (63) 43/104 (41) 12/20 (60)
16/74 (22) 32/62 (52) 26/63 (41) 26/104 (25) 10/20 (50)
27/74 (36) 31/62 (50) 33/63 (52) 34/104 (33) 12/20 (60)
5/10 (50) 18/27 (67) 3/6 (50) 1/7 (14) 1/3 (33)
175/323 (54)
110/323 (34)
137/323 (42)
28/53 (53)
*Including various forms of CLE such as hypertrophic lupus erythematosus, lupus erythematosus profundus, and chilblain lupus erythematosus.
to standard procedures.8,14,15 Test reactions were read immediately and 24 hours after irradiation. Provocative phototesting For provocative phototesting, areas (4 × 5 cm) of uninvolved skin on the upper back or extensor aspects of the arms were irradiated with single doses of UVA (100 J/cm2) or UVB (1.5 MED), respectively, daily for 3 consecutive days. Test areas were evaluated until specific lesions appeared for up to 4 weeks after the last irradiation. Controls were provoked according to this protocol. Selection and preparation of biopsy specimens Skin biopsy specimens were taken from primary lesions of all patients with untreated LE and from
pathologic provocation reaction sites after UVA or UVB irradiation. Tissues were fixed, embedded, and stained with hematoxylin-eosin for routine histologic evaluation or immediately frozen and stored at –80°C for direct immunofluorescence studies. Criteria for positive provocation tests Criteria for a positive provocative phototest result required that (1) the induced lesions clinically resembled LE, (2) the histopathologic findings were compatible with LE, and (3) the skin lesions developed slowly and persisted for several days or weeks. Serologic evaluations Antinuclear antibodies (ANAs) were assayed by a standard indirect immunofluorescence technique with
Kuhn et al 89
J AM ACAD DERMATOL VOLUME 45, NUMBER 1
Fig 2. Time course of induction of skin lesions after photoprovocation in patients with polymorphous light eruption (PLE, n = 110) and lupus erythematosus (LE, n = 175).
commercially available HEp-2 cells (Bio-Rad SDP GmbH, Freiburg, Germany). With this assay technique, serum ANA titers greater than 1:160 are abnormal compared with those of healthy controls, and anti-Ro(SS-A) and anti-La(SS-B) antibodies were determined by standardized enzyme-linked immunosorbent assays (ELISA; DPC Biermann, Bad Nauheim, Germany).
Table III. Relation between provocative phototest reaction and medical history of photosensitivity in lupus erythematosus
History of photosensitivity
Positive
Negative
Statistical analysis For testing associations with clinical data, the MannWhitney test was performed, and for testing associations between photoprovocation results and autoantibodies or photosensitivity, the χ2 test was performed to determine statistical significance. Confidence intervals were determined at 95%, and P values less than .05 were considered statistically significant.
Positive (n = 94) Negative (n = 71)
58 (62) 41 (58)
36 (38) 30 (42)
RESULTS Erythematous and pigmentary reactions The MED-UVB in 405 patients with different forms of LE was 99.5 ± 36.1 mJ/cm2, compared with 97.4 ± 39.2 mJ/cm2 in 540 patients in the control group (Table I). For UVA, the IPD threshold dose was 38.8 ± 21.9 J/cm2 and the MTD was 48.8 ± 22.5 J/cm2 in patients with LE compared with 36.4 ± 21.2 J/cm2 and 47.9 ± 22.4 J/cm2, respectively, in the control group. Statistical analysis revealed no significant differences in the time course with respect to the different clinical subtypes of LE or between these patients and the control group. Results of 15 years of provocative phototesting All 405 patients with different forms of LE underwent the phototesting procedure; however, ques-
Provocative phototest reaction, No. (%)
tionable results were found in 33 patients (8%), and 49 (12%) were not available for follow-up. Experimental reproduction of skin lesions was successful with UVA and/or UVB irradiation (Fig 1) and results from the remaining 323 patients with LE are presented in Table II. Altogether, skin lesions characteristic for LE were observed in 175 (54%) of 323 patients; 137 patients (42%) reacted to UVB irradiation only, and 110 (34%) to UVA irradiation only. Fifty-three patients were tested with combined UVA and UVB irradiation, and 28 of these patients (53%) displayed characteristic skin lesions. Patients with LET showed the highest frequency of positive phototest reactions, and, in our study, experimental phototesting revealed characteristic skin lesions in 47 (76%) of 62 patients with LET. Furthermore, skin lesions characteristic of LE were induced in 40 (63%) of 63 patients with SCLE, in 12 (60%) of 20 patients with SLE, and in 33 (45%) of 74 patients with DLE. Approximately 60% of patients were aware of an adverse effect of sunlight on their disease, and 62% showed pathologic test reactions (Table III). Patho-
90 Kuhn et al
J AM ACAD DERMATOL JULY 2001
Fig 3. Correlation between positive photoprovocation test reactions and antinuclear antibodies (ANAs), anti-Ro(SS-A) antibodies, and anti-La(SS-B) antibodies in patients with different forms of LE.
logic test reactions were also induced in 58% of patients who denied any effect of sun exposure on their disease. The onset of positive phototest reactions in LE was significantly slower and persisted longer than reactions in controls with other photodermatoses, such as polymorphous light eruption (Fig 2). In general, pathologic reactions in patients with LE appeared within 1 week (range, 1 day to 3 weeks) after irradiation and lasted for approximately 1 week to 2 months. Statistical analysis revealed no significant differences with respect to the different clinical subtypes of LE. In some cases, hypopigmentation or hyperpigmentation occurred in the test areas that persisted for several weeks after UV exposure. Histopathologic findings of UV-induced skin lesions The experimentally induced skin lesions produced by UVA and UVB showed histopathologically no significant differences compared with primary lesions of the different LE subtypes. Even in early lesions of DLE, epidermal changes such as hyperkeratosis and follicular plugging are present and might be accompanied by a thinned epidermis. Furthemore, in early lesions of DLE lymphocytes are arranged around the superficial plexus only, whereas
in later lesions, they are present around venules of superficial and deep plexuses. Fully developed lesions of DLE are marked by vacuolar alteration of the dermoepidermal junction and, in some cases, by a thickened basement membrane zone. Interstitial mucin deposits in variable amounts might be present. Lesions of SCLE have generally less hyperkeratosis and follicular plugging, and the epidermis is atrophic and displays vacuolar degeneration at the dermoepidermal junction. The sparse infiltrate is usually confined to the papillary dermis and consists of lymphocytes, and interstitial mucin deposits are also present. In LET, the epidermis is normal or slightly acanthotic and changes at the dermoepidermal junction are not found. Abundant mucin deposits are prominent in all patients. There is a perivascular and periadnexal superficial or deep lymphocytic infiltrate and, in some cases, scattered neutrophils are seen. The density of the infiltrate differs from slight to moderate. Direct immunofluorescence of UV-induced skin lesions In accordance with our previous findings, none of the UV-induced lesions showed immunoglobulin deposits at the dermoepidermal junction or around vessels.9,16,17
Kuhn et al 91
J AM ACAD DERMATOL VOLUME 45, NUMBER 1
Table IV. Phototesting in lupus erythematosus: Review of the literature since 1986 Positive phototest reactions in different subtypes of LE
Year
Authors
Tested patients/ Total No.
DLE
LET
SCLE
SLE
1986
Lehmann et al8
27/67 (40%)
40%
–
90%
10%
1989
Wolska et al18
49/202 (24%)
16%
–
63%
24%
1989 1990
Van Weelden et al19 Lehmann et al9
20/24 (83%) 55/128 (43%)
78% 42%
– –
88% 64%
86% 25%
1991
Beutner et al20
90/115 (78%)
60%
–
100%
74%
1993
Kind et al17
81/150 (54%)
36%
81%
63%
35%
1993
Nived et al21
6/23 (26%)
–
–
–
26%
1997
Walchner et al22
29/68 (43%)
39%
–
50%
40%
1997
Hasan et al23
46/67 (69%)
64%
–
100%
70%
1999
Leenutaphong and Boonchai24
6/15 (40%)
44%
–
–
33%
Association of autoantibodies with positive phototesting results Laboratory tests revealed ANAs with titers greater than 1:160 in 58 patients with LE (23%), and 61 (25%) of 248 tested patients showed a borderline result with titers of 1:160. The ANA fluorescence pattern was finely speckled or homogenous. AntiRo(SS-A) antibodies were detected in 39 patients (16%), and anti-La(SS-B) antibodies in 24 (10%). Interestingly, patients with a pathologic reaction to the UV provocation test revealed anti-Ro(SS-A) or anti-La(SS-B) antibodies more often than those with a negative phototest reaction; however, this was dependent on the clinical subtype of LE and was not statistically significant (Fig 3).
DISCUSSION In 1986, our group8 established standardized methods for testing photosensitive diseases, and, moreover, we showed that the action spectrum of LE included UVA in addition to UVB.9,17 Further studies by other groups followed, confirming that skin lesions in this disease might also occur after UVA irradiation (Table IV).18-24 During the past 15 years, protocols for phototesting in LE have been optimized by taking into account multiple factors (Table V). Nonlesional, non-sun-exposed areas of the upper back or extensor aspects of the arms were used for performance of the phototest reactions because other parts of the skin
Comment
First description of positive reactions after UVA irradiation Reproduction of skin lesions after single exposure of UVR Phototesting with visible light Induction of skin lesions with UVA and UVB irradiation Association between anti-Ro(SS-A) antibodies and systemic involvement Histologic studies of early and late UV-induced skin lesions More pronouncement of reactions to long-wave UVA light Overview on phototesting and photoprotection Comparison of photosensitivity and photoprovocation results Phototesting in Asian patients
might not react to the same extent, probably because of some kind of local predisposition of unknown nature other than UVR, such as thickness of the stratum corneum, vascularization, presence of antigens, or distribution of antigen-presenting cells.22 Furthermore, it is important to use a defined test area that should be sufficiently large to provide reactions. Onset of LE skin lesions is characterized by a latency of several days to 3 weeks, and they might persist in some patients for several months. For this reason, it might be difficult for patients to recognize the association between sun exposure and induction of lesions. Although provocation of a systemic disease in patients with SLE has not been observed, these patients should be watched carefully. During the past 15 years, photoprovocation test reactions have been evaluated in more than 400 patients with different forms of LE, and pathologic reactions were induced in 54%. In addition to our previous studies, combined UVA and UVB irradiation has been performed in the past few years, and, interestingly, most patients were provoked by this kind of testing regimen (Table II). It has been confirmed that the development of positive phototest reactions in patients with LE is considerably slower and that lesions persist longer than in other photodermatoses, such as polymorphous light eruption (Fig 2). Furthermore, there are substantial differences in clinical subsets with regard to response to UVR.
92 Kuhn et al
J AM ACAD DERMATOL JULY 2001
Table V. What have we learned about phototesting in lupus erythematosus in the past 15 years? Criteria
Test site Size of test field Pretesting
Dosage Evaluation Light sources
Pretreatment
Results
Comments
Non-sun-exposed, unaffected areas of the upper back or extensor aspects of arms Defined test areas should be sufficiently large to provide reactions (4 × 5 cm) MED, IPD, MTD
100 J/cm2 UVA and/or 1.5 MED-UVB on 3 consecutive d 24, 48, 72 h up to 4 wk after last irradiation UVA: UVASUN 3000 (330-460 nm), Mutzhas or UVA1 Sellas 2000 (340-440 nm), Sellas UVB: UV-800 with fluorescent bulbs, Philipps TL 20 W/12 (285-350 nm), Waldmann No pretreatment
Medication
If possible, no systemic medication for skin disease
Photosensitivity
Phototesting results are not always associated with photosensitivity
Criteria for positive photoprovocation
• Induced skin lesions clinically resemble LE • Skin lesions appear slowly over several days or weeks • Skin lesions persist up to several months • Clinical diagnosis is confirmed by histology UVA and UVB: 53% UVB: 42% UVA 34% LET: 76% SCLE: 63% DLE: 45% SLE: 60% Persistence of hyperpigmentation and hypopigmentation for several months after irradiation Exacerbation of cutaneous lesions in a few patients, no provocation of systemic disease in our studies
Results of phototesting (different wavelength) Results of phototesting (different LE subtypes) Local side effects
Induction of disease
Antibodies
Significant association between positive phototest results and anti-Ro(SS-A) or anti-La(SS-A) antibodies
Patients with LET had been found to be more photosensitive than patients with SCLE, and because LET has rarely been documented in the literature and is often difficult to differentiate from other photodermatoses, such as polymorphous light eruption,
Other parts of the skin might not react to the same extent Too small test areas or test areas different in size might not show reproducible results Testing of the MED is necessary to make data comparable; a prolonged erythematous response was not a conspicuous feature in our studies Single UV exposure is unlikely to induce positive reactions in all possible patients Follow-up shorter than 3 wk might miss positive provocative phototest results in some patients Different light sources with a different action spectrum can result in different numbers of positive phototests Any topical or systemic pretreatment might affect the phototesting procedure Systemic medication, such as antimalarial agents, corticosteroids, and immunosuppressive drugs might lead to false-negative results It might be difficult for patients to recognize the association between sun exposure and induction of skin lesions Positive phototest reactions are considerably slower and persist longer than other photodermatoses, such as polymorphous light eruption, persistent light reaction, photoallergy, hydroa vacciniforme, and solar urticaria Differences in phototest results are found because of different protocols and age of patients at onset of disease Differences in phototest results are found because of different protocols; LET patients are more photosensitive than SCLE patients Patients should be reminded of these possible side effects because they might lead to cosmetic problems Follow-up of SLE patients after phototesting is very important because reports in the literature describe exacerbation of systemic disease under phototesting Positive photoprovocation results in Ro(SS-A)and La(SS-B)-positive patients strengthen the role of these autoantigens in the pathomechanism of UV-induced LE skin lesions
this phototesting model proved to be useful in further characterizing this chronic form of CLE.13 Results of reported phototesting in patients with LE often differ between various groups because there are numerous technical differences between
Kuhn et al 93
J AM ACAD DERMATOL VOLUME 45, NUMBER 1
Table VI. Reported photosensitivity and provocative phototest reactions in different subsets of LE Diagnosis
DLE LET SCLE SLE
Reported photosensitivity5,13,20,22,26-52
Positive photoprovocation8,9,13,17-24
25%-90% 43%-50% 27%-100% 6%-94%
10%-64% 70%-81% 50%-100% 25%-85%
the studies that could explain the different findings (Table VI).8,9,13,17-24 Varying factors are light source, energy dose, wavelength, time points of provocation and evaluation, and location and size of test area. Most studies were conducted in white patients; however, there is one recent article on phototesting in 15 Asian patients with LE.24 Using exactly the same test protocol as our group, the incidence of positive phototest reactions in these patients seemed to be similar to or a little lower than that in white patients; there was also no correlation between a positive history of UV sensitivity and phototest reactions. Furthermore, classification of positive test results might be difficult in some patients because persistent erythema can occur, which is even hard to interpret histologically. It is also unclear why skin lesions cannot always be reproduced under the same conditions several months after the initial phototest and why phototesting results are not positive in all patients with LE who are tested, providing indirect evidence for variant factors in the pathophysiology of LE.25 A history of photosensitivity in patients with LE does not necessarily predict positive reactions on phototesting, and results of reported photosensitivity often differ between various groups (Table VI).5,13,22,26-52 This might be because skin lesions after UVR do not appear rapidly after sun exposure and, therefore, a relationship between sun exposure and exacerbation of LE does not seem obvious to the patient. An additional factor might be the age at onset of disease, as observed by Walchner, Messer, and Kind,22 who demonstrated that mainly patients younger than 40 years reported photosensitivity. Furthermore, the occurrence of photosensitivity varies between different types of LE, and some ethnic groups such as African blacks seem to be less photosensitive than others.36,40,42,45,46,49 Nevertheless, the term photosensitivity (skin rash as a result of unusual reaction to sunlight by patient history or physician observation) is poorly defined,53 although it is listed as one of the ARA criteria for the classification of SLE.5 In 1996, a high discrepancy between a personal history of photosensitivity and a decreased MED was documented by Doria et al,29 concluding
that the use of photosensitivity as a classification criterion for SLE remains questionable, at least when it is assessed according to the ARA criteria. In general, results of histopathologic and immunopathologic examination of UV-induced LE lesions are similar to the findings of spontaneously occurring primary skin lesions, but can give further insight into the earliest pathologic events in CLE lesions. Kind, Lehmann, and Plewig17 demonstrated that histopathologic examination of early UV-induced lesions (up to 10 days) in patients with CLE and SLE shows nonspecific changes such as superficial perivascular lymphocytic infiltration. On the other hand, late UV-induced lesions (more than 10 days) were characterized by parakeratosis, few necrotic basal keratinocytes, and vacuolar degeneration of the dermoepidermal zone. Furthermore, under experimental conditions the appearance of immunoglobulins in UV-induced LE lesions has been reported as a late phenomenon, and in our study, direct immunofluorescence findings were negative in all skin lesions investigated up to 3 weeks after UV exposure. This is in accordance with the findings of Cripps and Rankin,7 who detected the first immunoglobulin deposits 6 weeks after irradiation and mainly along the basement membrane. In contrast, Velthuis et al54 demonstrated that in UV-induced lesions of patients with LE, immunohistochemical changes can be induced similar to those in spontaneously evolved lesions. Furthermore, Nyberg, Skoglund, and Stephansson55 observed that in experimentally UV-induced lesions of patients with LE, dustlike particles, a specific fine-speckled, epidermalsubepidermal direct immunofluorescence staining pattern, can be detected within 2 weeks after UV exposure. A potential interplay of UVR with specific autoantibodies, particularly anti-Ro(SS-A) and anti-La(SS-B) antibodies, has been previously reported, and in different subtypes of LE, such as SCLE and neonatal LE, photosensitivity has been found to be strongly associated with the presence of such antibodies (for review see Lee and Farris53). Our observation strengthens the involvement of these autoantibodies in the pathogenetic mechanism of UV-induced skin lesions (Fig 3). Results of an early study by LeFeber et al56 indicated
94 Kuhn et al
that UVR of cultured keratinocytes led to increased IgG binding to the cell surface of keratinocytes; several years later, Norris57 noted increased antibody binding as a result of in vivo UVR to human skin. Golan et al58 independently observed UV-induced binding of antibodies from Ro(SS-A)-positive sera to a small percentage of cultured keratinocytes. Nevertheless, the strongest evidence supporting the possibility that these antibodies are involved in the pathogenesis of LE comes from patients with neonatal LE.59 These infants have maternally acquired anti-Ro(SS-A) antibodies and experience SCLE-like skin lesions, and because these antibodies are cleared from the infants’ circulation several months after birth, the skin lesions resolve spontaneously.60 In DLE, the association of skin disease with antibodies is much less clear, and, in previous studies, a clear association between the presence of anti-Ro(SS-A) antibodies and the clinical finding of photosensitivity was not found.53 However, because similar levels of anti-Ro(SS-A) antibodies are seen in other disorders such as Sjögren’s syndrome that are not usually associated with specific LE lesions, other factors must be involved in the production of LE inflammation. Results published to date suggest that UVR is of major importance in the induction of skin lesions in patients with different forms of LE, in particular LET and SCLE; however, the pathogenetic mechanisms of UV-induced lesions have not been fully elucidated. In the past 15 years, we have shown that phototesting with UVA and UVB irradiation is an optimal model to analyze the steps involved in the induction of such skin lesions because it allows the study of events that take place proximate to lesion formation. Therefore we are confident that provocative phototesting with standardized protocols will help to identify the pathogenesis of this disease in the future. REFERENCES 1. Pusey WA. Attacks of lupus erythematosus following exposure to sunlight or other weather factors. Arch Dermatol Syphil 1915;33:388. 2. Macleod JMH. Lupus erythematosus: some observations on its etiology. Arch Dermatol Syphil 1924;9:1-12. 3. Freund H. Inwiefern ist der Lupus erythematodes von allgemeinen Faktoren abhängig? Dermatol Wochenschr 1929;89: 1939-46. 4. Epstein JH, Tuffanelli DL, Dubois EL. Light sensitivity and lupus erythematosus. Arch Dermatol 1965;91:483-5. 5. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271-7. 6. Freeman RG, Knox JM, Owens DW. Cutaneous lesions of lupus erythematosus induced by monochromatic light. Arch Dermatol 1969;100:677-82. 7. Cripps DJ, Rankin J. Action spectra of lupus erythematosus and experimental immunofluorescence. Arch Dermatol 1973;107: 563-7.
J AM ACAD DERMATOL JULY 2001
8. Lehmann P, Hölzle E, v. Kries R, Plewig G. Lichtdiagnostische Verfahren bei Patienten mit Verdacht auf Photodermatosen. Zbl Haut- und Geschl-Kr 1986;152:667-82. 9. Lehmann P, Hölzle E, Kind P, Goerz G, Plewig G. Experimental reproduction of skin lesions in lupus erythematosus. J Am Acad Dermatol 1990;22:181-7. 10. Stern RS, Docken W. An exacerbation of SLE after visiting a tanning salon. JAMA 1986;255:3120. 11. Tronnier H, Petri H, Pierchalla P. UV-provozierte bullöse Hautveränderungen bei systemischem Lupus erythematodes. Z Hautkr 1988;154: 616-7. 12. Sontheimer RD. Photoimmunology of lupus erythematosus and dermatomyositis: a speculative review. Photochem Photobiol 1996;63:583-94. 13. Kuhn A, Richter-Hintz D, Oslislo C, Ruzicka T, Megahed M, Lehmann P. Lupus erythematosus tumidus: a neglected subset of cutaneous lupus erythematosus—report of 40 patients. Arch Dermatol 2000;136:1033-41. 14. Hölzle E, Plewig G, Lehmann P. Photodermatoses: diagnostic procedures and their interpretation. Photodermatology 1987;4: 109-14. 15. Lehmann P. Photodiagnostische Testverfahren. In: Macher E, Kolde G, Bröcker EB, editors. Jahrbuch der Dermatologie 1992/1993. Zülpich, Germany: Biermann Verlag; 1992. p. 81-100. 16. Kind P, Lehmann P. Photobiologie des Lupus erythematodes. Hautarzt 1990;41:66-71. 17. Kind P, Lehmann P, Plewig G. Phototesting in lupus erythematosus. J Invest Dermatol 1993;100:53S-7S. 18. Van Weelden H, Velthuis PJ, Baart de la Faille H. Light-induced skin lesions in lupus erythematosus: photobiological studies. Arch Dermatol Res 1989;281:470-4. 19. Wolska H, Blazczyk M, Jablonska S. Phototests in patients with various forms of lupus erythematosus. Int J Dermatol 1989;28: 98-103. 20. Beutner EH, Blaszczyk M, Jablonska S, Chorzelski TP, Kumar V, Wolska H. Studies on criteria of the European Academy of Dermatology and Venerology for the classification of cutaneous lupus erythematosus, I. Selection of clinical groups and study factors. Int J Dermatol 1991;30:411-7. 21. Nived O, Johansen PB, Sturfelt G. Standardized ultraviolet-A exposure provokes skin reaction in systemic lupus erythematosus. Lupus 1993;2:247-50. 22. Walchner M, Messer G, Kind P. Phototesting and photoprotection in LE. Lupus 1997;6:167-74. 23. Hasan T, Nyberg F, Stephansson E, Puska P, Hakkinen M, Sarna S, et al. Photosensitivity in lupus erythematosus, UV photoprovocation results compared with history of photosensitivity and clinical findings. Br J Dermatol 1997;136:699-705. 24. Leenutaphong V, Boonchai W. Phototesting in oriental patients with lupus erythematosus. Photodermatol Photoimmunol Photomed 1999;15:7-12. 25. Higuchi D, Ogura Y, Watanabe H, Takiuchi I. Experimental production of DLE lesion with a single exposure to UVB (2.7 MEDs) radiation. J Dermatol 1991;18:545-8. 26. Callen JP. Discoid lupus erythematosus: variants and clinical associations. Clin Dermatol 1985;3:49-57. 27. Callen JP, Klein J. Subacute cutaneous lupus erythematosus: clinical, serologic, immunogenetic, and therapeutic considerations in seventy-two patients. Arthritis Rheum 1988;31:100713. 28. Drosos AA, Dimou GS, Siamopoulou-Mavridou A, Hatzis J, Moutsopoulos HM. Subacute cutaneous lupus erythematosus in Greece: a clinical, serological, and genetic study. Ann Med Interne 1990;141:421-4. 29. Doria A, Biasinutto C, Ghirardello A, Sartori E, Rondinone R,
J AM ACAD DERMATOL VOLUME 45, NUMBER 1
30. 31.
32.
33.
34. 35.
36.
37.
38.
39.
40.
41.
42.
43.
44. 45.
Piccoli A, et al. Photosensitivity in systemic lupus erythematosus: laboratory testing of ARA/ACR definition. Lupus 1996;5: 263-8. Dubois EL, editor. Lupus erythematosus. 2nd ed. Los Angeles: University of Southern California Press; 1974. Grigor R, Edmonds J, Lewkonia R, Bresnihan B, Hughes GRV. Systemic lupus erythematosus: a prospective analysis. Ann Rheum Dis 1978;37:121-8. Harvey AM, Shulman LE, Tumulty PA, Conley CL, Schoenrich EH. Systemic lupus erythematosus: review of the literature and clinical analysis of 138 cases. Medicine 1954;33:291-437. Herrero C, Bielsa I, Font J, Lozano F, Ercilla G, Lecha M, et al. Subacute cutaneous lupus erythematosus: clinicopathologic findings in thirteen cases. J Am Acad Dermatol 1988;19:105762. Hymes SR, Russell TJ, Jordon RE. The anti-Ro antibody system. Int J Dermatol 1986;25:1-7. Lee PL, Urowitz MB, Bookman AM, Koehler BE, Smythe HA, Gordon DA, et al. Systemic lupus erythematosus: a review of 110 cases with reference to nephritis, the nervous system, infections, aseptic necrosis and prognosis. Q J Med 1977;46:132. Mody GM, Parag KB, Nathoo BC, Pudifin DJ, Duursma J, Seedat YK. High mortality with systemic lupus erythematosus in hospitalized African blacks. Br J Rheumatol 1994;33:1151-3. Mond CB, Peterson MG, Rothfield NF. Correlation of anti-Ro antibody with photosensitivity rash in systemic lupus erythematosus patients. Arthritis Rheum 1989;32:202-4. O’Loughlin S, Schroeter AL, Jordon RE. A study of lupus erythematosus with particular reference to generalized discoid lupus. Br J Dermatol 1978;99:1-11. Pande I, Sekharan NG, Kailash S, Uppal SS, Singh RR, Kumar A, et al. Analysis of clinical and laboratory profile in Indian childhood systemic lupus erythematosus and its comparison with SLE in adults. Lupus 1993;2:83-7. Petri M, Perez-Gutthann S, Craig Longenecker J, Hochberg M. Morbidity of systemic lupus erythematosus: role of race and socioeconomic status. Am J Med 1992;91:345-53. Pistiner M, Wallace DJ, Nessim S, Metzger AL, Klinenberg JR. Lupus erythematosus in the 1980s: a survey of 570 patients. Semin Arthritis Rheum 1991;21:55-64. Shou-yi S, Shu-fang F, Kang-huang L, Li Fang, Ke-fei K. Clinical study of 30 cases of subacute cutaneous lupus erythematosus. Chin Med J 1987;100:45-8. Sontheimer RD, Thomas JR, Gilliam JN. Subacute cutaneous lupus erythematosus: a cutaneous marker for a distinct lupus erythematosus subset. Arch Dermatol 1979;115:1409-15. Sontheimer RD. Subacute cutaneous lupus erythematosus: a decade’s perspective. Med Clin North Am 1989;73:1073-90. Sutej PG, Gear AJ, Morrison RC,Tikly M, de Beer M, Dos Santos L, et al.Photosensitivity and anti-Ro (SS-A) antibodies in black patients with systemic lupus erythematosus (SLE). Br J Rheumatol 1989; 28:321-4.
Kuhn et al 95
46. Taylor HG, Stein CM. Systemic lupus erythematosus in Zimbabwe. Ann Rheum Dis 1986;45:645-8. 47. Tuffanelli DL, Dubois EL. Cutaneous manifestations of systemic lupus erythematosus. Arch Dermatol 1964;90:377-86. 48. Vila LM, Mayor AM, Valentin AH, Rodriguez SI, Reyes 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. 49. Ward MM, Studenski S. Clinical manifestations of systemic lupus erythematosus: identification of racial and socioeconomic influences. Arch Intern Med 1990;150:849-53. 50. Wilson WA, Hughes GR. Rheumatic disease in Jamaica. Ann Rheum Dis 1979;38:320-5. 51. Wilson WA, Scopelitis E, Michalski JP. Association of HLA-DR7 with both antibody to SSA(Ro) and disease susceptibility in blacks with systemic lupus erythematosus. J Rheumatol 1984; 11:653-7. 52. Wysenbeek AJ, Block DA, Fries JF. Prevalence and expression of photosensitivity in systemic lupus erythematosus. Ann Rheum Dis 1989;48:461-3. 53. Lee LA, Farris AD. Photosensitivity diseases: cutaneous lupus erythematosus. J Invest Dermatol Symp Proc 1999;4:73-8. 54. Velthuis PJ, van Weelden H, van Wichen D, Baart de la Faille H. Immunohistopathology of light-induced skin lesions in lupus erythematosus. Acta Derm Venereol 1990;70:93-8. 55. Nyberg F, Skoglund C, Stephansson E. Early detection of epidermal dust-like particles in experimentally UV-induced lesions in patients with photosensitivity and lupus erythematosus. Acta Derm Venereol 1998;78:177-9. 56. LeFeber WP, Norris DA, Ryan RS, Huff JC, Lee LA, Kubo M. Ultraviolet light induces binding of antibodies to selected nuclear antigens on cultured keratinocytes. J Clin Invest 1984; 74:1545-51. 57. Norris DA. Pathomechanisms of photosensitive lupus erythematosus. J Invest Dermatol 1993;100:58S-68S. 58. Golan TD, Elkon KB, Gharavi AE, Krueger JG. Enhanced membrane binding of autoantibodies to cultured keratinocytes of systemic lupus erythematosus patients after ultraviolet B/ultraviolet A irradiation. J Clin Invest 1992;90:1067-76. 59. Lee LA. Neonatal lupus erythematosus. J Invest Dermatol 1993; 100:9S-13S. 60. Lee LA, Gaither JK, Coulter SN, Norris DA, Harley JB. Pattern of cutaneous immunoglobin G deposition in subacute cutaneous lupus erythematosus is reproduced by infusing purified anti-Ro (SSA) autoantibodies into human skin-graft mice. J Clin Invest 1989;83:1556-62.