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Photosensitivity is an important and distinguishing sign in various subtypes of cutaneous lupus erythematosus (CLE); however, it remains poorly defined. The purpose of this study was to evaluate whether standardized photoprovocation is a reproducible method to assess photosensitivity in subjects with CLE. A total of 47 subjects with CLE (subacute cutaneous lupus erythematosus (SCLE), n=14; discoid lupus erythematosus (DLE), n=20; lupus erythematosus tumidus (LET), n=13) and 13 healthy volunteers underwent photoprovocation at seven European sites. Of these, 22 (47%) subjects (57% SCLE, 35% DLE, and 54% LET) and none of the healthy volunteers developed photoprovoked lesions according to clinical analysis. Of these 22 subjects, 19 (86%) developed lesions that were histopathologically confirmed as specific for lupus erythematosus (LE). In CLE subjects who developed UV-induced lesions, 86% had Fitzpatrick's phototypes I or II, and the mean minimal erythema dose (MED) was significantly lower compared with subjects without UV-induced lesions (P=0.004). No significant differences in photoprovocation results were observed between study sites. Safety parameters showed no clinically meaningful differences between CLE subjects and healthy volunteers after photoprovocation. In conclusion, a standardized, safe, and reproducible protocol for photoprovocation using UVA and UVB radiation induced skin lesions in approximately half of all CLE subjects and showed comparable results across multiple sites. This method may therefore be used for future diagnostic testing and clinical trials.

Lupus erythematosus (LE) represents an autoimmune disease with great clinical variability in which photosensitivity is a common feature for all forms and subsets. The nature and characteristics of clinical photosensitivity in LE have been elucidated through standardized phototesting procedures. The development of skin lesions after UV-injury is typically delayed starting from a few days up to three weeks after the irradiation, and may persist for months. Therefore, patients may not be aware of the detrimental effects of sunlight for their disease. The most photosensitive subset of LE is LE tumidus, followed by subacute cutaneous LE. Phototesting has also been crucial for studying the pathophysiology of LE-photosensitivity. Abnormalities of generation and clearance of UV-triggered apoptotic cells in LE are an important source of autoantigens. Recent data demonstrate the linkage of innate with adoptive immune pathways in UV-induced autoimmune response. Plasmocytoid dendritic cells (PDC) and their secreted IFN-alpha play a central role in the LE-pathogenesis. The recruitment of relevant leukocyte subsets is dependant on certain chemokines, which have been characterized in recent studies. An amplification cycle has been postulated, in which UV induces apoptosis and necrosis resulting in the production and release of chemokines. Subsequently, effector memory T cells as well as PDCs are recruited and activated perpetuating an amplification process that leads to UV-induced cutaneous LE lesion.

Phototoxic side effects of pharmaceutical and cosmetic products are of increasing concern for patients, dermatologists and the chemical industry. Moreover, the need of new chemicals and drugs puts pressure on pre-clinical test methods for side effects, especially interactive adverse-effects with UV-light. So, the predictive potential of different established test methods, which are used regularly in our departments in order to detect the phototoxic potential of chemicals, were analyzed. Namely the fibroblast 3T3 test, the photo hen’s egg test, a guinea pig test for measuring acute photoreactions, and a modified Local Lymph Node Assay, the Integrated Model for the Differentiation of Skin Reactions. Various agents with different photoreactive potential were tested: quinolones like Bay y 3118, ciprofloxacin, enoxacin, lomefloxacin, moxifloxacin, ofloxacin, sparfloxacin, as well as promethazine, chlorpromazine, 8-methoxypsoralen and olaquindox serving as control. Special emphasis was taken to evaluate the capability of the employed test procedures to predict phototoxic side effects in patients. Following our results, both in vitro assays were useful tools to detect photoirritancy while the photoallergic potentials of tested compounds were exclusively detected by an in vivo assay. As long as no in vitro model for photoallergy is available, the UV-IMDS should be considered to evaluate photoallergic properties of a supposed photoreactive agent.

Background: In a recent study, we demonstrated that lupus erythematosus (LE) tumidus (LET) is a distinct subset of cutaneous LE (CLE), which is clinically characterized by erythematous, urticaria-like, nonscarring plaques in sun-exposed areas. Objective: Our purpose was to analyze skin biopsy specimens from 80 patients with this disease and to determine whether it could be differentiated from other variants of CLE on histopathologic grounds. Methods: Skin biopsy specimens from 53 primary and 38 UVA- and/or UVB-induced lesions of 80 patients with LET were examined and compared with skin biopsy specimens from patients with discoid LE (DLE) and subacute CLE (SCLE). Results: Specimens from LET lesions showed a characteristic and diagnostic pattern of perivascular and periadnexal cellular infiltrates in the papillary and reticular dermis composed almost entirely of lymphocytes. In some cases, few scattered neutrophils were present. Furthermore, interstitial mucin deposition was observed in all specimens, as confirmed by colloidal iron staining. In contrast to discoid LE and subacute CLE lesions, epidermal atrophy or alteration at the dermoepidermal junction was not detected. Conclusion: Skin lesions of patients with LET present with specific histopathologic features, and the differences compared with subacute CLE and discoid LE further support the concept to consider LET as a separate entity of CLE. (J Am Acad Dermatol 2003;48:901-8.)

Methotrexate is beneficial in rheumatoid arthritis and has been used in small studies of patients with systemic lupus erythematosus. We describe a patient with severe subacute cutaneous lupus erythematosus refractory to therapy with antimalarials and corticosteroids. Treatment with methotrexate resulted in complete clearing of the skin lesions without any side effects. (J Am Acad Dermatol 2002;46:600-3.)

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.)

Photosensitivity is a main criterion for the diagnosis of systemic lupus erythematosus (LE), and ultraviolet (UV) irradiation plays a key role in the pathogenesis of cutaneous LE. Patients with a tentative diagnosis of LE are routinely tested for skin lesion development after experimental UV irradiation, providing an ideal opportunity to evaluate early, preclinical events involved in the pathogenesis of LE. Several reports have shown expression of the cytokine-inducible nitric oxide synthase (iNOS) in autoimmune diseases. Therefore, we investigated the role of iNOS expression at mRNA and protein level in the pathogenesis of LE lesions. Skin biopsies from patients with different subtypes of LE were examined, and iNOS expression was found in six of 18 biopsies from cutaneous LE patients and two of three biopsies from systemic LE patients. In biopsies taken 4-20 d after UV irradiation, epidermal iNOS expression was seen in all patients (n = 10) after UVB and in four of 10 patients provoked by UVA. In healthy controls (n = 8) epidermal iNOS expression was detected 24 h after UV irradiation, persisting for another day before subsiding on day 3. In LE patients (n = 8) the exact reverse situation was seen: an iNOS-specific signal was undetectable in keratinocytes for 2 d after UV irradiation, but became positive on day 3 and persisted for up to 25 d in the evolving skin lesions. Our findings demonstrate a time-restricted, UV-induced iNOS expression in human skin; moreover, the results indicate that both the kinetics of iNOS induction as well as the time span of local iNOS expression may be critical to the development of cutaneous LE lesions.

Topical glucocorticosteroids represent the mainstay of antiinflammatory therapy in the treatment of inflammatory skin diseases. Their clinical use, however, is limited by local and systemic side-effects. Thus, in dermatopharmacology there is a large demand for alternative non-steroidal antiinflammatories. Other than transplantation models, most of the frequently used in vivo test systems for assessment of drug-induced immunosuppression measure changes in inflammatory skin responses by means of skin erythema and edema after challenge of sensitized animals. The aim of this study was to develop an alternative mouse model to detect and analyse immunosuppressive effects of topically applied drugs. On the basis of a modified local lymph node assay, we analysed effects of topical hydrocortisone, dexamethasone, mometasone furoate and FK506 (tacrolimus) during the induction phase of contact hypersensitivity. On 4 consecutive days, NMRI mice were treated on the dorsal surfaces of both ears with increasing concentrations of test compound. During the last 3 days, the mice received in addition the contact sensitizer, oxazolone (1%). On day 5, draining auricular lymph nodes were removed in order to assess lymph node cell counts and perform flow cytometric analysis of lymph node cell subpopulations (CD4+/CD25+, Ia+/CD69+, Ia+/B220+). All test compounds proved to exert significant immunosuppressive effects after topical application, but showed differences in their immunomodulatory potential. In conclusion, the local lymph node assay serves as an appropriate model to characterize immunosuppressive effects of topically applied drugs by measuring immunologically relevant end-points.

Background: A narrow-band UVB lamp (Philips TL 01) emitting a peak of approximately 311 nm was developed to improve the phototherapy for psoriasis. Only a few studies have been performed with promising results. Objective: The therapeutic efficacy of the Philips TL 01 lamp in a new 100 W version was compared with conventional broad-band lamps (Sylvania UV 6) in a controlled trial. Methods: Twenty-three patients with psoriasis were treated with half body exposures from the different UVB sources. The rate of clearing was monitored by estimation of the Psoriasis Area and Severity Index. All patients used emollients; excessive scaling was removed with salicylic acid in yellow petrolatum. In 13 patients dithranol in a modified Ingram regimen was added. In most cases the study was discontinued once a difference between the two sides was evident. Results: In 20 of 23 cases the TL 01 lamp proved to be significantly more effective than the conventional source. Application of dithranol provided a substantial additional therapeutic effect. With the high-intensity TL 01/100W bulbs, exposure times were comparable to broad-band UVB phototherapy. Conclusion: The therapeutic efficacy of Philips TL 01 / 100W and its practicability for psoriasis phototherapy have been demonstrated.

Ultraviolet (UV) irradiation is a major factor in the pathogenesis of certain variants of cutaneous lupus erythematosus. Photosensitivity constitutes one of the criteria of the American Rheumatism Association for the diagnosis of systemic lupus erythematosus, which further emphasizes its importance. The pathomechanism of UV-induced lupus erythematosus remains unknown. The characterization of photosensitive subacute cutaneous lupus erythematosus (SCLE) by Gilliam and Sontheimer has led to a new approach. Through the development of standardized test methods it has became possible to reproduce cutaneous lesions in the UV-A and UV-B spectrum. These standardized test methods allow a better definition of photosensitivity than clinical history does. Recent clinical data show that besides SCLE another variant, lupus erythematosus tumidus, also reveals pronounced photosensitivity. In this review article phototest procedures, phototest results, and clinical correlations in different subgroups are discussed.

Sunlight is a well-established factor in the induction and exacerbation of lupus erythematosus. Although experimental reproduction of lupus erythematosus lesions with wavelengths shorter than 320 nm was demonstrated previously, the effect of wavelengths longer than 320 nm was not investigated adequately. In this study we show that the action spectrum of lupus erythematosus reaches into the UVA region. A total of 128 patients with lupus erythematosus underwent phototesting with the use of polychromatic UVB and long-wave UVA. Subsets of the disease consisted of discoid lupus erythematosus (n = 86), subacute cutaneous lupus erythematosus (n = 22), and systemic lupus erythematosus (n = 20). Skin lesions clinically and histologically compatible with lupus erythematosus were induced in 64% of patients with subacute cutaneous lupus erythematosus, 42% of patients with discoid lupus erythematosus, and 25% of patients with systemic lupus erythematosus. The action spectrum of the induced lesions was within the UVB range in 33% of patients, in the UVA range in 14%, and in the UVB and UVA range in 53%. In positive test reactions patchy dark erythema and urticarial plaques developed within a few days. In some patients typical discoid lesions persisted for months.

Topical calcineurin inhibitors are licensed for the treatment of atopic dermatitis; however, the efficacy of tacrolimus in cutaneous lupus erythematosus (CLE) has only been shown in single case reports.In a multicenter, randomized, double-blind, vehicle-controlled trial, we sought to evaluate the efficacy of tacrolimus 0.1% ointment for skin lesions in CLE.Thirty patients (18 female, 12 male) with different subtypes of CLE were included, and two selected skin lesions in each patient were treated either with tacrolimus 0.1% ointment or vehicle twice daily for 12 weeks. The evaluation included scoring of clinical features, such as erythema, hypertrophy/desquamation, edema, and dysesthesia.Significant improvement (P.05) was seen in skin lesions of CLE patients treated with tacrolimus 0.1% ointment after 28 and 56 days, but not after 84 days, compared with skin lesions treated with vehicle. Edema responded most rapidly to tacrolimus 0.1% ointment and the effect was significant (P.001) in comparison to treatment with vehicle after 28 days. Clinical score changes in erythema also showed remarkable improvement (P.05) after 28 days, but not after 56 and 84 days. Moreover, patients with lupus erythematosus tumidus revealed the highest degree of improvement. None of the patients with CLE demonstrated any major side effects.The study was limited by the small sample size.Explorative subgroup analyses revealed that topical application of tacrolimus 0.1% ointment may provide at least temporary benefit, especially in acute, edematous, non-hyperkeratotic lesions of CLE patients, suggesting that calcineurin inhibitors may represent an alternative treatment for the various disease subtypes.

Polymorphous light eruption (PLE) is a common photo-dermatosis of unknown etiology. It afflicts mainly fair-skinned patients, with a preponderance of young females. There is, however, no absolute restriction as to age, sex, or race. Clinical variants include the papular, vesiculo-bullous, and hemorrhagic variety, as well as plaque, erythema multiforme—like, and insect bite (strophulus)-like types. Skin lesions appear only in certain exposed areas hours or a few days after intense sunshine, and are nearly always mono-morphous in the same patient. The rash subsides spontaneously within several days without leaving scars. The histopathologic picture is characteristic and shows a perivascular lymphocytic infiltrate in the upper and middle corium with subepidermal edema, vacuolization of basal cells, and spongiosis in the lower epidermis. The most important differential diagnoses are solar urticaria, photosensitive erythema multiforme, and lupus erythematosus. The action spectrum of PLE is under debate. Reproduction of skin lesions has been reported with UVB, UVA, and, rarely, visible light, with UVA probably being the most effective part of the spectrum. More important than treatment of PLE is prophylaxis. UVA- and UVB-effective sunscreens are of some help. Phototherapy and especially photochemotherapy (psoralen + UVA; PUVA) offer effective ways to decrease light sensitivity. Systemic treatment with chloroquine or β -car-otene has been disappointing. J Invest Dermatol 88:32s—38s, 1987

Steroid atrophy was induced in 3 volunteers by the continuous, occlusive application of clobetasol propionate to the forearms for 6 weeks. The changes were followed sequentially by light, scanning, and transmission electron microscopy. A 59% decrease in viable epidermal thickness was noted after the sixth week of treatment, as well as a flattening of the dermal-epidermal junction. The 3-dimensional architecture of the dermis was strikingly reorganized. This was largely brought about by resorption of the ground substance as revealed by a progressive dimunition of Hale's stain for acid mucopolysaccharides. Loss of ground substance resulted in decreased spaces between collagen and elastic fibers as shown by scanning and transmission electron microscopy. The fibrous network consequently collapsed, yielding a more compact papillary and reticular dermis. This compression caused the reorientation of both collagen and elastic fibers. However, no differences in collagen and elastin fine structure were noted. Fibroblasts were shrunken but not reduced in density. A marked decrease in number of mast cells was noted in 3-week specimens and virtually no mast cells were observed after 6 weeks. We found that the primary effect of short-term steroid use was a rearrangement of the geometry of the denial fibrous network. This was not due to alterations in the fibers themselves but a secondary consequence of the loss of ground substance.