Failure of physiologic doses of pure UVA or UVB to induce lesions in photosensitive cutaneous lupus erythematosus: implications for phototesting

BACKGROUND: Phototesting studies in cutaneous lupus erythematosus have yielded variable results, with most trials reporting photo-induction of lesions by both UVA and UVB in substantial numbers of patients. OBJECTIVES: To determine the minimal erythema dose in patients with subacute cutaneous lupus erythematosus (SCLE) and controls. PATIENTS/METHODS: We phototested nine patients with SCLE and 14 skin type-matched controls, using repetitive dosing of UVA1 and UVB, but with filters that removed most of the shorter UVC and longer infrared and visible light. In addition, DNA was isolated from anticoagulated blood to genotype the TNF-alpha 308 region in each patient and control. RESULTS: We were unable to demonstrate a difference in minimal erythema dose (MED) between patients and controls, or any correlation of MED with either TNF genotype or systemic drug therapy for SCLE. In addition, no SCLE skin lesions were induced in the nine patients with either UVA or UVB, and one patient cleared a skin lesion after low-dose UVA1 irradiation. CONCLUSIONS: The potential role of wavelengths outside the UVA and UVB range in the photo-induction of cutaneous lupus skin lesions needs to be investigated, and there is a need to standardize phototesting equipment and procedures for patients with cutaneous lupus erythematous.     

Mycophenolate sodium for subacute cutaneous lupus erythematosus resistant to standard therapy

Background Approximately 75–95% of patients with cutaneous lupus erythematosus respond to antimalarial therapy and/or topical glucocorticosteroids. Immunosuppressive agents are usually considered a second‐line approach in patients with resistant disease. Objectives This was a prospective, nonrandomized, open pilot study to evaluate the efficacy of mycophenolate sodium monotherapy in patients with recalcitrant subacute cutaneous lupus erythematosus (SCLE). Methods Monotherapy with oral enteric‐coated mycophenolate sodium 1440 mg daily was given for a total of 3 months. Treatment outcome was evaluated by means of a validated clinical score for cutaneous lupus erythematosus, the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), as well as 20‐MHz ultrasound measurements and colorimetry. Safety assessment included the monitoring of adverse effects and clinical laboratory parameters. Results Ten patients with active SCLE resistant to at least one standard therapy were included in the trial. Mycophenolate sodium led to a remarkable improvement of skin lesions, resulting in a significant decrease of the mean ± SD CLASI from 10·8 ± 6·0 at the beginning to 2·9 ± 2·6 at the end of therapy. Clinical improvement was confirmed by ultrasonographic assessments and colorimetry. No serious side‐effects were noted. Conclusions Mycophenolate sodium is beneficial and safe in the treatment of patients with SCLE that failed standard therapy. However, these preliminary data must be confirmed by randomized controlled trials including a larger sample size.     

Methotrexate treatment for refractory subacute cutaneous lupus erythematosus

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.     

Recombinant interferon α2a is effective in the treatment of discoid and subacute cutaneous lupus erythematosus

Ten patients suffering from either discoid lupus erythematosus (DLE) or subacute cutaneous lupus erythematosus (SCLE) were treated with interferon alpha 2a. Eight received low or intermediate doses (18-45 x 10(6) U/week) for a short period of time (4-8 weeks), with marked improvement of skin lesions in six, an exacerbation in one patient and no change in the other. Two patients with SCLE received high doses (100-120 x 10(6) U/week) over 12 weeks, with complete clearing of the lesions in one and a marked improvement in the other. The responses were of short duration and within a few weeks of stopping treatment all who had improved or cleared relapsed. The side-effects in all the patients were fever and a flu-like syndrome which necessitated a reduction of the dose in one case. In two patients there were increases in the liver enzyme levels, but no haematological toxicity was noted.     

Subacute cutaneous lupus erythematosus presenting as poikiloderma

Subacute cutaneous lupus erythematosus (SCLE) is a recognised variant of lupus erythematosus (LE), which accounts for 10–15% of all cases of cutaneous LE, occurring most commonly in young to middle‐aged white women. Diagnosis is based on the detection of anti‐Ro/SS‐A antibodies in the skin and serum, characteristic clinical and histological cutaneous involvement, and relatively mild systemic involvement. Several unusual variants of SCLE have been reported including erythrodermic SCLE, SCLE with vitiligo‐like lesions, acral SCLE and bullous SCLE. Poikoilodermatous SCLE is a recognised but rare variant of SCLE. There are currently only two case reports, comprising five individual cases, in the literature. We present a case of SCLE in which the main clinical findings were an extensive photodistributed poikilodermatous rash and alopecia.     

Subacute cutaneous lupus erythematosus

A large part of James N. Gilliam's abbreviated investigative career was devoted to testing a hypothesis that strong relationships do exist between the cutaneous and systemic manifestations of lupus erythematosus (LE). As a result of clinical observations made during his early studies designed to test this hypothesis, he introduced the term “subacute cutaneous lupus erythematosus” (SCLE) to designate a clinically distinctive nonscarring type of histologically confirmed cutaneous LE that he felt might represent a cutaneous marker for a discrete subset of LE patients.¹ A series of studies carried out in our and other laboratories have since confirmed that patients who develop SCLE skin lesions do indeed share other clinical, pathologic, serologic, and immunogenetic features. Dr. Gilliam died on June 6, 1984, before the full impact of his initial clinical observations had been fully recognized. I would, therefore, like to dedicate the following discussion of the clinical and laboratory features of patients with SCLE skin lesions to his memory.     

Clinical course and prognosis of cutaneous lupus erythematosus

Classical variants of specific cutaneous LE lesions are chronic discoid LE (CDLE) and subacute cutaneous LE (SCLE). CDLE and SCLE may appear at any age; however, the most common age of onset is between 20 and 40 years, with a female predominance of 3:1 in CDLE and 3-6:1 in SCLE. Nonspecific LE skin lesions such as generalized or acrolocalized vasculitis (4-30%), livedo reticularis (22-35%), and alopecia (38-78%) are frequently seen in patients with cutaneous LE. Other typical cutaneous LE subsets such as LE profundus/panniculitis, LE tumidus, urticaria vasculitis, hypertrophic LE, and bullous LE are rather rare variants. Butterfly rash and/or macular exanthema are characteristic skin lesions of systemic lupus erythematosus (SLE) rarely found in patients with cutaneous LE.     

Upregulation of epidermal surface molecule expression in primary and ultraviolet-induced lesions of lupus erythematosus tumidus

BACKGROUND: Lupus erythematosus tumidus (LET), a photosensitive skin disorder with characteristic clinical and histological features, has not been generally accepted as a subset of cutaneous lupus erythematosus (CLE). OBJECTIVES: To analyse the expression of epidermal surface molecules in skin biopsy specimens from patients with LET and to relate the results to other variants of CLE, such as discoid lupus erythematosus (DLE) and subacute CLE (SCLE). METHODS: In total, 45 patients with different subtypes of CLE were included in the study, and cryostat sections from primary and ultraviolet (UV) A- and UVB-induced skin lesions were investigated using immunohistochemical methods. RESULTS: In contrast to healthy controls, skin lesions of LET showed upregulation of intercellular adhesion molecule-1 (ICAM-1) and histocompatibility class II molecules (HLA-DR), with an expression pattern resembling that seen in DLE and SCLE. Furthermore, staining with a monoclonal antibody against 27E10, a distinct marker for cell activation and differentiation, revealed intense focal or band-like labelling of all epidermal layers independent of the type of lesion. CONCLUSIONS: Expression of epidermal surface molecules such as ICAM-1, HLA-DR and 27E10 is equally upregulated in primary and UV-induced lesions of patients with LET, DLE and SCLE. These results support our recent clinical findings that LET represents a distinct subset of CLE with a similar immunopathomechanism rather than a different disease.     

Scarring skin lesions of discoid lupus erythematosus are characterized by high numbers of skin-homing cytotoxic lymphocytes associated with strong expression of the type I interferon-induced protein MxA

BACKGROUND: Infiltrating T lymphocytes are considered to play a major pathological role in skin lesions of cutaneous lupus erythematosus (CLE), a cutaneous autoimmune disease of unknown aetiology. Earlier histological studies revealed that the inflammatory infiltrate in CLE skin lesions is predominantly composed of T lymphocytes, with a slight predominance of CD4+ over CD8+ T cells, but failed to explain the development of scarring skin lesions, characteristic for chronic discoid lupus erythematosus (CDLE). Because recent investigations have highlighted the relevance of cytotoxic lymphocytes in autoimmune tissue destruction, we hypothesized that the scarring CDLE lesions might be caused by cytotoxic T lymphocytes. OBJECTIVES: To analyse skin biopsies of 15 patients with CLE [10 female, five male; localized CDLE (lCDLE), n = 5; disseminated CDLE (dCDLE), n = 5, subacute CLE (SCLE), n = 5] and five control biopsies taken from healthy controls and to characterize the inflammatory infiltrate. Methods We used immunohistochemistry, including staining for the cytotoxic molecule granzyme B, the skin-homing molecule cutaneous lymphocyte antigen (CLA) and the protein MxA, which is specifically induced by type I interferons (IFNs). RESULTS: We found a strong coexpression of granzyme B and CLA on lesional lymphocytes of patients with scarring lCDLE and dCDLE, which was significantly enhanced when compared with nonscarring SCLE and healthy controls. The increased expression of granzyme B was closely associated with the lesional expression of the type I IFN-induced protein MxA. CONCLUSIONS: Our results provide evidence that type I IFNs and potentially autoreactive cytotoxic lymphocytes targeting adnexal structures are highly associated with scarring lupus erythematosus lesions and might be responsible for their scarring character.     

Leflunomide in subacute cutaneous lupus erythematosus - two sides of a coin

Background Subacute cutaneous lupus erythematosus (SCLE), a distinct clinical subset of lupus erythematosus, remains a therapeutic challenge, especially in cases resistant to topical and standard systemic therapy. Leflunomide, a novel antirheumatic drug, has shown efficacy in the treatment of systemic lupus erythematosus in pilot studies. Methods We report two patients with SCLE who demonstrated the spectrum of possible clinical responses to leflunomide therapy. Results One patient experienced a complete clinical remission of symptoms, whereas the other developed a massive skin reaction which was distinctly related to the commencement of leflunomide therapy. Conclusion To our knowledge, this is the first time that remission and deterioration of SCLE by leflunomide therapy have been described.     

两型亚急性皮肤型红斑狼疮病情演变的分离现象

目的：探讨两型亚急性皮肤型红斑狼疮（SCLE）患者病情演变的差异。方法：对40例SCLE患者进行3－14年的随访分析,比较两型SCLE患者临床表现和实验室检查异常变化、治疗反应及预后。结果：在随访中,环形红斑型患者的疹型变化较少,病情较轻,部分患者出现干燥症状;而丘疹鳞屑型患者中大部分逐渐演变成SLE。环形红斑型患者仅21.7％发生轻度肾脏受累,皮质类固醇用量较少,无死亡病例;丘疹鳞屑型患者中64.7％发生肾脏受累,皮质类固醇用量较大或合并使用免疫抑制剂,1例死亡,3例发展为尿毒症。结论：环形红斑型是SCLE中较为良性的一型,预后较好,而丘疹鳞屑型则易发展为SLE,预后较差。     

Terbinafine-induced subacute cutaneous lupus erythematosus

Terbinafine is a synthetic oral allylamine that is used for systemic treatment of microscopy- or culture-proven dermatophyte infections of skin and nails. It is normally well-tolerated and side effects include transient gastrointestinal symptoms and skin reactions that can occur in up to 2.3% of treated patients. Subacute cutaneous lupus erythematosus (SCLE) is a skin reaction that has been reported secondary to use of a variety of drugs. The number of reports of SCLE with terbinafine is limited. We demonstrate 2 patients in one dermatology clinic who presented with a predisposing autoimmune diathesis within 3 months of each other.     

UVB-induced leucocyte trafficking in the epidermis of photosensitive lupus erythematosus patients: normal depletion of Langerhans cells

BACKGROUND: The pathogenic mechanisms of UV-induced skin lesions of lupus erythematosus (LE) are unknown. In a recent study of pathogenic mechanisms of polymorphic light eruption (PLE), significantly more Langerhans cells (LCs) persisted in the epidermis after UVB overexposure than in healthy individuals. Interestingly, the same phenomenon was observed in one subacute cutaneous lupus erythematosus (SCLE) patient. It could therefore be hypothesized that both photodermatoses share a common pathogenic mechanism of photosensitivity. In the present study, we tested this hypothesis by investigating leucocyte trafficking in the initial phase of cutaneous LE after intense UVB exposure. METHODS: In 22 photosensitive LE patients (12 chronic discoid lupus erythematosus, seven systemic lupus erythematosus and three SCLE) and nine age/sex-matched controls, uninvolved buttock skin was exposed to six minimal erythemal dose (MED) UVB radiation. Subsequently, biopsies were taken after 24, 48 and 72 h, and one control biopsy was taken from unirradiated skin. Skin sections were stained for the presence of LCs, neutrophils and macrophages. Areal percentages of positively stained cells within the epidermis were quantified and compared between the patients and controls. RESULTS: A gradual decrease of epidermal LCs and a gradual increase of epidermal neutrophils and macrophages at several timepoints after six MED irradiation was observed equally in both LE patients and controls. CONCLUSION: Immunohistopathology of irradiated uninvolved skin of photosensitive LE patients did not reveal the same pathologic trafficking of LCs and neutrophils as described for PLE patients. We conclude that different mechanisms are operative in the pathogenesis of PLE and photosensitive LE.     

Successful treatment of subacute cutaneous lupus erythematosus with mycophenolate mofetil

Mycophenolate mofetil (MMF) is an immunosuppressive agent that has been shown to be effective in transplant patients. Some case reports and pilot studies have suggested efficacy against systemic lupus erythematosus (LE), particularly in the case of lupus nephritis. Reports on MMF treatment of skin manifestations of LE are still anecdotal. We report two cases with extensive skin lesions owing to subacute cutaneous LE (SCLE). Both patients had been treated with azathioprine and antimalarials without effect. Finally both patients were given highly dosed glucocorticosteroids, which were also ineffective but led to vertebral fractures because of long-term steroid treatment in one patient and steroid-induced psychosis in the other. MMF 2 g daily caused the skin manifestations to disappear within a few weeks in both patients. One patient was followed up for more than 24 months, and showed good toleration of MMF treatment. The skin remained stable over this period when at least 1 g MMF per day was administered. In conclusion, MMF appears to be an attractive treatment option in skin manifestations of SCLE, and seems to be beneficial for patients with steroid-refractory lesions that are also resistant to treatment with immunosuppressants or antimalarials. The observations suggest that further evaluation of this route in randomized controlled trials is warranted.     

Poikilodermatous subacute cutaneous lupus erythematosus

BACKGROUND: Subacute cutaneous lupus erythematosus (SCLE) is a distinct subset of lupus erythematosus with unique clinical, immunological and genetic features. Among the unusual variants of SCLE, there is a poikilodermic presentation. However, to date, only 1 case of poikilodermatous SCLE has been reported. OBJECTIVE: Our goal was to summarize the clinical characteristics and course as well as the pathological, laboratory and immunofluorescence findings of 4 patients with poikilodermatous SCLE. METHODS: A retrospective study was conducted including 54 patients diagnosed as having SCLE between 1980 and 2002. RESULTS: Four patients (7.4%) had SCLE. All patients were alive, and none developed severe systemic involvement in up to 36 years (median, 24 years) after the onset of disease. The most noteworthy laboratory finding was the cutaneous deposition of amyloid. CONCLUSION: Poikilodermatous SCLE represents an uncommon variant within the clinicopathological spectrum of SCLE following a favorable course, in spite of extensive cutaneous involvement. Photosensitivity is the pathomechanism explaining, theoretically, the development of both poikiloderma and cutaneous amyloidosis in such cases.     

Oral lesions in four cases of subacute cutaneous lupus erythematosus

Patients with subacute cutaneous lupus erythematosus (SCLE) present with intense photosensitivity. Clinical patterns comprise papulosquamous or annular lesions on sun-exposed areas; although the face is usually spared. Intraoral lesions have not been reported in most case series of SCLE, but are well-documented in other forms of lupus erythematosus. This study included four female patients diagnosed with SCLE, who presented with specific oral involvement consisting of palatal patches (three cases), buccal mucosal patches (one case), gingival keratotic erythema (one case), and lip lesions (one case). All patients presented with exuberant facial lesions, a condition not often observed in SCLE. Our findings suggest that oral involvement in SCLE may not be as rare as once thought, and that patients with intense facial lesions are at particular risk of developing oral lesions.     

The cutaneous pathology associated with seropositivity for antibodies to SSA (Ro): a clinicopathologic study of 23 adult patients without subacute cutaneous lupus erythematosus

Antibodies to Ro/SSA are found in patients with subacute cutaneous lupus erythematosus (SCLE), complement deficiency lupus erythematosus, systemic lupus erythematosus (SLE), neonatal lupus erythematosus, and Sj?gren syndrome (SS). Most studies describing the cutaneous pathology associated with anti-Ro antibodies have been of patients with SCLE. Over a 42-month period, we encountered skin biopsy specimens from 23 anti-Ro-positive patients who did not have SCLE: 15 had SLE variably manifesting as SCLE-like rashes; malar erythema; a dermatomyositis-like rash; vascular disease involving cutaneous, cardiac, peripheral, and central nervous systems; restrictive pulmonary disease; periorbital edema; and myositis. Two patients had primary Sj?gren syndrome, one had primary antiphospholipid antibody syndrome, and two had rheumatoid arthritis; all five had clinical evidence of cutaneous vasculopathy encompassing livedo, perniosis, and palpable purpura. Three additional patients presented with folliculocentric purpura without other stigmata to permit classification as a specific connective tissue disease. In the SLE patients, biopsy specimens of photodistributed eruptions showed an interface dermatitis accompanied by superficial vascular plexus density reduction. Vasculopathic reactions in patients with and without SLE comprised neutrophilic, lymphocytic, or pauciinflammatory thrombogenic subtypes. Although at times a marker of SCLE, the identification of anti-Ro antibodies may isolate a subset of patients at higher risk of multiorgan vasculopathy, myositis, and progressive pulmonary disease. We postulate that many of the features seen in these patients reflect the sequelae of antibody mediated endothelial cell injury.     

Matrix metalloproteinases as mediators of tissue injury in different forms of cutaneous lupus erythematosus

Background Matrix metalloproteinases (MMPs) contribute to tissue destruction, regeneration, inflammation and apoptosis and several of them are upregulated by ultraviolet (UV) radiation in skin. Although some MMPs associate with organ manifestations of systemic lupus erythematosus (SLE), their role in cutaneous lupus erythematosus (LE) is elusive. Objectives Our aim was to evaluate the expression of MMPs in SLE, subacute cutaneous LE (SCLE) and discoid LE (DLE) skin lesions and their relation to apoptosis and epidermal changes. Methods Lesional skin biopsies from 20 patients with SLE, 20 with DLE and 17 with SCLE, and from UVA/UVB‐photoprovoked skin of healthy volunteers were immunostained using antibodies to multiple MMPs and tissue inhibitors of metalloproteinases (TIMPs). The TUNEL (terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate nick end labelling) method was used for detection of apoptosis. Results MMP‐3, ‐10, ‐19 and ‐26 were abundantly expressed by keratinocytes in SLE, DLE and SCLE skin samples. MMP‐7 was detected in keratinocytes in regions of oedema and vacuolization especially in SLE and SCLE, while MMP‐14 was only occasionally observed in keratinocytes. Photoprovocation did not induce MMP‐10 or ‐26 expression in skin of healthy volunteers. Epithelial TIMP‐1 expression was low while occasional positive fibroblasts were seen in the dermis. TIMP‐3 was abundantly expressed in the epidermis, endothelial cells and macrophages. Conclusions Different subtypes of cutaneous LE are fairly similar in their MMP expression profile. MMP‐3 and ‐10 mediate both epidermal changes and dermal tissue remodelling but are not present in lymphocytes. Low expression of TIMP‐1 suggests that lupus skin is characterized by proteolytic events, and targeted action using selective MMP inhibitors may reduce lupus‐induced damage in inflamed tissues.     

Relationship between circulating anti-Ro/SS-A antibody levels and skin disease activity in subacute cutaneous lupus erythematosus

Anti-Ro/SS-A antibody levels in 80 serum specimens from 12 patients with subacute cutaneous lupus erythematosus (SCLE) were determined by immunodiffusion and enzyme-linked immunosorbent assay in order to examine the changes in this autoantibody response with time and to study the relationship between levels of this antibody and SCLE skin disease activity. Anti-Ro/SS-A antibody levels were found to vary considerably over time in a given patient when measured by both assays. Several patients who did not have detectable levels of this antibody at the time of their initial examination were found to be antibody positive at follow-up examinations. However, no significant relationship was found between antibody levels in either assay and SCLE skin disease activity. While not ruling out a pathogenetic role for this antibody in the elicitation of SCLE skin lesions, these results would suggest that other factors are likely to be involved.