Chilblain lupus erythematosus is associated with antibodies to SSA/Ro.

Chilblain lupus erythematosus (CL) of Hutchinson is a subtype of lupus erythematosus (LE) characterized by erythematous lesions induced by cold, damp climates. A number of patients affected by CL eventually develop features of systemic lupus erythematosus (SLE). We report here 9 patients with chilblain cutaneous lesions, 6 of them were affected by SLE and 2 by SCLE. The onset of CL preceded the diagnosis of LE, from 1 to 10 years in 3 cases, it was concurrent in one case and was subsequent in the remaining 4 cases. Raynaud's phenomenon and photosensitivity were other prominent clinical features in patients with CL. Nailfold capillaroscopy revealed pathological changes in every patient examined. ANA and anti-SSA/Ro antibodies were detected in all nine patients. Anti-SSB/La were detected in 2 cases, anti-Sm in one case, and anti-Sm and anti-RNP in a one case. Antibodies to dsDNA and complement consumption were found in the six patients with SLE. The fine specificity of anti-SSA/Ro was determined by immunoblotting: anti-60kD and anti-52 kD were detected in three sera, anti-60kD alone in 5 sera, while one serum did not blot. In conclusion, the present study suggests that chilblain LE is associated with SSA/Ro autoantibodies, as is SCLE, hypergammaglobulinemic purpura and neonatal lupus erythematosus.     

IL-17 in cutaneous lupus erythematosus

BackgroundLupus erythematosus (LE) is a heterogeneous disease with broad clinical spectrum from cutaneous to visceral and systemic inflammation. IL-17 isoforms (IL-17A and IL-17F) are proinflammatory cytokines with unclear implications in lupus erythematosus pathogenesis. In this study we focused upon IL-17 in normal and modified lupus skin with a correlative study between local and serological expression.Material and methods89 subjects were recruited and divided in 5 groups—10 patients with psoriasis (disease control group), 13 healthy controls, 26 with discoid chronic lupus (DLE), 23 with systemic lupus erythematosus (SLE) and 17 with subacute lupus erythematosus (SCLE). Blood samples and skin punched-biopsy specimens were performed. Serum IL-17A, IL-17F, and IL-23 concentrations were determined by ELISA. Skin IL-17A and CD4 expression were evaluated by immunohistochemistry.ResultsImmunohistochemical expression of IL-17A was higher in DLE, SCLE and SLE patients than in negative control subjects (all p < 0.05). Serum IL-17A concentrations were higher in DLE and SLE patients than in negative controls (p < 0.05). Serum IL-17A levels were similar in SCLE and negative controls (p > 0.05). Serum IL-17F concentrations were higher in DLE, SCLE and SLE patients than in healthy controls (all p < 0.05). In DLE, SCLE, SLE patients and healthy controls we observed comparable levels of IL-23 (p > 0.05). Serum anti Ro antibodies correlate with IL-17A+ lymphocytes from SCLE lesion and SLE normal skin (all p < 0.05).ConclusionIL-17 isoforms (IL-17A and IL-17F) are implicated in SLE but also in DLE and SCLE immunopathogenesis.     

Prevalence of anticardiolipin antibodies in subacute cutaneous lupus erythematosus.

We examined the prevalence of the antibodies to cardiolipin measured by solid-phase enzyme immunoassay during a prospective study of patients with subacute cutaneous lupus erythematosus (SCLE). Seven of 44 (16%) consecutive patients with SCLE had positive anticardiolipin antibodies; of these only three satisfied the American Rheumatism Association's revised criteria for the classification of systemic lupus erythematosus. Clinical findings probably associated with the positive anticardiolipin antibodies were found in four cases, including clotting abnormalities, thrombocytopenia, hemolytic anemia, livedo reticularis, chilblain lupus erythematosus lesions, migraine, leg venous thrombosis and pulmonary embolism after surgery, and spontaneous abortion. Our data suggest that it is reasonable to screen SCLE patients for these antibodies to confirm the presence of the antiphospholipid syndrome.     

Management of skin disease in patients with lupus erythematosus

Skin disease in patients with lupus erythematosus may be subdivided into two broad categories - those represented by a 'specific' histopathology, the interface dermatitis, and those with changes that are not specific to lupus erythematosus, for example, vasculitis, mucin infiltration, etc. The specific skin lesions that are most common are discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE). Evaluation will allow the treating physician to assign a prognosis. Cutaneous lesions can generally be managed with standard therapies. Patients with discoid LE and subacute cutaneous LE are generally photosensitive, and therefore sunscreens, protective clothing and behavioural alteration should be discussed with all patients. Topical corticosteroids are a standard form of therapy, but 'newer' agents such as retinoids, calcipotriene and tacrolimus might be effective. Antimalarial agents are generally effective. Attempts to reduce or stop smoking may aid in the control of cutaneous LE. The choice of alternative therapy is personal, and discussions of the risks and benefits should be carefully documented.     

Fine specificity of the Ro/SSA autoantibody response in relation to serological and clinical findings in 96 patients with self-reported cutaneous symptoms induced by the sun

Anti-Ro/SSA assays assist the clinician in distinguishing autoimmune diseases such as Sj?gren? syndrome (SS), systemic lupus erythematosus (SLE) and subacute cutaneous lupus erythematosus (SCLE). The objective of the study was to investigate the fine specificity of the autoantibodies in relation to clinical presentation as well as environmental and endogenous factors such as photosensitivity, smoking and immunoglobulin (Ig) levels in patients with Ro/SSA autoantibodies. Serum samples from 96 anti-Ro/SSA positive photosensitive patients were tested for autoantibody levels by enzyme-linked immunosorbent assay (ELISA) using purified recombinant Ro52 kd, Ro60 kd and La proteins as antigens. The highest levels of anti-Ro52 and anti-La were observed in patients with primary SS, and the lowest levels of anti-Ro52 in chronic cutaneous lupus erythematosus (CCLE). SCLE patients with systemic disease (SLE and/or SS) showed higher levels of anti-Ro52 than SCLE limited to the skin. A correlation between high serum levels of IgG and anti-Ro52 (P < 0.01) and between IgA and anti-Ro52 (P < 0.05) and anti-Ro60 (P < 0.05) was found. Polymorphic light eruption (PLE) was common in all diagnostic groups but did not correlate with autoantibody levels. Smoking was more common in lupus patients than in SS patients. Our findings thus propose different mechanisms for different clinical presentations of Ro/SSA positive patients. The testing of anti-Ro52 antibodies might serve as a prognostic tool in photosensitive cutaneous diseases.     

Systemic lupus erythematosus and gouty arthritis: an uncommon association

Objective. To examine the frequency of gouty arthritis in patientswith systemic lupus erythematosus (SLE) and elucidate the clinicalfactors that predispose to this occurrence. Methods. A chart review of in-patients (1989–2001) andout-patients (1999–2001) with ICD9 billing codes for goutyarthritis/tophaceous gout and SLE was performed. Twenty-sixpatients were identified. Patients meeting American Collegeof Rheumatism criteria for SLE and crystal-proven gout or aself-limited inflammatory arthritis felt to be crystal-induced(i.e. definite gout) were included. Results. Ten patients were identified. Their mean age was 46.5yr; 80% were African-American and 70% were women. Nine of theten had lupus nephritis and four had undergone renal transplantation.An acute worsening of renal function unrelated to lupus activitypreceded almost all gout flares. Lupus activity at the timeof the first gout attack as measured by the Systemic Lupus ActivityMeasure (SLAM) was low. Eight patients were on prednisone (meandose 8 mg/day) for their SLE at the time the attack of goutoccurred. Conclusions. Gouty arthritis is uncommon in SLE; it occurs primarilyin patients with long-standing SLE and nephritis. Worseningrenal function usually preceded gout attacks, but SLE diseaseactivity was minimal. Crystal-induced arthritis should be includedin the differential diagnosis of a lupus patient presentingwith acute inflammatory arthritis because the long-term treatmentof the two conditions differs substantially. KEY WORDS: Gout, Systemic lupus erythematosus, Arthritis, Lupus nephritis, Renal insufficiency.     

Subacute cutaneous lupus erythematosus. Clinical, serologic, immunogenetic, and therapeutic considerations in seventy-two patients

We studied 72 patients with subacute cutaneous lupus erythematosus (SCLE). Forty-nine of the patients had been part of an earlier study. The cutaneous disease was primarily annular in 17 patients, papulosquamous in 48, and a combination in 7. Although the major feature of SCLE is nonscarring, non-atrophy-producing lesions, scarring discoid lesions were observed in 21 patients. Thirty-six patients fulfilled criteria for systemic lupus erythematosus. Cytoplasmic antibodies were present in only 22 patients. However, in the group of 23 patients recently analyzed, 13 of 22 tested had anti-Ro (SS-A) and/or anti-La (SS-B). HLA-DR3 was present in 22 of 59 patients. Neither anti-Ro (SS-A) nor HLA-DR3 correlated with any clinical finding. Forty-seven patients have had continued activity of their disease, but in most patients, the disease has been controlled with sunscreens, topical and intralesional corticosteroids, and oral hydroxychloroquine. A broad spectrum of systemic lupus erythematosus-associated phenomena can occur in patients with SCLE. The disease is frequently easily controlled, and may become quiescent. This subset of lupus patients is less distinctive than has been previously suggested.     

Subacute cutaneous lupus erythematosus,and positive anti-MDA5 antibody in clinically amyopathic dermatomyositis with rapidly progressive interstitial lung disease: A case report and literature review

BackgroundClinically amyopathic dermatomyositis (CADM) is a subtype of DM with characteristic cutaneous lesion with normal creatinine kinase levels. Presence of anti-melanoma differentiation-associated gene 5 (MDA5) antibody is found to be associated with rapidly progressive interstitial lung disease (RP-ILD). Aim of the work: to report a CADM patient with positive anti-MDA5 antibody and RP-ILD with clinical features of systemic lupus erythematosus (SLE) who clinically responded to a combination of cyclophosphamide and other conventional immunosuppressant. Case presentation: A 44-year-old Indian woman presented with classical cutaneous lesions of DM with normal creatinine kinase levels amongst other clinical features. She was initially diagnosed with SLE before developing RP-ILD and a positive MDA5 antibody. Anti-nuclear antibody, anti-dsDNA and anti-Sm antibody were negative. Serum ferritin level was very high (1599 ng/mL) as compared to C-reactive protein (23.4 mg/L). Anti-Ro-52 and anti-PM-Scl 75 were positive. High resolution computed tomography (HRCT) of the lungs revealed features consistent with ILD. Histology of her skin biopsy was consistent with subacute cutaneous lupus erythematosus (SCLE). Her diagnosis was revised to CADM with overlapping SCLE. She responded to a combination of hydroxychloroquine, cyclosporine-A, mycophenolate mofetil, pulse methylprednisolone and pulse cyclophosphamide 750 mg/month for 6 months. Her cutaneous lesions gradually improved with normalization of serum ferritin level. Repeated HRCT showed no further progression of the pulmonary fibrosis. Conclusion: CADM with positive anti-MDA5 antibody associated with RP-ILD is rare with a high mortality rate. Early recognition and prompt treatment with a combination of immuno-suppressant may improve the outcome of this complex disease.     

Response criteria for cutaneous SLE in clinical trials

Systemic lupus erythematosus (SLE) is a complex phenotype characterized by a wide variety of clinical manifestations but the skin is involved in 70-80% of patients. Acute cutaneous lupus erythematosus lesions, like other organ manifestations of SLE wax and wane with other manifestations of active disease and quantifying it is a useful a "signal" to screen new therapies in SLE and pre- and post-treatment biopsies can be additionally informative. The ACR has recommended a priori response criteria for SLE Activity Measures (2) and that these be used along with organ specific response criteria in clinical trials. We review the literature on evaluation of skin manifestations in lupus erythematosus (LE) and propose the parameters of evaluating responsiveness and criteria for minimal clinically important changes in skin manifestations. The Committee presents two options for grading skin manifestations. These recommendations add to the tools of SLE trials.     

Improvement of irregularity of brain vessel walls in systemic lupus erythematosus by tacrolimus

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease that affects multiple organs. Neuropsychiatric SLE develops during the course of the disease in 50% to 74% of SLE patients. The pathogenesis of CNS manifestations is multifactorial. The most common neuropathological finding has, in various studies, been multifocal infarcts. The cerebral vascular lesions in SLE that can cause cerebral infarction can be categorized into thromboembolism and vasculitis. On the other hand, tacrolimus is an immunosuppressive drug used for several autoimmune diseases, which inhibits the calcineurin pathway in T cells and reduces accompanying inflammatory cytokine production. We experienced that treatment of a patient with SLE with tacrolimus and steroid pulse therapy yielded improvement of vasculitis of brain vessels on magnetic resonance angiography. We suggest that tacrolimus may play an important role in the treatment of vasculitis of SLE.     

BCL-2 EXPRESSION IS UNALTERED IN UNFRACTIONATED PERIPHERAL BLOOD MONONUCLEAR CELLS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

It has been postulated that the high levels of autoantibodiesobserved in systemic lupus erythematosus (SLE) patients couldresult from abnormal longevity of polyclonally activated B-cells.This increased survival could be due to dysfunction of apoptosis,the normal regulatory process governing their life span. Theprotein product of the bcl-2 gene can enhance lymphoid cellsurvival by interfering with apoptosis. Moreover, transgenicmice overexpressing bcl-2 in their B-cells developed an autoimmunesyndrome resembling SLE. To determine whether overexpressionof bcl-2 occurs in SLE patients, bcl-2 protein was measuredin peripheral blood mononuclear cells from 73 SLE patients,20 healthy individuals and 47 patients with other autoimmunediseases. Only three lupus patients had raised levels of bcl-2and there were no statistically significant differences in themean bcl-2 levels measured in SLE patients compared to controls.Bcl-2 levels did not correlate with overall disease activityin SLE patients. KEY WORDS: Systemic lupus erythematosus, Apoptosis, Lymphocytes, bcl-2     

ANA negative systemic lupus erythematosus sera revisited serologically

OBJECTIVE: To better define the serology of a panel of sera from patients with a clinical diagnosis of systemic lupus erythematosus (SLE) or subacute cutaneous lupus erythematosus (SCLE) with a negative antinuclear antibody (ANA) test on mouse liver. METHODS: Sensitive ELISA methods for anti-Ro/SSA, anti-La/SSB, and anti-U1RNP were applied to a panel of 76 sera with either SLE or SCLE and a negative ANA test on mouse liver. RESULTS: These sera had previously been shown to have a high prevalence of anti-Ro/SSA (68%) and anti-La/SSB (27%) precipitins respectively. None had precipitins to U1RNP or Sm. ELISA methodology revealed that all of the sera 76/76 (100%) had elevated levels (> mean +/- 2 SD of a panel of 21 normal sera) of anti-Ro/SSA, 36/76 (46%) had elevated levels of anti-La/SSB, and 27 of 76 (35%) had elevated levels of anti-U1RNP. CONCLUSION: The subset of patients with SLE and SCLE with a negative ANA test on mouse liver almost uniformly have antibodies to the Ro/SSA antigen by a sensitive ELISA. This adds evidence to the idea that this is a more homogeneous disease subset within the spectrum of SLE.     

Treatment of severe and difficult cases of systemic lupus erythematosus with tacrolimus. A report of three cases

OBJECTIVES—An analysis of the efficacy of tacrolimus treatment in three patients with difficult and severe systemic lupus erythematosus (SLE) whose active disease had been previously poorly controlled by cyclosporine and cyclophosphamide.
METHODS—A review of patient notes.
RESULTS—Two patients are well controlled after six and nine months of treatment with tacrolimus 0.06 mg/kg/day and 0.18 mg/kg/day. Previous persistent vasculitis had resolved and other features of active disease were controlled. The third patient's vasculitis had not improved significantly after two months of treatment and tacrolimus 0.17 mg/kg/day was discontinued because of nephrotoxicity.
CONCLUSION—Tacrolimus may be a useful additional immunosuppressive agent in some patients whose SLE is not well controlled by conventional treatments.

     

LUPUS AND NON-LUPUS CUTANEOUS MANIFESTATIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS

Abstract Mucocutaneous manifestations occur frequently in systemic lupus erythematosus (SLE). Common non-lupus dermatoses may be confused with lupus rashes, with important clinical consequences. A study of 84 consecutive patients with SLE was performed to determine the comparative frequency of lupus and non-lupus mucocutaneous abnormalities, the comparative sensitivity of routine histology and immunofluorescence in the diagnosis of lupus rashes, and the association of skin manifestations with other clinical and serological features. Thirty-five patients had dermatoses attributable to SLE (mean 3.7 per patient) and 58 had derrnatoses which were not directly attributable to SLE (mean 2.1 per patient), highlighting the need for accurate diagnosis of skin rashes in SLE patients. Routine histology confirmed the clinical diagnosis of typical cutaneous lupus in 100% of malar lupus rashes and in approximately 90% of subacute cutaneous and discoid lupus rashes. Direct immunofluorescence of the affected skin provided supportive evidence of cutaneous lupus in 60% of malar lupus rashes and approximately 50% of subacute cutaneous and discoid lupus rashes. This reaffirmed the poor sensitivity of immunofluorescence, compared with routine histology, in the diagnosis of lupus rashes. The association of subacute cutaneous lupus with anti-Ro antibodies was confirmed. (Aust NZ J Med 1987; 17: 501–506).     

The spectrum of cutaneous manifestations in lupus erythematosus--the Italian experience

We have evaluated the incidence of lupus erythematosus (LE)-specific skin disease in 186 patients with LE, seen retrospectively over a 10-year period at our Dermatology Department and determined the correlation of LE-nonspecific skin disease in patients with systemic involvement. Chronic cutaneous LE (CCLE) with classical discoid lesions (localized, 70%; generalized, 30%) was the most common cutaneous manifestation (72.5%). Subacute cutaneous LE (SCLE) represented only 8% of LE skin disease (annular-polycyclic type, 73%; papulo-squamous type, 27%). Acute cutaneous LE (ACLE) was detected in 15% of our patients: the butterfly erythema was the most frequent skin lesion (96%) while only one case of bullous LE and one case of widespread maculo-papular eruption in association with malar erythema were demonstrated. In 8 patients no LE-specific skin lesions (lupus sine lupo) were found. LE-nonspecific skin lesions were found in 31% of our patients with systemic LE (SLE): Raynaud's phenomenon was found in 23/58 (39.6%), cutaneous small vessel leukocytoclastic vasculitis in 8/58 (13.7%), nonscarring alopecia in 18/58 (31%), lupus pernio in 6/58 (10.3%), hemorrhagic lesions in 4/58 (6.8%), livedo reticularis in 5/58 (8.6%), mucosal ulcers in 3/58 (5.1%) and periungual telangiectasia in 12/58 (20.6%) SLE patients. LE-nonspecific skin lesions are detected only in patients with SLE and usually in the active phases of the disease.     

Tacrolimus therapy for systemic lupus erythematosus without renal involvement: a preliminary retrospective study

Abstract

We conducted a pilot study to investigate whether tacrolimus was effective for treating patients with systemic lupus erythematosus (SLE) without renal involvement. Ten SLE patients with symptoms such as arthritis and erythema, but no active nephritis, were treated with tacrolimus. They included 8 women and 2 men aged from 24 to 62 years [mean ± standard deviation (SD): 42.1 ± 11.3 years]. Tacrolimus was administered at doses of 1–3 mg daily, and efficacy was assessed from the SLE Disease Activity Index (SLEDAI) after 1 year. Two patients ceased treatment due to adverse reactions (after 4 days for chest pain and 7 months for recurrent infections). The other 8 patients completed 1 year of treatment, and significant improvement of disease activity was observed in 6 of them. The mean (±SD) SLEDAI showed a significant decrease after 1 year of tacrolimus therapy, from 6.8 ± 3.1 to 3.4 ± 0.9; p < 0.05 by Student’s paired t test. The mean (±SD) dose of prednisolone also decreased significantly, from 16.8 ± 8.6 to 9.3 ± 4.6 mg/day; p < 0.05. Although a prospective controlled study will be necessary to confirm, tacrolimus might be a treatment option for active SLE without renal involvement.     

Response to hydroxychloroquine in Japanese patients with systemic lupus erythematosus using the cutaneous lupus erythematosus disease area and severity index (CLASI)

We evaluated the cutaneous lupus erythematosus disease area and severity index (CLASI) in Japanese patients with systemic lupus erythematosus (SLE) in order to design a clinical trial of hydroxychloroquine (HCQ) in Japan. Our prospective cohort study consisted of seven SLE patients with active skin disease who started HCQ at Tokyo Metropolitan Tama Medical Center. The therapeutic responses were assessed at 4 months. Patients were categorized as responders (improved) or non-responders (unchanged or worsened) using the criteria of a 4-point or 20% decrease in the CLASI activity score. We also assessed joint pain determined by patient visual analog scale (VAS), malaise (VAS), patient global assessment of SLE (VAS), and constitutional and musculoskeletal symptoms according to the British Isles Lupus Assessment Group (BILAG) disease activity index. Six patients (86%) were categorized as responders. The median (range) CLASI activity score of all patients at assessment had changed from 8.0 (2–22) to 4 (2–10). All five patients with joint pain and all five patients with malaise showed improvement in patient VAS but the BILAG findings failed to capture these improvements. In conclusion, the cutaneous aspects of SLE can be measured by the CLASI. The CLASI activity score may be a reasonable primary endpoint when performing a clinical trial of HCQ.     

Skin lesions--an indicator of disease activity in systemic lupus erythematosus?

Cutaneous manifestations have great diagnostic value for systemic lupus erythematosus (SLE). In this study we tried to establish a correlation between lupus erythematosus LE-specific and LE-nonspecific cutaneous lesions and disease activity measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Sixty-six patients with SLE were evaluated. They were divided into three groups having: (1) only LE-specific lesions (38 or 58.46%); (2) only LE-nonspecific lesions (4 or 6.15%); and (3) both types of lesions (23 or 35.38%). Results were analyzed using the Student t-test. Patients with LE-nonspecific skin manifestations had significantly increased disease activity compared to those with only LE-specific lesions. The number of different skin lesion types also correlated with disease activity. It was significantly increased in a group with three different types of lesion, either specific or nonspecific. Patients with only one type of lesion had mild disease. An intermediate disease activity was found in the group with two different lesion types. Lupus-specific skin manifestations serve primarily as an important diagnostic clue. In conclusion, patients with LE-nonspecific lesions have significantly more active SLE than those with LE-specific lesions and may therefore require more intensive therapy and disease monitoring.     

Management of "refractory" skin disease in patients with lupus erythematosus

Skin disease in patients with lupus erythematosus can be subdivided into two broad categories-those lesions that, when biopsied, demonstrate an interface dermatitis and those that do not demonstrate an interface dermatitis. The skin lesions that are represented by the interface dermatitis include discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), and acute cutaneous lupus erythematosus. Many patients with these cutaneous lesions can be managed with "standard" therapies, including sunscreens, protective clothing and behavioral alteration, and topical corticosteroids with or without an oral antimalarial agent. These standard therapies are often not used appropriately, resulting in a situation in which the patient is felt to have refractory disease. This chapter discusses these therapies and defines what is meant by refractory disease and how the author approaches these patients.