The interferon-alpha signature of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prototypic multisystem autoimmune disorder where interplay of environmental and genetic risk factors leads to progressive loss of tolerance to nuclear antigens over time, finally culminating in clinical disease. The heterogeneity of clinical manifestations and the disease's unpredictable course characterized by flares and remissions are very likely a reflection of heterogeneity at the origin of disease, with a final common pathway leading to loss of tolerance to nuclear antigens. Impaired clearance of immune complexes and apoptotic material and production of autoantibodies have long been recognized as major pathogenic events in this disease. Over the past decade the type I interferon cytokine family has been postulated to play a central role in SLE pathogenesis, by promoting feedback loops progressively disrupting peripheral immune tolerance and driving disease activity. The identification of key molecules involved in the pathogenesis of SLE will not only improve our understanding of this complex disease, but also help to identify novel targets for biological intervention.

Overview of common, rare and atypical manifestations of cutaneous lupus erythematosus and histopathological correlates.

The skin is the second most frequently affected organ system in lupus erythematosus. Although only very rarely life threatening--an example is lupus erythematosus-associated toxic epidermal necrolysis--skin disease contributes disproportionally to disease burden in terms of personal and psychosocial wellbeing, vocational disability, and hence in medical and social costs. Since several manifestations are closely associated with the presence and activity of systemic lupus erythematosus, prompt and accurate diagnosis of cutaneous lupus erythematosus is essential. This review aims to cover common, rare, and atypical manifestations of lupus erythematosus-associated skin disease with a detailed discussion of histopathological correlates. Cutaneous lupus erythematosus covers a wide morphological spectrum well beyond acute, subacute and chronic cutaneous lupus erythematosus, which are commonly classified as lupus-specific skin disease. Other uncommon or less well-known manifestations include lupus erythematosus tumidus, lupus profundus, chilblain lupus, mucosal lupus erythematosus, and bullous lupus erythematosus. Vascular manifestations include leukocytoclastic and urticarial vasculitis, livedoid vasculopathy and livedo reticularis/ racemosa. Finally, we discuss rare presentations such as lupus erythematosus-related erythema exsudativum multiforme (Rowell syndrome), Kikuchi-Fujimoto disease, extravascular necrotizing palisaded granulomatous dermatitis (Winkelmann granuloma), and neutrophilic urticarial dermatosis.

Targeting human immunodeficiency virus type 1 with antibodies derived from patients with connective tissue disease.

During the budding process, human immunodeficiency virus (HIV) acquires several cellular proteins from the host. Thus, antibodies against self antigens found in sera patients with autoimmune disorders may cross react with host-derived or the HIV-specific proteins gp120 and gp41 on the viral envelope and probably neutralize HIV infection. To verify this hypothesis, 88 sera from HIV negative patients suffering from systemic lupus erythematosus (SLE) and other autoimmune disorders were analysed for cross reacting antibodies against HIV-1 by Western blot and FACS analysis indicating that antibodies cross-react with epitopes expressed on HIV infected or non-infected cells. Virus capture assays revealed that HIV-1(IIIB) was directly recognized by 60% of sera from patients with autoimmune disorders. Sera were also tested in HIV neutralization assays with stimulated T cells. Reduction of the viral load by patient sera correlated with their reactivity in Western blot analysis. Complement further enhanced the reduction of viral titres, although no complement-mediated lysis was observed. These data suggest a possible protective role of auto-antibodies against HIV infection in lupus patients.

Skin manifestations of systemic lupus erythematosus refractory to multiple treatment modalities: poor results with mycophenolate mofetil.

OBJECTIVE: Skin disease can be one of the most refractory clinical manifestations of systemic lupus erythematosus (SLE). The standard therapy consists of sunscreens, topical corticosteroids and antimalarials. However in difficult cases a variety of other drugs have been tried. Here we describe our clinical experience with mycophenolate mofetil (MMF) in patients with cutaneous manifestations of SLE. METHODS: Seven patients with SLE and skin involvement (including acute cutaneous lupus, subacute cutaneous lupus, discoid lupus erythematosus, vasculitis, urticarial rash and chilblain lupus) who had received treatment with MMF were included. The clinical characteristics, serologicalfindings and response to treatment were recalledfrom retrospective review of the files. RESULTS: Our results showed no response in 5 patients, partial response in 1 patient and initial response but skin flare whilst on MMF in 1 patient. The median dose of MMF was 2 g (range 2-3 g). Adverse events on MMF were mild, mainly gastrointestinal and occurred in 5 patients. No patients discontinued MMF due to adverse events. CONCLUSIONS: MMF appears not to be particularly effective in the treatment of skin disease in SLE. It should be noted that our group of patients had previously failed to respond to a median of 4 (range 2-10) different drugs used to treat SLE skin disease. Thus, the patients in the study could be considered at the severe end of skin disease spectrum.

Nephrogenic fibrosing dermopathy in two patients with systemic lupus erythematosus.

Nephrogenic fibrosing dermopathy (NFD) is a novel fibrosing disorder of the skin with characteristic histopathology. It affects patients with impaired renal function and appears to be independent from the type of kidney disease. Its aetiopathology is unknown and presently no standard therapy exists. We report a patient with systemic lupus erythematosus (SLE) and glomerulonephritis who developed diffuse indurated erythematous plaques covering nearly the entire legs and trunk. She had never received dialysis. The second patient suffered from SLE and antiphospholipid syndrome related thrombotic glomerulopathy. After 10 weeks of haemodialysis she developed the same skin condition. To the best of our knowledge, these are the first reports of NFD occurring in patients with SLE.

Apoptosis of CD34+ cells after incubation with sera of leukopenic patients with systemic lupus erythematosus.

Leukopenia and anaemia are observed in about a fifth of all patients with systemic lupus erythematosus (SLE) and may be due either to the destruction of blood cells or their decreased production. The former may be humoral or cell-mediated or result from apoptosis of peripheral blood cells. Several observations suggest the occurrence of the latter reduced in vitro proliferation of pluripotent bone marrow progenitors from the bone marrow aspirates of SLE patients,reduced counts of CD34+ cells in bone marrow aspirates in SLE patients, apoptosis of lymphopoietic progenitors and apoptosis of bone marrow cells. The aim of our study was to investigate whether humoral factors may induce suppression of haematopoiesis by increased apoptosis of CD34+ cells. For this purpose, we incubated allogeneic CD34+-enriched cells with sera of 18 leukopenic SLE patients. Apoptosis was induced by four of 18 sera. This effect was independent of complement-inhibition and FAS-blockade. Although reduced proliferation of autologous pluripotent bone marrow progenitors has been attributed to an IgG serum inhibitor, removal of IgG from these four proapoptotic sera had no effect on apoptosis of allogeneic CD34+ cells. The proapoptotic effect was associated with high titres of anti-dsDNA antibodies and low haemoglobin concentrations, but not with high titres of antinuclear antibodies, TNF-alpha and IFN-alpha of the sera tested.

Drug-induced lupus-like syndrome associated with severe autoimmune hepatitis.

Atorvastatin and other members of the statin family are widely used for the treatment of hypercholesterolaemia in order to reduce the risk of atherosclerosis and cardiovascular disease. Atorvastatin-induced adverse events are mostly mild and only a few cases of lupus-like syndrome or severe acute hepatitis have been documented. In this case report we describe a patient who developed an atorvastatin-induced severe autoimmune hepatitis. In addition, this patient presented with a concomitant systemic lupus-like syndrome which has been already described for statins but not in association with severe liver disease. Although the drug was immediately withdrawn the disease persisted and even deteriorated to a fulminant disease with evidence of acute hepatic failure. The patient failed to respond to conventional immunosuppression with corticosteroids and azathioprine. Only the introduction of intense immunosuppressive therapy, as used in solid organ transplantation, led to a complete and sustained recovery of the patient. Interestingly, the patient was HLA DR3- and HLA DR4-positive, which are well-known genetic factors associated with autoimmune diseases. This case is the first report of a drug-induced lupus-likesyndrome concomitant with a severe autoimmune hepatitis in a genetically predisposed patient.

Aseptic meningo-encephalitis related to dexibuprofen use in a patient with systemic lupus erythematosus: a case report with MR findings.

We report of a 22-year-old woman with systemic lupus erythematosus (SLE) who was admitted to the intensive care unit (ICU) because of obtundation and a febrile illness. These symptoms had occurred after ingestion of 16 tablets of dexibuprofen. Cerebral magnetic resonance imaging (MRI) disclosed multiple hyperintense white matter abnormalities without gadolinium enhancement. No infectious origin or signs of a lupus flare were found. Our report is the first description of MR findings in dexibuprofen-induced aseptic meningitis, which here is actually a case of meningo-encephalitis. Patients suffering from SLE show increased susceptibility to non steroidal anti-inflammatory drug (NSAID)-induced aseptic meningitis/encephalitis, an important differential diagnosis to be considered at the work-up of altered mental status.

Extravascular necrotizing palisaded granulomas as the presenting skin sign of systemic lupus erythematosus.

We recently examined a patient who presented clinically with tender, erythematous papules associated with a febrile illness and polyarthralgias. Histopathological examination revealed extravascular palisaded neutrophilic granulomas, a skin reaction pattern originally described in Churg-Strauss disease but subsequently observed in a variety of other systemic disorders characterized by immune complex generation. A diagnosis of systemic lupus erythematosus (SLE) was established. To our knowledge, this is the first report of extravascular necrotizing palisaded granulomas as the presenting skin sign of SLE.