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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In recent years, large controlled trials have tested several new agents for systemic lupus erythematosus (SLE). Unfortunately, none of these trials has met its primary outcome. This does not mean progress has not been made. In fact, a great deal has been learned about doing clinical trials in lupus and about the biological and clinical effects of the drugs being tested. Many of these drugs were designed to target B cells directly, e.g., rituximab, belimumab, epratuzumab, and transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin (TACI-Ig). The enthusiasm for targeting B cells derives from substantial evidence showing the critical role of B cells in murine models of SLE, as well promising results from multiple open trials with rituximab, a chimeric anti-CD20 monoclonal antibody that specifically depletes B cells (Martin and Chan in Immunity 20(5):517-527, 2004; Sobel et al. in J Exp Med 173:1441-1449, 1991; Silverman and Weisman in Arthritis Rheum 48:1484-1492, 2003; Silverman in Arthritis Rheum 52(4):1342, 2005; Shlomchik et al. in Nat Rev Immunol 1:147-153, 2001; Looney et al. in Arthritis Rheum 50:2580-2589, 2004; Lu et al. in Arthritis Rheum 61(4):482-487, 2009; Saito et al. in Lupus 12(10):798-800, 2003; van Vollenhoven et al. in Scand J Rheumatol 33(6):423-427, 2004; Sfikakis et al. Arthritis Rheum 52(2):501-513, 2005). Why have the controlled trials of B-cell-targeting therapies failed to demonstrate efficacy? Were there flaws in design or execution of these trials? Or, were promising animal studies and open trials misleading, as so often happens? This perspective discusses the current state of B-cell-targeting therapies for human lupus and the future development of these therapies.
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PMID:A perspective on B-cell-targeting therapy for SLE. 1966 89

Rituximab is a chimeric monoclonal antibody currently used for the treatment of non-Hodgkin lymphoma that targets the transmembrane protein CD20 of B cells. Recently it has also been used for the treatment of several autoimmune diseases, including skin disorders such as Paraneoplastic Pemphigus, Pemphigus Vulgaris, Pemphigus Foliaceus, Mucosal pemphigoid, Bullous pemphigoid, Epidermolysis bullosa acquisita, Systemic lupus erythematous and Dermatomyositis. Frequently all these conditions required intolerably high doses of corticosteroids and additional immunosoppressants, which can increase the risk of severe adverse events. Therefore, new therapeutic options are needed for such patients. The intent of the authors in this review is to provide the reader with a panoramic view of the studies reported to date.
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PMID:Rituximab in dermatological diseases. 1975 55

Patients with systemic lupus erythematosus (SLE) are susceptible to the development of lymphoproliferative disorders and postulated causes include intrinsic defects in immune surveillance and iatrogenic administration of immunosuppressants. Since the introduction of mycophenolate mofetil (MMF) to the immunosuppressive regimen for the management of post-organ transplantation, there have been reports of primary lymphoma of the central nervous system (PCNSL). MMF has been widely used to treat active SLE patients with Class IV lupus nephritis. In addition to two previously reported cases of PCNSL among SLE patients on long-term MMF, we report a third patient who has been on treatment with MMF for 8 years. The histology showed features compatible with diffuse large B-cell lymphoma with strong immunohistochemical staining for CD20 and positive signal for Epstein-Barr virus (EBV)-encoded RNA by in-situ hybridization that is similar to other case reports, suggesting EBV driven B-cell lymphoproliferative disease. The patient responded to withdrawal of MMF, intravenous methotrexate, rituximab and whole brain radiotherapy. With the increasing use of MMF in active renal as well as non-renal exacerbations of SLE, PCNSL should be included in the differential diagnosis in patients who present with gradual onset of focal neurological deficit.
Lupus 2010 Mar
PMID:Diffuse large B-cell lymphoma of the central nervous system in mycophenolate mofetil-treated patients with systemic lupus erythematosus. 1989 21

Severe retinal vasculitis is a rare, but potentially blinding, complication of patients with systemic lupus erythematosus (SLE). We describe here the first reported case of treating severe bilateral SLE-associated retinal vasculitis with the anti-CD20 monoclonal antibody rituximab, a drug which has established its role in rheumatoid arthritis and has shown promise in case series for the treatment of severe SLE that is unresponsive to other therapies. This case suggests that rituximab-induced B-cell depletion may provide an important new therapeutic option for refractory cases of this devastating ocular complication.
Lupus 2010 Mar
PMID:Bilateral retinal vasculitis in a patient with systemic lupus erythematosus and its remission with rituximab therapy. 1990 Sep 82

B cells are thought to play a major role in the pathogenesis of systemic lupus erythematosus (SLE). Rituximab (RTX), a chimeric anti-CD20 mAb, effectively depletes CD20( +) peripheral B cells. Recent results from EXPLORER, a placebo-controlled trial of RTX in addition to aggressive prednisone and immunosuppressive therapy, showed similar levels of clinical benefit in patients with active extra-renal SLE despite effective B cell depletion. We performed further data analyses to determine whether significant changes in disease activity biomarkers occurred in the absence of clinical benefit. We found that RTX-treated patients with baseline autoantibodies (autoAbs) had decreased anti-dsDNA and anti-cardiolipin autoAbs and increased complement levels. Patients with anti-dsDNA autoAb who lacked baseline RNA binding protein (RBP) autoAbs showed increased complement and decreased anti-dsDNA autoAb in response to RTX. Other biomarkers, such as baseline BAFF levels or IFN signature status did not predict enhanced effects of RTX therapy on complement or anti-dsDNA autoAb levels. Finally, platelet levels normalized in RTX-treated patients who entered the study with low baseline counts. Together, these findings demonstrate clear biologic activity of RTX in subsets of SLE patients, despite an overall lack of incremental clinical benefit with RTX in the EXPLORER trial.
Lupus 2010 Feb
PMID:Baseline autoantibody profiles predict normalization of complement and anti-dsDNA autoantibody levels following rituximab treatment in systemic lupus erythematosus. 1994 34

The objective of this study was to investigate the efficacy and safety of anti-CD20 treatment in Hispanic patients with refractory systemic lupus erythematosus and to determine whether baseline parameters predict disease flare. Fifty-two patients with systemic lupus erythematosus, 13 with active lupus nephritis, eight with thrombocytopenia, three with leukocytopenia, 25 with severe musculoskeletal involvement and three with skin involvement) refractory to conventional therapy were treated with anti-CD20 treatment (rituximab; MabThera, Roche) plus ongoing immunosuppressive treatment. Disease activity was assessed monthly using the SLEDAI validated for the Mexican population with a follow-up period of 6 months. At 6 months of follow-up, significant clinical improvements were detected, with a reduction in the global SLEDAI validated for the Mexican population score. Five of the 13 patients with lupus nephritis (38.4%) had a complete renal response and five (38.4%) had a partial response. Rituximab was also effective in patients with autoimmune thrombocytopenia, inducing a significant increase in platelet counts (p = 0.012). Nineteen of 25 patients with severe musculoskeletal involvement had remission of arthritis. Only one of the three patients with skin involvement had no lesions at 6 months. Rituximab treatment also allowed a reduction of the oral prednisone dose in the majority of patients. No baseline predictors of flare were found. Treatment was discontinued after the first infusion in two patients due to serum sickness and in another due to pulmonary infection. In conclusion, the addition of rituximab to conventional immunosuppressive therapy may be an effective strategy for lupus nephritis, autoimmune thrombocytopenia and inflammatory polyarthritis in patients with refractory systemic lupus erythematosus.
Lupus 2010 Feb
PMID:Anti-CD20 therapy in patients with refractory systemic lupus erythematosus: a longitudinal analysis of 52 Hispanic patients. 1996 44

In the past year there has been remarkable activity and some important success in the development of B cell-targeted therapies for the treatment of systemic lupus erythematosus (SLE). The most promising studies were BLISS-52 and BLISS-76, large phase III studies that demonstrated measurable efficacy for belimumab, a monoclonal antibody against B cell-activating factor (BAFF). The moderate-sized phase II/III trials EXPLORER and LUNAR that tested rituximab, an anti-CD20 monoclonal antibody, for treatment of non-renal and renal lupus, disappointed many investigators with anecdotal success in refractory patients. These rituximab trials were intended to detect a large clinical effect in patients with very active disease and this was not found. Nevertheless, arguments can be made for additional studies in targeted populations or with a change in design to detect smaller or longer-term effects. Epratuzumab, a monoclonal antibody against the B cell surface antigen CD22, and atacicept, a chimeric molecule formed by a receptor for BAFF and a proliferation-inducing ligand (APRIL) with immunoglobulin (Ig)-G, have both been promising in initial small trials and now larger clinical trials are underway. Thus, recent clinical trial data show that B cell-targeting therapies are beginning to fulfil their promise as treatments for SLE and there are good reasons to hope for further progress in the near future.
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PMID:B cell-targeted therapies for systemic lupus erythematosus: an update on clinical trial data. 2029 67

Delineating the relative contributions of B lymphocytes during the course of autoimmune disease has been difficult. Therefore, the effects of depleting all mature B cells using a potent CD20 mAb, or of depleting circulating and marginal zone B cells using a ligand-blocking CD22 mAb, were compared in NZB/W F(1) mice, a model for human systemic lupus erythematosus. Single low-dose mAb treatments depleted B cells efficiently in both NZB/W F(1) and C57BL/6 mice. Prophylactic B cell depletion by repeated CD20 mAb treatments prolonged survival during pristane-accelerated lupus in NZB/W F(1) mice, whereas CD22 mAb had little effect. Despite effective B cell depletion, neither mAb treatment prevented autoantibody generation. In addition, CD20, CD22, and control mAb-treated NZB/W F(1) mice developed anti-mouse IgG autoantibodies in contrast to parental NZB and NZW strains, which may have reduced the effectiveness of B cell depletion. Despite this, low-dose CD20 mAb treatment initiated in 12-28-wk-old mice, and administered every 4 wk thereafter, significantly delayed spontaneous disease in NZB/W F(1) mice. By contrast, B cell depletion initiated in 4-wk-old mice hastened disease onset, which paralleled depletion of the IL-10-producing regulatory B cell subset called B10 cells. B10 cells were phenotypically similar in NZB/W F(1) and C57BL/6 mice, but were expanded significantly in young NZB/W F(1) mice. Thus, B cell depletion had significant effects on NZB/W F(1) mouse survival that were dependent on the timing of treatment initiation. Therefore, distinct B cell populations can have opposing protective and pathogenic roles during lupus progression.
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PMID:Protective and pathogenic roles for B cells during systemic autoimmunity in NZB/W F1 mice. 2036 80

Lupus mastitis is an uncommon presentation of lupus erythematosus profundus or lupus panniculitis, a rare variant of lupus erythematosus characterized by inflammation of the subcutaneous fat. Lupus mastitis can present as single or multiple subcutaneous or deep breast masses, often clinically mimicking malignancy. Although lupus mastitis is rare, with less than 25 cases reported, the histologic features are distinct. Awareness of the entity and familiarity with the histologic features allow for accurate diagnosis and appropriate patient management. It most commonly affects women with a mean age at diagnosis of 40 years and an age range of 18 to 70 years. Typical histologic findings in lupus mastitis include a lymphocytic lobular panniculitis with plasma cells and hyaline fat necrosis. The lymphocytic infiltrate can be nodular, diffuse, periductal, and/or perilobular and germinal centers can frequently be identified. Lymphocytic vasculitis is also common. Immunohistochemistry shows a mixed T and B-cell population, with predominantly CD3+ CD4+ T cells intermixed with CD20-positive B cells and polyclonal plasma cells. Most commonly, lupus mastitis is seen in patients with a previous diagnosis of systemic or discoid lupus; however, it can also be the initial presentation of lupus in some patients. We report on 2 cases of lupus mastitis where the clinical impression was to rule out malignancy and review the literature to highlight the key clinicopathologic features.
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PMID:Lupus mastitis: an uncommon complication of systemic or discoid lupus. 2041 Aug 9

The most prevalent severe manifestation of systemic lupus erythematosus is nephritis, which is characterized by immune complex deposition, inflammation, and scarring in glomeruli and the tubulointerstitium. Numerous studies indicated that glomerulonephritis results from a systemic break in B cell tolerance, resulting in the local deposition of immune complexes containing Abs reactive with ubiquitous self-Ags. However, the pathogenesis of systemic lupus erythematosus tubulointerstitial disease is not known. In this article, we demonstrate that in more than half of a cohort of 68 lupus nephritis biopsies, the tubulointerstitial infiltrate was organized into well-circumscribed T:B cell aggregates or germinal centers (GCs) containing follicular dendritic cells. Sampling of the in situ-expressed Ig repertoire revealed that both histological patterns were associated with intrarenal B cell clonal expansion and ongoing somatic hypermutation. However, in the GC histology, the proliferating cells were CD138(-)CD20(+) centroblasts, whereas they were CD138(+)CD20(low/-) plasmablasts in T:B aggregates. The presence of GCs or T:B aggregates was strongly associated with tubular basement membrane immune complexes. These data implicate tertiary lymphoid neogenesis in the pathogenesis of lupus tubulointerstitial inflammation.
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PMID:In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. 2118 39


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