Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammatory responses to cell-associated or tissue-associated immune complexes are key elements in the pathogenesis of several autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and immune thrombocytopenic purpura. Effector cells, such as monocytes, macrophages and neutrophils, bind immune complexes in a process mediated by Fcgamma receptors, and these cells then initiate inflammatory reactions that lead to tissue destruction. Rituximab is an anti-CD20 monoclonal antibody that suppresses inflammation effectively in autoimmune diseases. It was initially approved by the FDA for the treatment of B-cell lymphomas and later for rheumatoid arthritis refractory to anti-tumor necrosis factor therapies. Rituximab is hypothesized to suppress disease injury in autoimmune diseases by promoting rapid and long-term elimination of circulating and possibly lymphoid-tissue-associated B cells. We suggest, however, that a different mechanism may underlie much of the therapeutic action of rituximab in autoimmune diseases: binding of tens of thousands of rituximab-IgG molecules to B cells generates decoy sacrificial cellular immune complexes that efficiently attract and bind Fcgamma receptor-expressing effector cells, which diminishes recruitment of these effector cells at sites of immune complex deposition and, therefore, reduces inflammation and tissue damage.
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PMID:Drug insight: the mechanism of action of rituximab in autoimmune disease--the immune complex decoy hypothesis. 1729 46

The European League Against Rheumatism (EULAR)'s guidelines for lupus state that mycophenolate mofetil has at least equivalent efficacy to and less toxicity than cyclophosphamide for the short-and medium-term treatment of lupus nephritis but that long-term data are available only for cyclophosphamide. New therapies are needed to reduce toxicity and the need for steroids and to offer the possibility of cure. Therapies under investigation include other immunosuppressive agents, anti-cellular therapies, drugs that modify cell-cell interactions, (anti-)cytokine therapy, hormone therapy and lupus-specific immunomodulation. Rituximab has shown promise in patients refractory to conventional immunosuppression, which suggests that targeting B cells may be successful. Other anti-cell therapies include epratuzumab, belimumab and alemtuzumab. Anti-cytokine approaches include tumour necrosis factor alpha blockade with infliximab, anti-interleukin 6-receptor therapy with tocilizumab and interferon-alpha blockade. As antidouble-stranded DNA antibodies correlate with flares of lupus nephritis, they may represent another therapeutic target--as do monocyte chemoattractant protein-1 and protein kinase CK2. Therapeutic options to prevent damage in lupus nephritis include non-immunosuppressive treatments aimed at reducing cardiovascular risk (such as statins, angiotensin-converting enzyme inhibitors and aspirin). As was the case with rheumatoid arthritis, a change in therapeutic aims--from survival through prevention of renal failure to induction of remission--may modify outcomes. EULAR's guidelines state that renal biopsy is the best monitor of clinical outcome in lupus nephritis, as immunological tests have limited predictive value. Measurement of urinary mRNA for cytokine and growth factor genes may provide a more sensitive, non-invasive method of monitoring therapeutic response.
Lupus 2007
PMID:Exploring new territory: considering the future. 1743 11

The main goal of therapy for lupus nephritis is to achieve remission, as this has a major impact on patient and renal survival. Furthermore, early treatment success has been shown to improve long-term prognosis. This has traditionally been achieved with intravenous cyclophosphamide, but recent data show that mycophenolate mofetil is equally effective and causes fewer adverse effects. Research is ongoing to find new treatment targets. Possible future therapies include monoclonal antibodies against CD20 (rituximab), CD22 (epratuzumab) and CD40, and therapies targeted at cytokine secretion, immunoglobulin secretion, B-cell maturation and T-cell proliferation and differentiation. Rituximab has shown promise in patients with active proliferative lupus nephritis, which suggests that B-cell depletion may be successful. Anti-double-stranded DNA antibodies correlate with flares of lupus nephritis and may represent another therapeutic target. Therapy with LIP 394, which crosslinks anti-double-stranded DNA antibodies in solution or on the B-cell surface, has been shown to reduce flares. Cardiovascular disease is a major cause of mortality in systemic lupus erythematosus, and this must also be addressed if long-term outcomes are to be improved. Many patients with systemic lupus erythematosus have subclinical atherosclerosis quite early in the disease course, and the risk of coronary artery disease at any level of traditional cardiovascular risk factors is higher than in the general population. Specific lupus-associated risk factors include the inflammatory process itself and anticardiolipin antibodies. Possible strategies to reduce the risk include reduction of disease activity to improve endothelial function and reduction of steroid dose whenever possible. Therapy with aspirin or statins may be another possibility. Thus treatment of lupus nephritis is evolving from standardised therapy to individualised therapy based on analysis of organ involvement, risk factors and cytokine, antibody or cell profiles.
Lupus 2007
PMID:Exploring new territory: the move towards individualised treatment. 1743 12

Although corticosteroids and immunosuppressants are widely used for the treatments of systemic lupus erythematosus (SLE), safer and more effective therapies are prerequisite. We and others have reported that anti-CD20 antibody rituximab targeting B cells are effective for refractory SLE and, therefore, safety and clinical efficacy of rituximab in SLE was evaluated by a multicenter phase I/II clinical trial. An open-label, multicenter study of 15 patients with active and refractory SLE (total British Isles Lupus Assessment Group [BILAG] score 8 to 17) was conducted. Rituximab was administered to 5 SLE patients as 4 infusions of 500 mg/body every week and to 10 SLE patients as 2 infusions of 1000 mg/body every other week. Assessment of safety, infusion reactions and adverse effects was used as the primary outcome for clinical tolerability and was evaluated by 28 weeks. Rituximab was well tolerated, with most experiencing no significant adverse effects. B cells rapidly reduced in all patients and remained low until 6 months post-treatment. Four patients developed human antichimeric antibodies without affecting efficacy of rituximab. Changes in routine safety laboratory tests clearly related to rituximab were not observed. Nine among 14 evaluable patients achieved the major or partial clinical response of BILAG score and prednisolone dose significantly decreased at the 28 weeks. Rituximab therapy appears to be safe for the treatment of active SLE patients and holds significant therapeutic promise, at least for the majority of patients experiencing profound B-cell depletion.
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PMID:A multicenter phase I/II trial of rituximab for refractory systemic lupus erythematosus. 1756 73

Nephritis is the most frequent severe manifestation of anti-neutrophil cytoplasm antibody associated (ANCA) systemic vasculitis (AASV) and systemic lupus erythematosus (SLE) and carries substantial morbidity. Although immunosuppressive medications and glucocorticoids are effective at inducing remission, patients still suffer from high relapse rates and experience significant treatment-related toxicity. Rituximab (RTX), a chimeric antibody directed against CD20, found on B lymphocytes, shows potential as a treatment for both AASV and SLE. Although direct comparisons with standard therapies are currently unavailable, patients in several studies of refractory and relapsing disease have achieved a remission despite the failure of standard therapies. These reports are supported by several lines of experimental evidence that underlie the rationale for using targeted B-cell therapies and have improved our understanding of the pathogenesis of these complex diseases. Future randomized control trials and long-term follow-up studies are required to confirm the role of RTX and other B-cell targeting therapies in AASV and SLE.
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PMID:Rituximab in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis and systemic lupus erythematosus: past, present and future. 1760 93

We report a 47-year-old female with Sjogren's syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy, who was treated with the monoclonal anti CD-20 antibody rituximab at a weekly dose of 375 mg/m2 for four consecutive weeks. Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias. The improvement was sustained and progressive and eight months after the last dose, she was able to walk for 60 meters without aid or rest. Rituximab may be considered as an effective and promising novel therapy in SS patients with neurological involvement.
Lupus 2007
PMID:Successful treatment of refractory neuroSjogren with Rituximab. 1767 Aug 52

Rituximab is a monoclonal antibody against CD20 that was developed for the treatment of relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). Recent controlled trials have shown that B cell-targeted therapy with rituximab is effective in RA (which suggest that B lymphocytes may be critical in its pathogenesis of RA) and early exposure data suggest that the tolerability and safety profile of rituximab may be even better in RA than in NHL patients. Rituximab is generally well tolerated, with a low incidence of serious adverse events, including serious infections. Available evidence suggests that its clinical benefits depend on effective B cell depletion, and the fact that its novel mode of action leads to the depletion of B cells makes it distinct from other biological therapies for RA that target T cells and their related cytokines. Although complete peripheral B cell depletion is regularly seen in RA and other autoimmune diseases, especially systemic lupus erythematosus (SLE), incomplete depletion has been reported in a subset of patients, even after full dosing with rituximab.
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PMID:What is the role of rituximab in the treatment of rheumatoid arthritis? 1785 48

Rituximab (RTX), an anti-CD20 monoclonal antibody, has been proposed for use in the therapy of systemic lupus erythematosus (SLE). We present the initial long-term experience of the safety and efficacy of rituximab for treatment of SLE in children. Eighteen patients (mean age 14 +/- 3 years) with severe SLE were treated with rituximab after demonstrating resistance or toxicity to conventional regimens. There was a predominance of female (16/18) and ethnic African (13/18) patients. All had lupus nephritis [World Health Organization (WHO) classes 3-5] and systemic manifestations of vasculitis. Clinical disease activity of the SLE was scored with the SLE-disease activity index 2K (SLEDAI-2K). Patients were followed-up for an average of 3.0 +/- 1.3 years (range 0.5 to 4.8 years). B-cell depletion occurred within 2 weeks in all patients and persisted for up to 1 year in some. Clinical activity scores, double-stranded DNA (dsDNA) antibodies, renal function and proteinuria [urine protein to creatinine ratio (Upr/cr)] improved in 93% of the patients. Five patients required multiple courses of RTX for relapse, with B-cell repopulation. One died of infectious endocarditis related to severe immunosuppression. In conclusion, our data support the efficacy of rituximab as adjunctive treatment for SLE in children. Although rituximab was well tolerated by the majority of patients, randomized controlled trials are required to establish its long-term safety and efficacy.
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PMID:Rituximab therapy for juvenile-onset systemic lupus erythematosus. 1809 88

Rituximab, a chimeric anti-CD20 monoclonal antibody, has a proven track record for over a decade in the treatment of lymphomas, where it has been used to eradicate malignant lymphocytes. In appreciation of the putative role of B cells, especially with respect to autoantibody production, in the pathogenesis of autoimmune diseases, successful trials of B-cell depletion therapy in RA, SLE, and other autoimmune diseases have been carried out. In these trials, clinical benefit has generally correlated with the extent and duration of B-cell depletion, but at times imperfectly, and autoantibody reduction only selectively. Additional mechanisms whereby rituximab may assert its clinical benefit in autoimmune diseases have been examined including a look at B-cell functions as T-cell modulator and antigen-presenting cell, T-regulatory cell behavior, NK cell activity, and macrophage activities in immune inflammation. The available data on rituximab's action in autoimmune diseases is reviewed.
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PMID:Rituximab: beyond simple B cell depletion. 1824 27

Lupus treatment has evolved considerably with spectacular advances that can be summarized in 10 points. Hydroxychloroquine and cyclophosphamide are still standard drugs, provided their use is optimized. Contraception and postmenopausal hormone replacement therapy have finally been tested in randomized studies with fairly reassuring results, although prudence remains essential in patients with severe lupus and above all in those with thrombotic complications (antiphospholipid syndrome). Mycophenolic acid has been shown to be useful in the treatment of lupus nephropathies, but its specific place in the therapeutic strategy remains to be defined. Other drugs (sirolimus, abatacept) are currently being evaluated. Anti-lymphocyte B therapies are growing in popularity. Rituximab and other drugs (anti-BAFF, TACI-Fc) are also being evaluated and their results appear very interesting. Interferon alpha (type I) inhibition is an attractive therapeutic approach in lupus but its use in humans is still premature. Peptide vaccination with fragments of autoantibodies or autoantigens is an elegant strategy, and preliminary results justify further studies. Anti-TNF molecules may be beneficial in lupus. Complement inhibition can be useful in lupus and antiphospholipid syndrome but drugs usable in humans (anti-C5) must be developed. Atheromatosis in lupus is the principal cause of morbidity and mortality and must be managed. Smoking cessation is essential, but other approaches (statins) should also be discussed. Many futuristic types of immune manipulation may be envisioned (proteasome inhibition, modulation of Fc gammaRIIB, and modulation of cell signaling (PI3kgamma)). Hence the perspectives are numerous. We will soon be able to optimize the treatment of our patients. Nevertheless, rigorous evaluation of the risk/benefit ratio of new drugs and of their most appropriate place in the therapeutic strategy against systemic lupus is indispensable.
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PMID:[Systemic lupus erythematosus: news and therapeutic perspectives]. 1824 45


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