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)

In rheumatic disease, monoclonal antibodies have been used for the treatment of refractory rheumatoid arthritis, systemic lupus erythematosus, unresponsive vasculitis and relapsing polychondritis. Our greatest experience has however been with rheumatoid arthritis. After molecular engineering, hybrid monoclonal antibodies constructed from animal sources become largely human, and thus well tolerated, and highly specific. They can be focused selectively to particular targets, but the problem is to identify the causative antibody. In rheumatoid arthritis, we do know a great deal about the pathogenesis of the disease and rational targets can be selected. The major histocompatibility complex class II molecules would theoretically be the most effective target, but no specific antigen has been identified. Total blockade of all class II molecules would probably result in unacceptable immunosuppression. Despite this handicap, anti-HLA-DR4 monoclonal antibodies have been used in humans in an attempt to generate an anti-idiotypic response against DR4. T lymphocytes are known to play a major role in the pathogenesis of rheumatoid arthritis, thus targeting their surface markers would be a reasonable approach to monoclonal antibody therapy. Trials have been conducted using antibodies against the surface markers CD7, CD5, CDw52 and CD4. Further work has centered on differentiation antigens. Preliminary evidence suggests anti-interleukin-2-receptor monoclonal antibodies may be effective in rheumatoid arthritis. There have also been reports of attempts at anti-cytokine immunotherapy. Adhesion molecules would be another potential target. The ongoing trials have given us much insight into the pathogenesis of rheumatoid diseases and led us to the stage where we are now attempting to identify appropriate therapeutic regimes and combinations to maximise patient benefit. At present, we must continue our research for the causative antigen.
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PMID:Monoclonal antibody therapy in rheumatic disease. 802 42

Although precise diagnosis of the systemic vasculitides can provide general prognostic information and help to guide initial therapy, recent studies on the long-term clinical course have revealed considerable variation in clinical severity. Therefore, anatomic distribution of involvement and speed of progression should be the principle determinants of the intensity of immunosuppressive therapy. In progressive pulmonary or renal disease, eg, Wegener's granulomatosis, aggressive "standard" therapy is obligatory, eg, daily cyclophosphamide and glucocorticoids. Such regimens, however, should be applied with caution in chronic or indolent and abortive forms of systemic vasculitis, because follow-up studies (eg, in Wegener's granulomatosis) have revealed treatment-associated morbidity rates of up to 42%, disease-related morbidity, and a high incidence of relapse under treatment. Moreover, less toxic therapeutic strategies are being pursued with remarkable success: low-dose weekly methotrexate, monthly intravenous or oral pulses of cyclophosphamide plus glucocorticoids, and high-dose intravenous immunoglobulin. Long-term remission of intractable (non-antineutrophil cytoplasmic antibody-associated) systemic vasculitis has been achieved using humanized monoclonal antibodies (ie, anti-CD4/anti-CDw52); and amelioration of glomerulonephritis in immune complex diseases (eg, systemic lupus erythematosus) has been achieved with nafamostat mesilate, an inhibitor of complement serine proteases. In addition, leukocytoclastic vasculitis has been effectively controlled with pentoxifylline, presumably by neutralizing proinflammatory cytokines, and hepatitis C virus-associated mixed cryoglobulinemia has been successfully treated with interferon alfa.
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PMID:New developments in the treatment of systemic vasculitis. 803 74

Rheumatoid arthritis is a chronic inflammatory disease. Established treatment is limited because of the clinical response or the induction of adverse effects. New biological agents evaluated for treatment of rheumatoid arthritis have shown varied clinical success. These agents target cytokines such as tumour necrosis factor-alpha (TNFalpha), interleukin (IL)-1 or IL-6, or cell surface molecules such as CD4, CD5, CD7, IL-2 receptor, CDw52 or CD54. Amongst these new drugs, only a few have shown clinical effectiveness in double-blind placebo-controlled trials. These include the primatised nondepleting anti-CD4 monoclonal antibody (mAb) CE9.1 (keliximab), the TNFalpha-blocking mAbs cA2 (infliximab) and CDP-571, the human recombinant soluble TNFalpha receptors p55 (lenercept) and p80, as well as the human recombinant IL-1 receptor antagonist protein, anakinra. Thus, only these agents qualify for evaluation of combination treatment in rheumatoid arthritis. Rationales for combination therapy include: combining drugs with different sites of action to increase efficacy or with different toxicities to minimise risk; combining drugs with different kinetics, thus improving clinical activity; using a combination of drugs for the prevention of tachyphylaxis; or using a second drug which helps to prevent or delay the development of resistance to the first one. In addition, combination therapy could help to prevent or minimise adverse effects caused by treatment with biological agents. Based on knowledge from trials with biological agents, and on the different properties attributed to the established disease-modifying antirheumatic drugs (DMARDs) in ex vivo and in vitro studies, we propose evaluation of the following combination regimens involving biological agents. First, biological agents targeting TNFalpha (such as the mAbs cA2 or CDP-571, or the TNFalpha receptor p55-IgG1 fusion protein) given as a single infusion for rapid clinical response could be followed by continuation treatment with methotrexate, possibly combined with chloroquine, azathioprine or cyclosporin. Combination of specific anti-TNFalpha strategies with sulfasalazine should be avoided because of the induction of double-stranded DNA antibodies seen after TNFalpha blockade in vivo and reports on a systemic lupus erythematosus-like syndrome as an adverse effect during treatment with biological agents directed against TNFalpha or with sulfasalazine. Alternatively, continuous inhibition of TNFalpha or IL-1 with TNFalpha receptor p80-IgG1 fusion protein or IL-1 receptor antagonist, respectively, could be combined with methotrexate, with the disadvantage of a slower initial improvement of clinical symptoms. Combination regimens with the primatised CD4 mAb could include methotrexate as concomitant medication, with chloroquine or sulfasalazine as additional medication. Importantly, combination of different biological agents might induce more severe adverse effects than seen with monotherapy. Thus, protocols involving combinations of biological agents with established DMARDs promise better acceptance than combinations of 2 new and as yet unestablished drugs with possibly synergistic adverse effects because of their antigenic properties.
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PMID:Biological agents in rheumatoid arthritis: which ones could be used in combination? 1802 May 67