Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned?
Rheumatoid arthritis (RA), a systemic disease, is characterized by a chronic inflammatory reaction in the synovium of joints and is associated with degeneration of cartilage and erosion of juxta-articular bone. Many pro-inflammatory cytokines including TNF alpha, chemokines, and growth factors are expressed in diseased joints. The rationale that TNF alpha played a central role in regulating these molecules, and their pathophysiological potential, was initially provided by the demonstration that anti-TNF alpha antibodies added to in vitro cultures of a representative population of cells derived from diseased joints inhibited the spontaneous production of IL-1 and other pro-inflammatory cytokines. Systemic administration of anti-TNF alpha antibody or sTNFR fusion protein to mouse models of RA was shown to be anti-inflammatory and joint protective. Clinical investigations in which the activity of TNF alpha in RA patients was blocked with intravenously administered infliximab, a chimeric anti-TNF alpha monoclonal antibody (mAB), has provided evidence that TNF regulates IL-6, IL-8, MCP-1, and VEGF production, recruitment of immune and inflammatory cells into joints, angiogenesis, and reduction of blood levels of matrix metalloproteinases-1 and -3. Randomized, placebo-controlled, multi-center clinical trials of human TNF alpha inhibitors have demonstrated their consistent and remarkable efficacy in controlling signs and symptoms, with a favorable safety profile, in approximately two thirds of patients for up to 2 years, and their ability to retard joint damage. Infliximab (a mAB), and etanercept (a sTNF-R-Fc fusion protein) have been approved by regulatory authorities in the United States and Europe for treating RA, and they represent a significant new addition to available therapeutic options.
Feldmann
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Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, 1 Aspenlea Road, London W6 8LH, United Kingdom. m.feldmann@ic.ac.uk
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D000918:Antibody Specificity; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D002634:Chemotaxis, Leukocyte; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003131:Combined Modality Therapy; D016207:Cytokines / Q000502:physiology; D004195:Disease Models, Animal; D004311:Double-Blind Method; D000068800:Etanercept; D006801:Humans; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000276:immunology / Q000627:therapeutic use; D007143:Immunoglobulin Heavy Chains; D007142:Immunoglobulin gamma-Chains; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D000069285:Infliximab; D051379:Mice; D015337:Multicenter Studies as Topic; D016032:Randomized Controlled Trials as Topic; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use; D012449:Safety; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007142:Immunoglobulin gamma-Chains; D007166:Immunosuppressive Agents; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C402162:CDP 571; C099374:Ro 45-2081; D000069285:Infliximab; D000068800:Etanercept