Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin (IL)-1 is a proinflammatory cytokine that plays important roles in inflammation, host defense, and the neuro-immuno-endocrine network. IL-1 receptor antagonist (ra) is an endogenous inhibitor of IL-1 and is supposed to regulate IL-1 activity. However, its pathophysiological roles in a body remain largely unknown. To elucidate the roles of IL-1ra, IL-1ra-deficient mice were produced by gene targeting, and pathology was analyzed on different genetic backgrounds. We found that all of the mice on a BALB/cA background, but not those on a C57BL/6J background, spontaneously developed chronic inflammatory polyarthropathy. Histopathology showed marked synovial and periarticular inflammation, with articular erosion caused by invasion of granulation tissues closely resembling that of rheumatoid arthritis in humans. Moreover, elevated levels of antibodies against immunoglobulins, type II collagen, and double-stranded DNA were detected in these mice, suggesting development of autoimmunity. Proinflammatory cytokines such as IL-1beta, IL-6, and tumor necrosis factor alpha were overexpressed in the joints, indicating regulatory roles of IL-1ra in the cytokine network. We thus show that IL-1ra gene deficiency causes autoimmunity and joint-specific inflammation and suggest that IL-1ra is important in maintaining homeostasis of the immune system. Possible involvement of IL-1ra gene deficiency in RA will be discussed.
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PMID:Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. 1063 75

Recent clinical development programs for new therapeutic agents in rheumatoid arthritis have included assessment of radiographic progression comparing changes with treatment to placebo and active controls. Studies now use reliable methods of assessment and sufficient study length to detect radiographic changes. Although patient populations and characteristics differ, and radiographic scoring methods vary, the direction of a series of studies appears to indicate that leflunomide (LEF), methotrexate (MTX), sulfasalazine (SSZ), etanercept, infliximab, and IL-1ra are all effective in retarding radiographic progression, as measured by erosions and joint space narrowing. Interpretation of radiograph data in future trials will be aided by utilization of common reading methods and by continuing comparison across differing rheumatoid arthritis protocol populations.
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PMID:Radiography of rheumatoid arthritis in the time of increasing drug effectiveness. 1117 70

The University of Pittsburgh is developing MFG-IRAP gene therapy for the potential treatment of arthritis. Phase II studies have commenced, including one trial in arthritis patients [225365]. A retrovirus (MFG-IRAP) is used in the ex vivo transfer of a cDNA encoding the human interleukin-1 receptor antagonist (IL-1Ra). The therapy is being tested in post-menopausal women, and involves the removal of some of their synovium, which is then transfected with the IRAP gene and reimplanted into the joint [188197]. A phase I rheumatoid arthritis trial of a therapy using the IL-1 antagonist gene therapy in synergy with soluble TNF alpha receptors was reported in March 1999 and was considered to be effective in producing an anti-arthritic effect [318398].
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PMID:MFG-IRAP University of Pittsburgh. 1124 73

This report concerns a clinical trial for rheumatoid arthritis (RA), approved by the US National Institutes of Health and the Food and Drug Administration. An amphotropic retrovirus (MFG-IRAP) was used ex vivo to transfer a cDNA encoding human interleukin-1 receptor antagonist (IL-1Ra) to synovium. The protocol required the transduced cells to secrete at least 30 ng IL-1Ra/10(6) cells per 48 h before reimplantation. Here we have evaluated various protocols for their efficiency in transducing cultures of human rheumatoid synoviocytes. The most reliably efficient methods used high titer retrovirus (approximately 10(8) infectious particles/ml). Transduction efficiency was increased further by exposing the cells to virus under flow-through conditions. The use of dioctadecylamidoglycylspermine (DOGS) as a polycation instead of Polybrene (hexadimethrine bromide) provided an additional small increment in efficiency. Under normal conditions of static transduction, standard titer, clinical grade retrovirus (approximately 5 x 10(5) infectious particles/ml) failed to achieve the expression levels required by the clinical trial. However, the shortfall could be remedied by increasing the time of transduction under static conditions, transducing under flow-through conditions, or transducing during centrifugation.
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PMID:Approaches to enhancing the retroviral transduction of human synoviocytes. 1143 45

(1) Anakinra is an interleukin-1 receptor antagonist (IL-1ra), which blocks interleukin-1 (IL-1), a protein involved in the inflammation and the joint destruction associated with rheumatoid arthritis (RA). (2) The manufacturer's submission for drug approval is currently under review by Health Canada and the FDA. (3) In randomized controlled trials, patients with severe RA were treated with anakinra. Significant improvement was demonstrated in several clinical, radiologic and health-related quality of life measures in patients treated with anakinra versus placebo. (4) Minimal adverse effects, mainly injection site reactions, were reported.
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PMID:Anakinra: interleukin-1 receptor antagonist therapy for rheumatoid arthritis. 1177 80

Three biologic therapies significantly slow radiographic progression in active rheumatoid arthritis. This paper compares the effects of anakinra, a recombinant human interleukin-1 receptor antagonist, with those of etanercept and infliximab, two drugs that target tumor necrosis factor-alpha. A Medline search identified controlled clinical trials that included radiographic progression as an endpoint. Anakinra 30 to 150 mg subcutaneously each day for 24 weeks was significantly more effective than placebo in slowing progression of erosion, joint-space narrowing, and total composite scores, as assessed by the Genant method, and erosive joint count, as assessed by the Larsen method. Erosion scores were slowed even further during a 24-week extension. Etanercept 25 mg subcutaneously twice weekly and infliximab 3 to 10 mg/kg intravenously every 4 or 8 weeks also slowed progressive joint damage, but these agents were studied under different study designs, patient populations, and radiographic assessments than those used in the anakinra study. Despite these differences, however, each biologic therapy appeared to slow progressive joint damage. In some studies, control of clinical symptoms did not correlate with slowing of radiographic progression. Agents that block interleukin-1 or tumor necrosis factor-alpha appear similarly effective in slowing radiographic progression in patients with active rheumatoid arthritis. Treatment strategies for this disease may need to consider clinical symptoms, progressive joint damage, and long-term safety effects separately.
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PMID:Efficacy of anakinra in bone: comparison to other biologics. 1200 59

Interleukin-1 (IL-1) has been implicated in the pathogenesis of rheumatoid arthritis (RA). We investigated whether IotaL-1 gene locus polymorphisms are associated with susceptibility to or severity of RA. Genotyping for IL-1alpha, IL-1beta and IL-1Ra single nucleotide polymorphisms (SNPs) performed in a cross-sectional group of 312 consecutive RA patients (RA-group 1) and a cohort of 94 incident female RA patients (RA-group 2) revealed that the rare IL-1RN + 2017 C allele was significantly increased in RA compared to controls (n = 245). A retrospective analysis in RA-group 1 showed no significant associations between IL-1 genotypes and disease severity. A prospective study in RA-group 2 demonstrated that the extent of joint destruction over 12 years was higher in patients genotyped heterozygous for the IL-1 A + 4845, IL-1B + 3953 and IL-1RN + 5111 SNPs compared to homozygous wildtype patients, although differences did not reach statistical significance. These data indicate that the IL-1RN + 2017 polymorphism is associated with susceptibility to RA.
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PMID:Relationship of polymorphisms of the Interleukin-1 gene cluster to occurrence and severity of rheumatoid arthritis. 1202 39

Anakinra, a recombinant human interleukin-1 (IL-1) receptor antagonist, is the first biological agent approved to block the pro-inflammatory effects of IL-1 in patients with rheumatoid arthritis. In a double-blind, randomised trial in 472 patients with active, severe or very severe rheumatoid arthritis, recipients of subcutaneous anakinra 150 mg/day achieved higher response rates [assessed using the American College of Rheumatology (ACR) composite score] and accumulated more mean productivity days after 6 months than placebo recipients. However, the response rates and accumulated productivity days of patients receiving subcutaneous anakinra 30 or 75 mg/day for 6 months were similar to those of placebo. With respect to the total Genant radiographic scores, the same study showed that all anakinra treatment regimens slowed disease progression after 6 months to a greater extent than placebo. In double-blind, randomised trials in patients with rheumatoid arthritis, combined treatment with anakinra and methotrexate was associated with higher ACR 20, 50 and 70 response rates than with methotrexate alone. Anakinra, used alone or in combination with methotrexate, was generally well tolerated, with the most frequent adverse event being a mild injection-site reaction of transient duration. Infections requiring antibacterial therapy or hospitalisation occurred more commonly in anakinra recipients than in placebo recipients, but were a rare cause for discontinuation of anakinra therapy (approximately 1%) in clinical trials.
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PMID:Anakinra. 1219 41

Destruction of articular joints occurs progressively in patients with rheumatoid arthritis (RA). Although the exact aetiology of RA has not been fully elucidated, a large body of evidence supports a role for interleukin-1 (IL-1) in cartilage and bone erosion. In vitro studies suggest that IL-1 can cause cartilage destruction by stimulating the release of matrix metalloproteinases and other degradative products, and it can increase bone resorption by stimulating osteoclast differentiation and activation. In animal models of RA, blocking the effects of IL-1 with either IL-1 receptor antagonist (IL-1Ra; endogenous), anti-IL-1 monoclonal antibodies, or soluble IL-1 type II receptors significantly reduced cartilage destruction and bone erosion. Gene therapy with IL-1Ra was also effective in reducing joint destruction in experimental RA and osteoarthritis (OA) models. In clinical studies, anakinra, a human recombinant IL-1 receptor antagonist (IL-1ra; exogenous), significantly slowed radiographic progression of RA relative to placebo and significantly reduced clinical symptoms when used as monotherapy or in addition to existing methotrexate therapy. These results demonstrate that blocking IL-1 protects bone and cartilage from progressive destruction in RA.
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PMID:Blocking the effects of IL-1 in rheumatoid arthritis protects bone and cartilage. 1220 29

Anakinra, a recombinant human interleukin-1 receptor antagonist offers a new potent treatment for rheumatoid arthritis(RA). It is administered as a daily single subcutaneous injection. Recent randomized, double-blind, placebo-controlled trials revealed that anakinra significantly reduces the signs and symptoms of RA, reduces joint destruction, and is safe and tolerated. It was also revealed that anakinra is more potent when used in combination with methotrexate.
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PMID:[Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist]. 1251 Mar 68


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