Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neonatal-onset multisystem inflammatory disease (NOMID) is a rare, childhood-onset disease that is characterized by chronic, systemic inflammation. The purpose of this report is to describe the effects of interleukin-1 (IL-1) blockade on the clinical symptoms of 2 patients with NOMID. At the time of this report, the patients had been treated with anakinra (Kineret), a recombinant human IL-1 receptor antagonist, for 1.5 and 2 years, respectively. Both patients demonstrated rapid improvement in clinical symptoms and laboratory markers of inflammation. The use of anakinra in these patients seemed to be effective, without any safety concerns. These observations suggest that IL-1 plays a critical role in the pathogenesis of this inflammatory disease, and that blockade with anakinra should be further studied as a treatment for patients with NOMID and related disorders.
Arthritis Rheum 2005 Apr
PMID:Interleukin-1 blockade by anakinra improves clinical symptoms in patients with neonatal-onset multisystem inflammatory disease. 1581 7

The treatment of juvenile idiopathic arthritis has changed a great deal in the last few years. Pharmacomedical treatment, physiotherapy and teaching the patients and parents are the mainstays of successful therapy. Using all available treatment options and thanks to new therapeutic options (TNFalpha-blockade) and due to a better understanding of the pathogenesis, individual therapeutic strategies provide adequate disease control in the large majority of cases. According to the subtype of juvenile idiopathic arthritis, different medications are used in combination with nonsteroidal antiinflammatory drugs (NSAID) which are used initially. Methotrexate (MTX) and steroids in various applications are the drugs of choice for the systemic and polyarticular courses; intraarticular steroids, sulfasalazine and hydroxychloroquine for the oligoarticular subtype. The new option of TNFalpha-blockade (Etanercept, Infliximab, Adalimumab) offers significant clinical benefit in patients with polyarticular involvement, who do not respond to MTX. Further biological agents (Anakinra, Abatacept, Atlizumab) are used in children and adolescents in clinical studies. Rarely azathioprine, cyclosporine A, leflunomide and cyclophosphamide are used. Stem cell transplantation has been tried as a very last resort but interpretation of the results is controversial. Due to the improvement of the therapeutic options, the approaches to the patients and their disease has changed and cautious optimism is justified.
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PMID:[The treatment of juvenile rheumatism: pharmacotherapy]. 1596 15

Juvenile idiopathic arthritis is group of diseases of unknown aetiology characterised by the occurrence of chronic arthritis during childhood. Compared to adult onset rheumatoid arthritis, its course is more variable. Increasing knowledge of the inflammatory process as well as in molecular genetics and biotechnology has enable the production of new drugs, the biologicals. These are able to specifically block mechanisms of immune activation and thereby interfere with the inflammatory process. An increasing number of biologicals have been tried in clinical studies in adults suffering from rheumatoid arthritis, psoriasis or psoriasis arthritis and a couple of them were already licensed for treatment. Treatment of juvenile idiopathic arthritis by blockade of tumournecrosis-factor (TNF) using the soluble receptor Etanercept or the monoclonal antibodies Infliximab and Adalimumab showed comparable clinical efficacy. Blockade of TNF therefore already reached a certain place in the therapeutic algorythm for treatment of juvenile idiopathic arthritis. Currently, only Etanercept is licensed for treatment of active juvenile polyarthritis refractory to methotrexate. Studies using Infliximab and Adalimumab will be completed in the near future. However, antibodies blocking TNF may already be used in patients suffering from active uncontrolled chronic uveitis in whom visual impairment is threatening. TNF blockers may also be indicated in juvenile ankylosing spondylitis. The use of further biologicals, the interleukin-1 receptor antagonist Anakinra, Atlizumab (MRA) blocking the receptor for interleukin-6 or Abatacept, an inhibitory ligand of the co-stimulatory T cell membrane molecule CD28, remain experimental and should be preserved for clinical studies.
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PMID:[Importance of the new biologicals and cytokine antagonists in the treatment of juvenile idiopathic arthritis (JIA)]. 1596 16

Inflammation is an important homeostatic mechanism that limits the effects of infectious agents. However, inflammation might be self-damaging and therefore has to be tightly controlled or even abolished by the organism. Interleukin 1 (IL-1) is a crucial mediator of the inflammatory response, playing an important part in the body's natural responses and the development of pathological conditions leading to chronic inflammation. While IL-1 production may be decreased or its effects limited by so-called anti-inflammatory cytokines, in vitro IL-1 inflammatory effects are inhibited and can be abolished by one particularly powerful inhibitor, IL-1 receptor antagonist (IL-1Ra). Recent research has shown that in the processes of rheumatoid arthritis (RA) IL-1 is one of the pivotal cytokines in initiating disease, and IL-1Ra has been shown conclusively to block its effects. In laboratory and animal studies the inhibition of IL-1 by either antibodies to IL-1 or IL-1Ra proved beneficial to the outcome. Because of its beneficial effects in many animal disease models, IL-1Ra has been used as a therapeutic agent in human patients. The recombinant form of IL-1Ra, anakinra (Kineret, Amgen) failed to show beneficial effects in septic shock and displays weak effects in RA patients. However, IL-1 blockade by anakinra is dramatically effective in systemic-onset juvenile idiopathic arthritis, in adult Still's disease and in several autoinflammatory disorders, most of the latter being caused by mutations of proteins controlling IL-1beta secretion. Importantly, to be efficacious, anakinra required daily injections, suggesting that administered IL-1Ra displays very short-term effects. Better IL-1 antagonists are in the process of being developed.
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PMID:Is IL-1 a good therapeutic target in the treatment of arthritis? 1698 Feb 12

Immunization of genetically susceptible strains of mice with heterologous type II collagen leads to the induction of a self-limiting polyarthritis that begins to subside around 10 days after onset of clinical disease. The aims of this study were to compare pro- and anti-inflammatory cytokine expression in the joints during the course of arthritis in order to identify cytokines involved in spontaneous remission of arthritis. DBA/1 mice were immunized with type II collagen and an immunohistochemical analysis of expression of proinflammatory cytokines [tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6] and anti-inflammatory cytokines [IL-10, IL-1ra, transforming growth factor (TGF)-beta1, TGF-beta2 and TGF-beta3] in joints was carried out over the course of the disease. Both pro- and anti-inflammatory cytokines were found to be expressed in early arthritis. However, around 10 days after onset of arthritis, the level of expression of proinflammatory cytokines declined while the level of expression of anti-inflammatory cytokines, particularly TGF-beta1 and TGF-beta2, increased. Surprisingly, TNF-alpha continued to be expressed at low levels during the period of disease remission (30 days after onset). Blockade of TNF-alpha during the period of disease remission had no effect on TGF-beta expression. This study confirms that the level of inflammation in arthritis correlates strongly with the balance of pro- and anti-inflammatory cytokine expression in the joints. Of the anti-inflammatory cytokines studied, TGF-beta1 and TGF-beta2 predominate during the time of disease remission, suggesting that these cytokines are involved in regulating disease activity.
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PMID:Remission of collagen-induced arthritis is associated with high levels of transforming growth factor-beta expression in the joint. 1703 81

Despite strong linkage of ankylosing spondylitis (AS) with human leukocyte antigen (HLA) B27, its contribution to disease susceptibility is only 15%, and additional genetic factors are likely to be involved in AS. Interleukin (IL)-1 locus has been linked to AS in European population. Thus, we studied IL-1 receptor antagonist polymorphism in Indian patients with AS. One hundred and sixty-two patients with AS and ethnically matched healthy controls were included. IL-1Ra variable number tandem repeat polymorphism was studied by polymerase chain reaction (PCR). HLA B27 was done by amplification refractory mutation system PCR. Clinical details regarding severity of articular disease, presence of peripheral arthritis, and extra-articular manifestations were collected. The mean age of these 162 patients was 35 years, and the mean duration of disease was 10.8 years. Of these 162 patients, 137 were HLA B27 positive. The commoner alleles--IL-1RN*1 and IL-1RN*2--together accounted for 99.5% of the IL-1RN alleles in the control population and 98.5% of the cases. The allele frequency as well as the carriage rate of allele IL-1RN*2 were significantly higher in patients with AS than the control populations (26.3 vs 16.2% and 41.97 vs 22.5%, respectively; p=0.015 and 0.0002). The IL-1RN*2 allele was not associated with any difference in clinical disease expression. The IL-1RN*2 allele is a susceptibility marker for AS in the Indian population but does not influence disease phenotype.
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PMID:IL1RN*2 allele of IL-1receptor antagonist VNTR polymorphism is associated with susceptibility to ankylosing [corrected] spondylitis in Indian patients. 1789 5

Patients with systemic juvenile idiopathic arthritis (sJIA) have a characteristic daily spiking fever and elevated levels of inflammatory cytokines. Members of the interleukin-1 (IL-1) gene family have been implicated in various inflammatory and autoimmune diseases, and treatment with the IL-1 receptor antagonist, Anakinra, shows remarkable improvement in some patients. This work describes the most comprehensive investigation to date of the involvement of the IL-1 gene family in sJIA. A two-stage case-control association study was performed to investigate the two clusters of IL-1 family genes using a tagging single nucleotide polymorphism (SNP) approach. Genotyping data of 130 sJIA patients and 151 controls from stage 1 highlighted eight SNPs in the IL1 ligand cluster region and two SNPs in the IL1 receptor cluster region as showing a significant frequency difference between the populations. These 10 SNPs were typed in an additional 105 sJIA patients and 184 controls in stage 2. Meta-analysis of the genotypes from both stages showed that three IL1 ligand cluster SNPs (rs6712572, rs2071374 and rs1688075) and one IL1 receptor cluster SNP (rs12712122) show evidence of significant association with sJIA. These results indicate that there may be aberrant control of the activity of the IL-1 family in sJIA patients causing the increased susceptibility to the disease.
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PMID:Comprehensive association study of genetic variants in the IL-1 gene family in systemic juvenile idiopathic arthritis. 1841 95

The University of Pittsburgh is developing an MFG-IRAP gene therapy for the potential treatment of arthritis. Clinical 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. The production of IL-1, 6, 8 and PGE2 is monitored [188197]. In the first clinical trial, a 68-year old woman received cultured synovial cells, transfected with the gene, in two knuckles. Two other knuckles received normal cells and acted as a control. The therapy was well-tolerated and successful transfer and expression of the therapeutic gene were detected. Three further post-menopausal women less than 75 years old are undergoing treatment and nine will be recruited all together [233384]. The initial studies were sponsored by Procter & Gamble [156779]. In rabbits, expression of IL-1ra in the lavage fluid of knees was evident for 4 to 6 weeks following ex vivo introduction of the gene into the synovial lining by the retrovirus construct. Levels were sufficient to offer protection in the inflammatory antigen-induced arthritis model [248952].
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PMID:MFG-IRAP University of Pittsburgh. 1846 59

This paper provides the first evidence of a clinical response to gene therapy in human arthritis. Two subjects with rheumatoid arthritis received ex vivo, intraarticular delivery of human interleukin-1 receptor antagonist (IL-1Ra) cDNA. To achieve this, autologous synovial fibroblasts were transduced with a retrovirus, MFG-IRAP, carrying IL-1Ra as the transgene, or remained as untransduced controls. Symptomatic metacarpophalangeal (MCP) joints were injected with control or transduced cells. Joints were clinically evaluated on the basis of pain; the circumference of MCP joint 1 was also measured. After 4 weeks, joints underwent surgical synovectomy. There were no adverse events in either subject. The first subject responded dramatically to gene transfer, with a marked and rapid reduction in pain and swelling that lasted for the entire 4 weeks of the study. Remarkably, joints receiving IL-1Ra cDNA were protected from flares that occurred during the study period. Analysis of RNA recovered after synovectomy revealed enhanced expression of IL-1Ra and reduced expression of matrix metalloproteinase-3 and IL-1beta. The second subject also responded with reduced pain and swelling. Thus, gene transfer to human, rheumatoid joints can be accomplished safely to produce clinical benefit, at least in the short term. Using this ex vivo procedure, the transgene persisted within the joint for at least 1 month. Further clinical studies are warranted.
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PMID:Clinical responses to gene therapy in joints of two subjects with rheumatoid arthritis. 1898 19

Rilonacept (IL-1 Trap/Arcalyst) is a long-acting interleukin-1 (IL-1) blocker developed by Regeneron Pharmaceuticals. Initially, Regeneron entered into a joint development effort with Novartis to develop rilonacept for the treatment of rheumatoid arthritis (RA) but this was discontinued following the review of phase II clinical data showing that IL-1 blockade appeared to have limited benefit in RA. In February 2008, Regeneron received Orphan Drug approval from the Food and Drug Administration for rilonacept in the treatment of two cryopyrin-associated periodic syndromes (CAPS) disorders, namely, familial cold-induced autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), for children and adults 12 years and older. CAPS is a group of inherited inflammatory disorders consisting of FCAS, MWS, neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic, cutaneous and articular (CINCA) syndrome, all associated with heterozygous mutations in the NLRP3 (CIAS1) gene, which encodes the protein NLRP3 or cryopyrin. Prior to the discovery of the NLRP3 (CIAS1) mutations and the advent of IL-1-targeted therapy, treatment was aimed at suppressing inflammation but with limited success. The dramatic success of selective blockade of IL-1beta, initially with the IL-1 receptor antagonist (IL-1Ra; Kineret(R) or anakinra/ Amgen, Inc.), not only provided supportive evidence for the role of IL-1beta in CAPS but also demonstrated the efficacy of targeting IL-1beta for treatment of these conditions. A high-affinity protein called rilonacept has been produced by cytokine Trap technology and was developed by Regeneron. The desirable longer half-life of rilonacept offers potential alternatives to patients who do not tolerate daily injections very well or have difficulty with drug compliance. The initial evidence for the beneficial effects of rilonacept for MWS and FCAS suggests that it would also be a suitable treatment for CNICA/NOMID. It is yet to be determined whether rilonacept would be an effective treatment for other chronic inflammatory conditions such as gout, familial Mediterranean fever and systemic juvenile idiopathic arthritis.
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PMID:Rilonacept in the treatment of chronic inflammatory disorders. 1964 32


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