Rheumatoid Arthritis: Jones G

Ding C, Jones G. · Menzies Research Institute, Hobart, Tasmania, Australia. · Rev Recent Clin Trials. · Pubmed #18473972 No free full text.

Abstract: Tocilizumab (namely MRA), a humanized anti-interleukin (IL)-6 receptor monoclonal antibody, is under development by Roche for the treatment of inflammatory autoimmune diseases such as rheumatoid arthritis (RA), systemic onset juvenile idiopathic arthritis (JIA), adult-onset Still's disease, Castleman's disease and Crohn's disease. Tocilizumab has a long plasma half-life, so it can be administered intravenously biweekly or monthly. Phase I and II clinical trials showed that tocilizumab (2, 4, 5, 8 or 10 mg/kg) reduced disease activity significantly in a dose-dependent manner. Tocilizumab not only improved signs and symptoms, but also normalized inflammatory markers such as C-reactive protein, erythrocyte sedimentation rate (ESR), fibrinogen and serum amyloid A, and reversed joint damage of RA. The efficacy of tocilizumab in the treatment of RA was at least as good as methotrexate. Tocilizumab was generally safe and well tolerated. Some adverse events such as significant rises in total cholesterol and triglyceride levels, liver function disorders, decreases in white blood cell counts, diarrhoea and infection were observed. In summary, preliminary clinical results suggest that tocilizumab is effective and generally well tolerated in the treatment of IL-6-related inflammatory autoimmune diseases. Like other anti-cytokine immunotherapies, caution and close monitoring for the adverse events, especially infection, are necessary in subsequent clinical trials.

Jones G, Halbert J, Crotty M, Shanahan EM, Batterham M, Ahern M. · Menzies Centre for Population Health Research, GPO Box 252-23, Hobart, Tasmania 7000. · Rheumatology (Oxford). · Pubmed #12509606 links to  free full text

Abstract: OBJECTIVE: To undertake a systematic review of randomized placebo-controlled trials to assess and rank the efficacy of pharmacological interventions in preventing radiological progression of rheumatoid arthritis. METHODS: The two outcome measures were the weighted standardized mean difference and the odds of progression of X-ray scores pooled as close to 12 months as possible to minimize heterogeneity. RESULTS: A total of 38 trials were identified. Of these, 13 were excluded, leaving data on 3907 subjects. Infliximab, cyclosporin, sulphasalazine, leflunomide, methotrexate, parenteral gold, corticosteroids, auranofin and interleukin 1 receptor antagonist were statistically better than placebo in terms of change in erosion scores. All agents were equivalent statistically, with the exception of infliximab (which was superior to the last five agents). There were similar findings for the odds of progression, with the exception of auranofin (P=0.06) and the infliximab-methotrexate comparison (P=0.07). Other agents did not reach statistical significance in either outcome measure. With the exception of the antimalarials, the magnitude of the effect was consistent with the effect seen in short-term disease activity trials. CONCLUSION: There is published evidence which supports the efficacy of nine agents in decreasing radiological progression in rheumatoid arthritis.

Ding C, Jones G. · Menzies Research Institute, University of Tasmania, Hobart 7000, Tasmania, Australia. · Curr Opin Investig Drugs. · Pubmed #16729724 No free full text.

Abstract: Belimumab, the lead in a series of human monoclonal antibodies against the human protein B-lymphocyte stimulator (BLyS), is under development by Human Genome Sciences, Cambridge Antibody Technology and GlaxoSmithKline for the potential treatment of autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). By January 2006, belimumab had completed phase II clinical trials in SLE and RA; a phase III clinical SLE trial is scheduled to begin later this year.

Foley SJ, Lord SR, Srikanth V, Cooley H, Jones G. · Menzies Research Institute, University of Tasmania, Australia. · Osteoarthritis Cartilage. · Pubmed #16460970 No free full text.

Abstract: OBJECTIVE: To describe the association between knee and hip radiographic osteoarthritis (ROA), a measure of knee pain, stiffness and functional ability and objectively measured physiological falls risk predictors. METHODS: Cross-sectional, population-based study of 850 randomly selected men and women aged 50-80 years (mean 62.5, SD 7.4). Falls risk (Z score) was determined objectively with the short form Physiological Profile Assessment (PPA). Two observers assessed knee and hip ROA using the Altman atlas. Pain, stiffness and functional ability were assessed using the Western Ontario McMasters Osteoarthritis index (WOMAC). RESULTS: Overall, the study population was at a mild risk of falling. In multivariable analysis, the WOMAC function and pain score were significantly associated with reaction time, balance, proprioception, knee extension strength, and edge contrast sensitivity. Stiffness was associated with knee extension strength and edge contrast sensitivity. Males had a dose response association between the global WOMAC score and falls risk (r=0.17, P<0.001). Those who reported a global WOMAC score of 50 and above had a higher risk of falling compared to those with a score below 50 (Z score: 0.53 vs 0.14, P<0.001). Hip joint space narrowing (JSN) was significantly associated with knee extension strength (r=-0.10, P=0.003), however, no other significant associations were observed between ROA and falls risk predictors. CONCLUSION: Self-reported functional ability and pain, and to a lesser extent, stiffness (but not knee and hip ROA), have a modest but independent association with physiological predictors of falls risk.

Ding C, Jones G. · Menzies Centre for Population Health Research, University of Tasmania, 17 Liverpool Street, Hobart 7000, Tasmania, Australia. · IDrugs. · Pubmed #12800058 No free full text.

Abstract: Lumiracoxib, an inhibitor of cyclooxygenase 2 (COX-2), is under development by Novartis for the potential treatment of osteoarthritis, rheumatoid arthritis and pain. By late December 2000, phase III trials had been initiated and were ongoing in December 2001.

Ding C, Jones G. · Menzies Centre for Population Health Research, University of Tasmania, 17 Liverpool Street, Hobart, 7000 TAS, Australia. · Curr Opin Mol Ther. · Pubmed #12669473 No free full text.

Abstract: Chugai, the Japanese subsidiary of Roche, is developing a humanized anti-interleukin (IL)-6 receptor monoclonal antibody MRA for the potential treatment of multiple myeloma, rheumatoid arthritis, Crohn's disease and other IL-6-related disorders. MRA is currently undergoing phase II clinical trials for these indications.

Pascual M, Matarán L, Jones G, Shing D, van der Slik AR, Giphart MJ, Schreuder GM, de Vries RR, Breedveld FC, Roovers E, Zanelli E, Martin J. · Instituto de Parasitologia y Biomedicina López Neyra, CSIC, Granada, Spain. · Scand J Rheumatol. · Pubmed #12455817 No free full text.

Abstract: Our aim was to examine, using microsatellite (ms) markers, the contribution of the telomeric part of the HLA region to rheumatoid arthritis (RA) predisposition in the Spanish population. We have looked at the distribution of DQB1, DRBI and five ms loci (D6S1014, D6S273, D6STNFa, MIB and C1-2-5) within the HLA region in 147 Spanish RA patients and 202 control subjects. A total of 19 conserved ms configurations were observed, twelve of them in linkage disequilibrium with particular DQB1-DRB1 haplotypes. Interestingly, haplotype c1 (DQB1*0201-DRB1*0301-D6S1014*143-D6S273*139-D6STNFa*99-MIB*350-C1-2-5*196) was significantly associated with RA predisposition. As part of this haplotype, the MIB*350 allele was found to be a risk factor independently of the RA-predisposing haplotypes. The present results along with data from others prove the existence of a second predisposing locus located inside the MHC region, and suggest that might be located within the TNFa-HLA-B region.

Jones G, Cooley HM, Stankovich JM. · Menzies Centre for Population Health Research, Hobart, Tasmania, Australia. · J Rheumatol. · Pubmed #12180736 No free full text.

Abstract: OBJECTIVE: To describe the association between sex, smoking, physical activity, occupation, and previous digit fracture and hand osteoarthritis (OA). METHODS: Cross sectional study of 522 subjects from 101 Tasmanian families (348 women, 174 men). Hand OA was assessed by 2 observers using the OARSI atlas for joint space narrowing and osteophytes at distal interphalangeal (DIP) and carpometacarpal joints as well as a score for Heberden's nodes based on hand photography. A structured questionnaire collected information regarding physical activity, sport participation, occupation, and smoking history. RESULTS: Women had a higher prevalence of hand OA and the increase with age was significantly higher for women at all sites (all p < 0.05). Ever smoking was associated with less frequent (OR 0.59, 95% CI 0.38, 0.92) and less severe Heberden's nodes (beta -0.60, 95% CI -1.03, -0.17), but not radiological disease. Recall of occupation, physical activity, and sport participation between the ages of 20 and 40 years had no association with the prevalence or severity of hand OA, while self-reported digital fracture was significantly associated with more common (OR 2.42, 95% CI 1.22, 4.83) and severe DIP joint disease (beta +3.92, 95% CI +1.50, +6.36). No factors were associated with carpometacarpal disease. CONCLUSION: In this sample, women had a higher prevalence of hand OA at all sites as well as greater severity and a steeper age gradient (implying higher incidence rates). Smoking may decrease the risk of Heberden's nodes while having no effect on radiological hand OA, suggesting a differential effect possibly at the time of disease onset. With the exception of digital fracture, these data do not support a causal role for occupation or activity in earlier life with regard to hand OA.

Zanelli E, Jones G, Pascual M, Eerligh P, van der Slik AR, Zwinderman AH, Verduyn W, Schreuder GM, Roovers E, Breedveld FC, de Vries RR, Martin J, Giphart MJ. · Department of Immunohaematology and Blood Transfusion, Leiden University Medical Centre, The Netherlands. · Hum Immunol. · Pubmed #11165717 No free full text.

Abstract: We have evaluated the possible contribution of genes besides DQ and DR to the association of HLA with rheumatoid arthritis (RA). To this end, we have looked at the allele distributions of six microsatellites, D6S1014, D6S2673, TNFalpha, MIB, C1-2-5, and C1-3-2 among 132 RA patients and 254 controls. We have defined 19 microsatellite clusters corresponding to previously described ancestral haplotypes. One of them was D6S1014*143-D6S273*139-TNFalpha*99-MIB*350-C1-2-5*196-C1-3-2*354, often found associated with DQB1*0201-DRB1*0301. As part of this microsatellite cluster, the allele MIB*350 was found to be a RA-predisposing factor, independent of DRB1*0301 and RA-predisposing haplotypes DQB1*03-DRB1*04 and DQB1*0501-DRB1*01. We conclude that the telomeric part of the HLA region contains a locus conferring predisposition to RA independently of HLA class II.