Rheumatoid Arthritis: Karsh J

Maksymowych WP, Inman RD, Gladman D, Thomson G, Stone M, Karsh J, Russell AS, Anonymous00134. · The University of Alberta, Edmonton, Canada. · J Rheumatol. · Pubmed #12784417 No free full text.

Abstract: Spondyloarthritis (SpA) represents a group of related arthritides characterized by their association with HLA-B27 and the development of sacroiliitis and enthesitis. Functional impairment, disability, and loss of quality of life may resemble that observed in rheumatoid arthritis. The SpA Research Consortium of Canada (SPARCC) is an informal association of rheumatologist members of the Canadian Rheumatology Association (CRA) with a special interest in therapeutics and outcomes research in SpA. Recent experience with anti-tumor necrosis factor-a (anti-TNF-a) directed therapies prompted a consensus-based evaluation of the evidence supporting their efficacy, safety, and appropriate use in SpA. We evaluated the clinical evidence in support of anti-TNF-a directed therapies in SpA. Medline was searched using appropriate keywords. Abstracts of the 1999-2002 annual meetings of the American College of Rheumatology and the European Congress of Rheumatology were extracted and admitted if sufficient detail was available to determine the level of evidence. Recommendations were based on randomized placebo-controlled trials (Level A evidence) and clinical studies without randomization (Level B evidence). Where the scientific literature was incomplete, recommendations reflected the consensus of SPARCC members (Level C evidence). Following development of an original draft document, consensus for revisions was achieved among members of SPARCC. The document was then posted on the CRA website prior to its final revision. The following recommendations have been endorsed by the Therapeutics Committee of the CRA: Infliximab and etanercept are indicated for reduction of signs and symptoms of moderate to severely active SpA in patients who have had an inadequate response to maximal doses of > or = 2 nonsteroidal antiinflammatory drugs (NSAID) over a 3-month period of observation; and either sulfasalazine or methotrexate is indicated in those with predominantly active peripheral arthritis. Current evidence supports their use as monotherapy (level of evidence A) for at least one year. NSAID and/or second line therapy with either sulfasalazine or methotrexate can be continued concomitantly. There is no evidence addressing potential advantages or disadvantages of combining methotrexate with anti-TNF therapy for SpA. Recommended doses for adults are: infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter; etanercept 25 mg subcutaneously twice weekly. No therapy has been shown to slow progression of axial disease in SpA, and prognostic factors for determining response to therapy remain to be determined. It is the position of the CRA that all therapeutic options should be equally available according to the best judgments of the treating physician and the informed decision of the patient.

Attar SM, Bunting PS, Smith CD, Karsh J. · Department of Internal Medicine, King AbdulAziz University, PO Box 80215, Jeddah 21589, Kingdom of Saudi Arabia. Tel. +966 (2) 6408243. Fax. +966 (2) 6408315. E-mail: · Saudi Med J. · Pubmed #19271083 No free full text.

This publication has no abstract.

Karsh J, Chen Y, Lin M, Dales R. · Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada. · Eur J Epidemiol. · Pubmed #16170662 No free full text.

Abstract: BACKGROUND: Antagonism between Th1 and Th2 lymphocyte mediated responses has been proposed to explain the observed 20th Century population increase in Th2 mediated allergic disease and reciprocal decrease in infectious disease, which stimulates a Th1 mediated response. OBJECTIVE: To determine if Th1/Th2 antagonism would be consistent with associations between non-infectious diseases, we tested the hypothesis that the population prevalence of Th2 mediated allergies is inversely related to the prevalence of Th1 mediated rheumatoid arthritis. METHODS: The analysis was based on data from the Canadian Community Health Survey conducted by Statistics Canada in 2000-2001 of those at least 12 years of age from 125,129 households. Each subject was asked if he or she had certain chronic health conditions that had been diagnosed by a health professional. Logistic regression models were used to evaluate the association between rheumatoid arthritis and allergies with consideration of other important variables. RESULTS: Allergy history was positively related to the prevalence of rheumatoid arthritis both in women (adjusted odds ratio (OR): 1.57, 95% CI: 1.43, 1.73) and in men (adjusted OR: 1.55, 95% CI: 1.36, 1.77). CONCLUSIONS: The reported population prevalences of allergies and rheumatoid arthritis were positively associated and not explained by Th1/Th2 anatagonism suggesting that this mechanism may only be applicable to the association between an infectious and an immunologic disease. Mechanisms accounting for positive associations between immunologic diseases deserve further study.

Grant DD, Goldstein R, Karsh J, Birnboim HC. · Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ontario, Canada. · Environ Mol Mutagen. · Pubmed #11774357 No free full text.

Abstract: Rheumatoid arthritis (RA) is an inflammatory disease in which high levels of reactive nitrogen oxygen species (RNOS) may be present in the affected joints. RNOS are known to produce small-scale mutational events (transitions, transversions, small insertions, and small deletions) but the ability of these compounds to cause deletion of large segments of genomic DNA has not been previously determined. To address this question, a human lymphoblastoid cell line (WIL2-NS) was exposed to nitric oxide (NO)-donating drugs and hypoxanthine phosphoribosyltransferase (hprt)-negative clones were selected and analyzed by multiplex-PCR. Large-scale deletions accounted for 60-80% of hprt mutations arising in drug-treated cultures compared to 12% in untreated cultures (P-values of 0.006 and 0.0001, respectively, in two experiments). Deletion mutations in untreated cultures affected exon 9, whereas 75% of drug-induced deletion mutations affected exons 2, 3, and 9, and the remainder were very large, ranging from 26 to 1200 kbp. To compare this spectrum of NO-induced mutations in a lymphoblastoid line to that arising in vivo in arthritis patients, T-cells from RA patients, osteoarthritis (OA) patients, and controls were cloned and similarly analyzed. We previously showed that the overall frequency of Hprt mutant clones from patients is appreciably elevated compared to that of control subjects. Large-scale hprt deletions (0.5 to >26 kb) were detected in mutant T-cell clones from both RA and OA patients and also from control subjects. A total of 54 mutant clones from 16 RA patients and 19 mutant clones from 6 OA patients were studied. Of these, 6 clones (from 3 RA and 1 OA patient) had suffered large-scale deletions. A total of 9 control subjects were studied and 62 mutant clones were obtained. Of these, 19 had suffered large-scale deletions, arising in 7 of 9 control subjects. In conclusion, (1) RNOS are capable of inducing large-scale deletion mutations in a human lymphoblastoid cell line and (2) large-scale deletion mutations were found in 10-30% of T-cell clones from RA and OA patients and controls, which we hypothesize may be induced by RNOS.

Cranney A, Goldstein R, Pham B, Newkirk MM, Karsh J. · Department of Medicine, University of Ottawa, Canada. · Ann Rheum Dis. · Pubmed #10531075 links to  free full text

Abstract: OBJECTIVE: To assess factors associated with a poor outcome in rheumatoid arthritis (RA), a measure was developed of limited joint motion and deformity, a deformity index (DI), and correlated biochemical and genetic variables with the magnitude of the DI. METHODS: Forty patients were evaluated in a cross sectional study. Clinical measures included the DI and Health Assessment Questionnaire, and disease variables included the erythrocyte sedimentation rate, C reactive protein, rheumatoid factor, and HLA-DRB1 and DQB1 alleles. RESULTS: Significant correlations were noted between increasing DI and duration of RA and concentration of C reactive protein. Patients with a DQB1*301 allele or DR4 allele had a higher DI than those without, and a positive trend was noted between increasing DI and dose of DRB1 RA susceptibility alleles. The trend was lost when a non-linear regression technique was used to remove the effect attributable to C reactive protein, suggesting an interrelation between persistent inflammation and genetics in determining total joint damage. CONCLUSIONS: The DI may be useful to study interactions between genetic and inflammatory processes in rheumatoid disease progression.

Grant DD, Goldstein R, Karsh J, Birnboim HC. · Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada. · J Immunol Methods. · Pubmed #10365782 No free full text.

Abstract: The study of T cell clones at the genomic level is expanding our understanding of their role in diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS). We have been carrying out genotypic analysis by PCR of hypoxanthine phosphoribosyltransferase (hprt) mutations in these cells. Mutant T cells in the population can be cloned on the basis of their resistance to the cytotoxic drug, 6-thioguanine-(6-TG). A difficulty is that the majority of primary human T cells are capable of only limited growth ex vivo, even in the presence of 'feeder' cells. PCR analysis of DNA from such clones is made difficult by the limited number of viable mutant (drug-resistant) T cells and the large number of dead (drug-sensitive) mononuclear cells and feeder cells. DNA from the 'dead' cells remains sufficiently intact for many weeks in culture and can represent a significant source of background in PCR analysis. Here we describe a method employing hypotonic shock and micrococcal nuclease that reliably eliminates non-viable 6-TG-sensitive cells, allowing the study of the hprt gene in < 200 T cells by PCR.