Rheumatoid Arthritis: Bykerk V

Bykerk V. · Dr. V. Bykerk, Mount Sinai Hospital, Joseph and Wolfe Lebovic Building, 60 Murray Street, Main Floor, Room 2-005, Toronto, Ontario M5G 1X5. E-mail: · J Rheumatol Suppl. · Pubmed #19509330 No free full text.

Abstract: Despite recent advances in the treatment of rheumatoid arthritis (RA), including the introduction of biologic therapies and employment of combination disease-modifying antirheumatic drug (DMARD) strategies, remission rates remain suboptimal and patients with RA are still missing a significant number of work days. Early diagnostic criteria are needed to ensure that appropriate treatment is initiated early so as to prevent joint damage. Better prognostic markers are also needed to identify patients with the potential for poor outcomes, in whom more aggressive strategies can be applied at the outset. Because of stringent inclusion criteria and heterogeneous definitions of remission, results seen in clinical trials of RA are not necessarily generalizable to results seen in clinical practice. As a result, existing guidelines may not adequately reflect current practice. In the absence of biomarkers to predict the course of disease, methotrexate remains the standard of care initially for most patients with RA. The ability to predict the course of disease could allow more appropriately targeted therapy and higher rates of remission.

Walker EJ, Hirschfield GM, Xu C, Lu Y, Liu X, Lu Y, Coltescu C, Wang K, Newman WG, Bykerk V, Keystone EC, Mosher D, Amos CI, Heathcote EJ, Siminovitch KA. · University of Toronto, Toronto General Hospital, and Mount Sinai Hospital, Toronto, Ontario, Canada. · Arthritis Rheum. · Pubmed #19333938 No free full text.

Abstract: OBJECTIVE: The co-occurrence of different autoimmune diseases in patients and their families suggests the presence of shared genetic risk factors. Two compelling candidate autoimmune disease susceptibility genes are those that encode CTLA4 and inducible costimulator (ICOS), immunoregulatory proteins. Associations of CTLA4 polymorphisms with various autoimmune diseases have been reported, but for rheumatoid arthritis (RA) and primary biliary cirrhosis (PBC), the association data are inconsistent and have largely excluded analysis of polymorphisms in the ICOS gene adjacent to CTLA4. We undertook this study to examine whether CTLA4 and ICOS influence RA and PBC susceptibility by testing CTLA4/ICOS polymorphisms for association with these diseases in Canadian subjects. METHODS: Caucasian RA patients (n = 1,140), PBC patients (n = 481), and controls (n = 1,248) were typed for 21 biallelic polymorphisms across the CTLA4/ ICOS genes using a multiplex genotyping array, and the results were analyzed using a false discovery rate method to correct for multiple testing. RESULTS: Significant associations of multiple CTLA4 and ICOS gene polymorphisms with RA and PBC were observed, with the strongest association signals for both diseases coming from a CTLA4/ICOS intergenic single-nucleotide polymorphism, rs17268364 (corrected P [P(corr)] = 6.0 x 10(-4) and P(corr) < 1.0 x 10(-4), respectively). Significant associations, which were common to both diseases, were also observed with other alleles and haplotypes across 3 linkage disequilibrium blocks within the CTLA4 gene, the intergenic region, and the ICOS gene. CONCLUSION: Our results provide evidence for RA and PBC association with the CTLA4/ICOS locus and suggest that the risk allele(s) within this region may be common to both diseases.

Edworthy S, Zummer M, Garner S, Boire G, Leclercq S, Bykerk V, Kraag G, Markland J, Thomas D, Thomson J, Henderson J. · University of Calgary, Calgary, Alberta, Canada. · J Rheumatol. · Pubmed #18597407 No free full text.

Abstract: OBJECTIVE: To investigate rheumatology practice in Canada with regard to evaluating disease activity status and treatment regimens in patients with rheumatoid arthritis (RA). It was hypothesized that patients with "smoldering" disease activity were not being adequately treated. METHODS: Rheumatologists were invited to participate by the Canadian Rheumatology Association in an audit entitled the Assessment in Rheumatology (AIR) program. From across Canada, 65 rheumatologists participated. One thousand five hundred ninety-six consecutive patients with RA seen in regular clinics were classified according to 4 states of disease activity: remission, controlled adequately, smoldering, and uncontrolled. Demographics (age, sex, geographic region), therapy (nonsteroidal antiinflammatory drugs, disease modifying antirheumatic drugs, biologicals, steroids), joint counts (tender/swollen), comorbidity, and treatment decisions at the time of the visit were recorded. Data were collected at the time of the visit with personal digital assistants (PDA) and aggregated, without personal identifiers, for analysis in SPSS. RESULTS: The majority of patients had "smoldering" (29%) or "uncontrolled" disease (23%), with the remainder in "remission" (15%) or "controlled adequately" (33%) at the time of their visit. Following the appointment, the uncontrolled group had a 100% increase (from 10.4% to 23.4%) in the addition of biological agents; however, there was no significant increase in the rates for those with smoldering disease (19.4% to 20.5%). CONCLUSION: Despite Canada's universal healthcare system, current treatment regimens may not be optimized on the basis of disease activity. A large proportion of patients with RA (29%) seen in Canadian rheumatology practices may be experiencing unnecessary disease for a variety of reasons.

Haraoui B, Bykerk V. · No affiliation provided · Ther Clin Risk Manag. · Pubmed #18360618 links to  free full text

Abstract: Etanercept (ETN) is the first anti-tumor necrosis factor (TNF) agent to be approved for the treatment of rheumatoid arthritis (RA). Over the last 8 years, several clinical trials have shown its efficacy and safety in established and early RA, as well as a monotherapy or in combination with methotrexate. ETN not only reduces the signs and symptoms of RA, but also retards the progression of radiographic damage and improves the quality of life and function of patients. Its safety profile has been predictable since the first clinical trials with no new major safety concerns. Beyond its efficacy in RA, ETN is also indicated for the treatment of psoriatic arthritis. This current report reviews the evidence and the data in RA and psoriatic arthritis (PsA).

Galligan CL, Baig E, Bykerk V, Keystone EC, Fish EN. · Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada. · Genes Immun. · Pubmed #17568789 No free full text.

Abstract: Gene expression profiling of rheumatoid arthritis (RA) and osteoarthritis (OA) joint tissue samples provides a unique insight into the gene signatures involved in disease development and progression. Fibroblast-like synovial (FLS) cells were obtained from RA, OA and control trauma joint tissues (non-RA, non-OA) and RNA was analyzed by Affymetrix microarray. Thirty-four genes specific to RA and OA FLS cells were identified (P<0.05). HOXD10, HOXD11, HOXD13, CCL8 and LIM homeobox 2 were highly and exclusively expressed in RA and CLU, sarcoglycan-gamma, GPR64, POU3F3, peroxisome proliferative activated receptor-gamma and tripartite motif-containing 2 were expressed only in OA. The data also revealed expression heterogeneity for patients with the same disease. To address disease heterogeneity in RA FLS cells, we examined the effects of clinical disease parameters (Health Assessment Questionnaire (HAQ) score, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF)) and drug therapies (methotrexate/prednisone) on RA FLS cell gene expression. Eight specific and unique correlations were identified: human leukocyte antigen (HLA)-DQA2 with HAQ score; Clec12A with RF; MAB21L2, SIAT7E, HAPLN1 and BAIAP2L1 with CRP level; RGMB and OSAP with ESR. Signature RA FLS cell gene expression profiles may provide insights into disease pathogenesis and have utility in diagnosis, prognosis and drug responsiveness.