Dianne Mosher

CTLA4/ICOS gene variants and haplotypes are associated with rheumatoid arthritis and primary biliary cirrhosis in the Canadian population

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.

Clinical and Serological Features of Patients Referred through a Rheumatology Triage System because of Positive Antinuclear Antibodies

Background The referral of patients with positive anti-nuclear antibody (ANA) tests has been criticized as an inappropriate use of medical resources. The utility of a positive ANA test in a central triage (CT) system was studied by determining the autoantibody profiles and clinical diagnoses of patients referred to rheumatologists through a CT system because of a positive ANA test. Methods Patients that met three criteria were included: (1) referred to Rheumatology CT over a three year interval; (2) reason for referral was a “positive ANA”; (3) were evaluated by a certified rheumatologist. The CT clinical database was used to obtain demographic and clinical information and a serological database was used to retrieve specific ANA and/or extractable nuclear antigen (ENA) test results. Clinical information was extracted from the consulting rheumatologists report. Results 15,357 patients were referred through the CT system; 643 (4.1%) of these because of a positive ANA and of these 263 (40.9%) were evaluated by a certified rheumatologist. In 63/263 (24%) of ANA positive patients, the specialist provided a diagnosis of an ANA associated rheumatic disease (AARD) while 69 (26.2%) had no evidence of any disease; 102 (38.8%) had other rheumatologic diagnoses and 29 (11%) had conditions that did not meet AARD classification criteria. Of ANA positive archived sera, 15.1% were anti-DFS70 positive and 91.2% of these did not have an AARD. Conclusions This is the first study to evaluate the serological and clinical features of patients referred through a CT system because of a positive ANA. The spectrum of autoantibody specificities was wide with anti-Ro52/TRIM21 being the most common autoantibody detected. Approximately 15% of referrals had only antibodies to DFS70, the vast majority of which did not have clinical evidence for an AARD. These findings provide insight into the utility of autoantibody testing in a CT system.

Sex Differences in Pain Scores and Localization in Inflammatory Arthritis: A Systematic Review and Metaanalysis

Objective. To systematically identify and examine reports of sex-stratified pain measurements in patients with inflammatory arthritis. Methods. Data sources included PubMed (1950 to April 2010), Embase (1980 to April 2010), and manual searches of reference lists and conference abstracts. We included cohort studies and randomized trials comparing pain scores, treatment efficacy at reducing pain, or pain localization, between females and males with inflammatory arthritis [rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis, and reactive arthritis]. Results. Twenty-six cohorts and 1 randomized trial reported sex-stratified pain scores, and all but 1 cohort identified worse pain scores at enrollment in females. In a metaanalysis of mean visual analog scale (VAS) scores (0 to 10) in 16 RA cohort studies (reporting on 21,612 females and 6871 males), the standardized mean difference in VAS was 0.21 (95% CI 0.16, 0.26). Treatment with disease-modifying therapy results in improvement in mean scores for both sexes; however, female absolute scores remain higher. In 12 spondyloarthropathy cohorts reporting pain localization, females develop more peripheral arthritis during their disease course (68.9% vs 51.2%) but less inflammatory back pain (50.6% vs 66.4%). Conclusion. We identified important sex differences in pain scores in inflammatory arthritis, with higher pain levels in females. In spondyloarthritis, females develop more peripheral arthritis and have less frequent spinal involvement compared to males. These differences may affect a clinician’s perception of disease severity and activity, and thus influence management decisions.

Relative urgency for referral from primary care to rheumatologists: The Priority Referral Score

Timely access to rheumatology consultation is fundamental to appropriate and effective management of patients with musculoskeletal and autoimmune diseases. Yet, for a variety of reasons, limited and delayed access is commonplace. Moreover, information exchange for referral is often inadequate or poorly communicated. The objective of this work was to improve referral from primary care to rheumatology by formulating and testing a clinically coherent, reliable, and non–diagnosis‐dependent Priority Referral Score (PRS).

Canadian Recommendations for Use of Methotrexate in Patients with Rheumatoid Arthritis

Objective. To develop recommendations for the use of methotrexate (MTX) in patients with rheumatoid arthritis. Methods. Canadian rheumatologists who participated in the international 3e Initiative in Rheumatology (evidence, expertise, exchange) in 2007–2008 formulated 5 unique Canadian questions. A bibliographic team systematically reviewed the relevant literature on these 5 topics. An expert committee consisting of 26 rheumatologists from across Canada was convened, and a set of recommendations was proposed based on the results of systematic reviews combined with expert opinions using a nominal group consensus process. Results. The 5 questions addressed drug interactions, predictors of response, strategies to reduce non-serious side effects, variables to assess clinical response, and incorporating patient preference into decision-making. The systematic review retrieved 93 pertinent articles; this evidence was presented to the expert committee during the interactive workshop. After extensive discussion and voting, a total of 9 recommendations were formulated: 2 on drug interactions, 1 on predictors of response, 2 on strategies to reduce non-serious side effects, 3 on variables to assess clinical response, and 1 on incorporating patient preferences into decision-making. The level of evidence and the strength of recommendations are reported. Agreement among panelists ranged from 85% to 100%. Conclusion. Nine recommendations pertaining to the use of MTX in daily practice were developed using an evidence-based approach followed by expert/physician consensus with high level of agreement.

Time to Disease-modifying Antirheumatic Drug Treatment in Rheumatoid Arthritis and Its Predictors: A National, Multicenter, Retrospective Cohort

Objective. To determine the proportion of patients with rheumatoid arthritis (RA) under rheumatologic care treated with disease-modifying antirheumatic drugs (DMARD) within 6 months from symptom onset and the components of time to treatment and its predictors. Methods. A historical inception cohort of 339 patients with RA randomly selected from 18 rheumatology practices was audited. The proportion that initiated DMARD treatment within 6 months from symptom onset was estimated using Kaplan-Meier analysis. Time to each component of the care pathway was estimated. Multivariable modeling was used to determine predictors of early treatment using 12 preselected variables available in the clinical charts. Bootstrapping was used to validate the model. Results. Within 6 months from symptom onset, 41% (95% CI 36%−46%) of patients were treated with DMARD. The median time to treatment was 8.4 (interquartile range 3.8−24) months. Events preceding rheumatology referral accounted for 78.1% of the time to treatment. The most prominent predictor of increased time to treatment was a concomitant musculoskeletal condition, such as osteoarthritis or fibromyalgia. The significance of other variables was less consistent across the models investigated. Included variables accounted for 0.69 ± 0.03 of the variability in the model. Conclusion. Fewer than 50% of patients with RA are treated with DMARD within 6 months from symptom onset. Time to referral to rheumatology represents the greatest component delay to treatment. Concomitant musculoskeletal condition was the most prominent predictor of delayed initiation of DMARD. Implications of these and other findings warrant further investigation.

Development of System-level Performance Measures for Evaluation of Models of Care for Inflammatory Arthritis in Canada

Objective. To develop system-level performance measures for evaluating the care of patients with inflammatory arthritis (IA), including rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis, and juvenile idiopathic arthritis. Methods. This study involved several methodological phases. Over multiple rounds, various participants were asked to help define a set of candidate measurement themes. A systematic search was conducted of existing guidelines and measures. A set of 6 performance measures was defined and presented to 50 people, including patients with IA, rheumatologists, allied health professionals, and researchers using a 3-round, online, modified Delphi process. Participants rated the validity, feasibility, relevance, and likelihood of use of the measures. Measures with median ratings ≥ 7 for validity and relevance were included in the final set. Results. Six performance measures were developed evaluating the following aspects of care, with each measure being applied separately for each type of IA except where specified: waiting times for rheumatology consultation for patients with new onset IA, percentage of patients with IA seen by a rheumatologist, percentage of patients with IA seen in yearly followup by a rheumatologist, percentage of patients with RA treated with a disease-modifying antirheumatic drug (DMARD), time to DMARD therapy in RA, and number of rheumatologists per capita. Conclusion. The first set of system-level performance measures for IA care in Canada has been developed with broad input. The measures focus on timely access to care and initiation of appropriate treatment for patients with IA, and are likely to be of interest to other arthritis care systems internationally.

Development of key performance indicators to evaluate centralized intake for patients with osteoarthritis and rheumatoid arthritis

IntroductionCentralized intake is integral to healthcare systems to support timely access to appropriate health services. The aim of this study was to develop key performance indicators (KPIs) to evaluate centralized intake systems for patients with osteoarthritis (OA) and rheumatoid arthritis (RA).MethodsPhase 1 involved stakeholder meetings including healthcare providers, managers, researchers and patients to obtain input on candidate KPIs, aligned along six quality dimensions: appropriateness, accessibility, acceptability, efficiency, effectiveness, and safety. Phase 2 involved literature reviews to ensure KPIs were based on best practices and harmonized with existing measures. Phase 3 involved a three-round, online modified Delphi panel to finalize the KPIs. The panel consisted of two rounds of rating and a round of online and in-person discussions. KPIs rated as valid and important (≥7 on a 9-point Likert scale) were included in the final set.ResultsTwenty-five KPIs identified and substantiated during Phases 1 and 2 were submitted to 27 panellists including healthcare providers, managers, researchers, and patients in Phase 3. After the in-person meeting, three KPIs were removed and six were suggested. The final set includes 9 OA KPIs, 10 RA KPIs and 9 relating to centralized intake processes for both conditions. All 28 KPIs were rated as valid and important.ConclusionsArthritis stakeholders have proposed 28 KPIs that should be used in quality improvement efforts when evaluating centralized intake for OA and RA. The KPIs measure five of the six dimensions of quality and are relevant to patients, practitioners and health systems.

2014 Update of the Canadian Rheumatology Association/Spondyloarthritis Research Consortium of Canada Treatment Recommendations for the Management of Spondyloarthritis. Part I: Principles of the Management of Spondyloarthritis in Canada

Objective. The Canadian Rheumatology Association (CRA) and the Spondyloarthritis Research Consortium of Canada (SPARCC) have collaborated to update the recommendations for the management of spondyloarthritis (SpA). Methods. A working group was assembled and consisted of the SPARCC executive committee, rheumatologist leaders from SPARCC collaborating sites, Canadian rheumatologists from across the country with an interest in SpA (both academic and community), a rheumatology trainee with an interest in SpA, an epidemiologist/health services researcher, a member of the CRA executive, a member of the CRA therapeutics committee, and a patient representative from the Canadian Spondylitis Association. An extensive review was conducted of literature published from 2007 to 2014 involving the management of SpA. The working group created draft recommendations using multiple rounds of Web-based surveys and an in-person conference. A survey was sent to the membership of the CRA to obtain an extended review that was used to finalize the recommendations. Results. Guidelines for the management of SpA were created. Part I focuses on the principles of management of SpA in Canada and includes 6 general management principles, 5 ethical considerations, target groups for treatment recommendations, 2 wait time recommendations, and recommendations for disease monitoring. Also included are 6 modifications for application to juvenile SpA. Conclusion. These recommendations were developed based on current literature and applied to a Canadian healthcare context. It is hoped that the implementation of these recommendations will promote best practices in the treatment of SpA.

Non-biologic disease-modifying antirheumatic drugs (DMARDs) improve pain in inflammatory arthritis (IA): a systematic literature review of randomized controlled trials

Evidence supports early use of non-biologic DMARDs to prevent irreversible damage in inflammatory arthritides, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and possibly ankylosing spondylitis (AS). However, there is a paucity of data exploring their effects on pain as a primary outcome in these conditions. This systematic literature review investigated the effect of non-biologic DMARDs on pain levels in IA and examined whether disease duration impacted efficacy. We searched Medline, Embase, Cochrane Central, and Cochrane Database of Systematic Reviews, abstracts from the 2008 to 2010 American College of Rheumatology annual congresses, and citation lists of retrieved publications. Only randomized, double-blind controlled trials were analyzed. Quality was assessed with the Risk of Bias tool. Descriptive statistics were used in meta-analysis. 9,860 articles were identified, with 33 eligible for inclusion: 8 in AS, 6 in PsA, 9 in early RA (ERA), and 10 in established RA. In ERA and established RA, all studies of DMARDs (monotherapy and combination therapies) consistently revealed statistically significant reductions in pain except three oral gold studies. In AS, sulfasalazine studies showed significant pain reduction, whereas use of other DMARDs did not. In PsA, 5 of 6 studies reported VAS-pain improvement. From the studies included, we were unable to assess the influence of disease duration on pain outcomes in these rheumatic conditions. DMARDs improve pain in early and established RA. Sulfasalazine may improve pain in AS and PsA. Further study is needed to assess the relationship between disease duration and DMARD efficacy in reducing pain in these conditions.