Lara J. Maxwell

Responsiveness of patient reported outcomes including fatigue, sleep quality, activity limitation, and quality of life following treatment with abatacept for rheumatoid arthritis

Objective: To evaluate the responsiveness of patient reported outcomes (PROs), including fatigue, sleep, activity limitation, and quality of life, in patients with rheumatoid arthritis (RA). Methods: Data were considered from a randomised controlled trial comparing abatacept (n = 258) with placebo (n = 133) on a background of DMARD treatment in RA patients who were inadequate responders to anti-TNF therapy (ATTAIN study). PROs assessed included SF-36, activity limitation, fatigue, and sleep. For each outcome the treatment difference, relative per cent improvement, standardised response mean (SRM), and relative efficiency for assessing an outcome’s ability to detect a treatment effect relative to tender joint count (TJC) were calculated. A relative efficiency >1 suggests a measure that is more efficient than TJC in detecting treatment effect. Results: Moderate to large SRMs (⩾0.6) were observed for the PRO measures. In particular, SRMs (95% confidence interval) were: physician global, 0.72 (0.51 to 0.94); HAQ, 0.63 (0.42 to 0.85); SF-36 physical component score, 0.62 (0.40 to 0.83); SF-36 bodily pain, 0.68 (0.46 to 0.90); and fatigue, 0.59 (0.38 to 0.81). Relative efficiencies for physician global (1.6), SF-36 bodily pain domain (1.4), pain intensity (1.4), HAQ (1.2), SF-36 physical component score (1.2), fatigue (1.1), and patient global assessment (1.04) were all more responsive than TJC. The SF-36 mental component score (0.3), swollen joint count (0.6), activity limitation (0.8), sleep (0.7), and C reactive protein (0.9) were less responsive. Conclusions: Using PROs for evaluating treatments for RA can detect improvements and will identify changes that are important to patients. In general, physical assessments are more responsive to an effective treatment than mental assessments.

Abatacept for Rheumatoid Arthritis: A Cochrane Systematic Review

Objective. To perform a systematic review of efficacy and safety of abatacept in patients with rheumatoid arthritis (RA). Methods. We searched the Cochrane Library, MEDLINE, EMBASE, ACP Journal Club, and Biosis Previews for randomized controlled trials (RCT) comparing abatacept alone or in combination with disease modifying antirheumatic drugs (DMARD)/biologics to placebo or other DMARD/biologics in patients with RA. Two reviewers independently assessed search results, risk of bias, and extracted data. Results. Seven trials with 2908 patients were included. Compared with placebo, patients with RA treated with abatacept were 2.2 times more likely to achieve an American College of Rheumatology 50% response (ACR50) at one year (relative risk 2.21, 95% CI 1.73, 2.82) with a 21% (95% CI 16%, 27%) absolute risk difference between groups. The number needed to treat to achieve an ACR50 response was 5 (95% CI 4, 7). Significantly greater improvements in physical function, disease activity, pain, and radiographic progression were noted in abatacept-treated patients compared to placebo. Total adverse events (AE) were greater in the abatacept group (RR 1.05, 95% CI 1.01, 1.08). Other harm outcomes were not significant, with the exception of serious infections at 12 months, which were more common in the abatacept group versus control group (Peto odds ratio 1.91, 95% CI 1.07, 3.42). Serious AE were more numerous in the abatacept + etanercept group versus the placebo + etanercept group (RR 2.30, 95% CI 1.15, 4.62). Conclusion. Abatacept seems to be efficacious and safe in the treatment of RA. Abatacept should not be used in combination with other biologics to treat RA. Further longterm studies and postmarketing surveillance are required to assess for longer-term harms and sustained efficacy.

Updated Method Guidelines for Cochrane Musculoskeletal Group Systematic Reviews and Metaanalyses

The Cochrane Musculoskeletal Group (CMSG), one of 53 groups of the not-for-profit, international Cochrane Collaboration, prepares, maintains, and disseminates systematic reviews of treatments for musculoskeletal diseases. It is important that authors conducting CMSG reviews and the readers of our reviews be aware of and use updated, state-of-the-art systematic review methodology. One hundred sixty reviews have been published. Previous method guidelines for systematic reviews of interventions in the musculoskeletal field published in 2006 have been substantially updated to incorporate methodological advances that are mandatory or highly desirable in Cochrane reviews and knowledge translation advances. The methodological advances include new guidance on searching, new risk-of-bias assessment, grading the quality of the evidence, the new Summary of Findings table, and comparative effectiveness using network metaanalysis. Method guidelines specific to musculoskeletal disorders are provided by CMSG editors for various aspects of undertaking a systematic review. These method guidelines will help improve the quality of reporting and ensure high standards of conduct as well as consistency across CMSG reviews.

Optimal Strategies for Reporting Pain in Clinical Trials and Systematic Reviews: Recommendations from an OMERACT 12 Workshop

Objective. Pain is a patient-important outcome, but current reporting in randomized controlled trials and systematic reviews is often suboptimal, impeding clinical interpretation and decision making. Methods. A working group at the 2014 Outcome Measures in Rheumatology (OMERACT 12) was convened to provide guidance for reporting treatment effects regarding pain for individual studies and systematic reviews. Results For individual trials, authors should report, in addition to mean change, the proportion of patients achieving 1 or more thresholds of improvement from baseline pain (e.g., ≥ 20%, ≥ 30%, ≥ 50%), achievement of a desirable pain state (e.g., no worse than mild pain), and/or a combination of change and state. Effects on pain should be accompanied by other patient-important outcomes to facilitate interpretation. When pooling data for metaanalysis, authors should consider converting all continuous measures for pain to a 100 mm visual analog scale (VAS) for pain and use the established, minimally important difference (MID) of 10 mm, and the conventionally used, appreciably important differences of 20 mm, 30 mm, and 50 mm, to facilitate interpretation. Effects ≤ 0.5 units suggest a small or very small effect. To further increase interpretability, the pooled estimate on the VAS should also be transformed to a binary outcome and expressed as a relative risk and risk difference. This transformation can be achieved by calculating the probability of experiencing a treatment effect greater than the MID and the thresholds for appreciably important differences in pain reduction in the control and intervention groups. Conclusion. Presentation of relative effects regarding pain will facilitate interpretation of treatment effects.

Is health equity considered in systematic reviews of the Cochrane Musculoskeletal Group

OBJECTIVE To determine whether Cochrane Musculoskeletal Group (CMSG) systematic reviews and corresponding primary studies of rheumatoid arthritis interventions report and analyze the data needed to assess the effectiveness of interventions in reducing socioeconomic differences in health and/or improving the health of the poor. METHODS We selected all CMSG reviews on rheumatoid arthritis published since issue 1, 2003. Fourteen reviews were identified; 147 of the 156 primary studies included in these reviews were obtained and assessed. We extracted data on whether the dimensions place of residence, race/ethnicity/culture, occupation, gender, religion, education, socioeconomic status, and social capital and networks (PROGRESS) were reported or analyzed, and whether any interventions were aimed at disadvantaged or low- and middle-income country populations. RESULTS Among the dimensions of PROGRESS reported at baseline in 147 primary studies, gender (89%) was the most commonly reported, followed by education (25%) and race/ethnicity (18%). Less than 50% of the systematic reviews reported dimensions of PROGRESS even when they had been reported in the primary study. Of 147 primary studies, 6 (5%) were aimed specifically at disadvantaged populations; another 6 reported on effectiveness by at least 1 dimension of PROGRESS. CONCLUSION Primary studies of interventions for rheumatoid arthritis generally reported few variables necessary to answer questions about health inequalities. Most CMSG systematic reviews failed to assess those variables even when described in the primary studies. The Cochrane Health Equity Field welcomes the opportunity to provide guidance to systematic review authors on incorporating equity considerations into their reviews.

Update of Strategies to Translate Evidence from Cochrane Musculoskeletal Group Systematic Reviews for Use by Various Audiences

For rheumatology research to have a real influence on health and well-being, evidence must be tailored to inform the decisions of various audiences. The Cochrane Musculoskeletal Group (CMSG), one of 53 groups of the not-for-profit international Cochrane Collaboration, prepares, maintains, and disseminates systematic reviews of treatments for musculoskeletal diseases. While systematic reviews provided by the CMSG fill a major gap in meeting the need for high-quality evidence syntheses, our work does not end at the completion of a review. The term “knowledge translation” (KT) refers to the activities involved in bringing research evidence to various audiences in a useful form so it can be used to support decision making and improve practices. Systematic reviews give careful consideration to research methods and analysis. Because the review is often long and detailed, the clinically relevant results may not be apparent or in the optimal form for use by patients and their healthcare practitioners. This paper describes 10 formats, many of them new, for ways that evidence from Cochrane Reviews can be translated with the intention of meeting the needs of various audiences, including patients and their families, practitioners, policy makers, the press, and members of the public (the “5 Ps”). Current and future knowledge tools include summary of findings tables, patient decision aids, plain language summaries, press releases, clinical scenarios in general medical journals, frequently asked questions (Cochrane Clinical Answers), podcasts, Twitter messages, Journal Club materials, and the use of storytelling and narratives to support continuing medical education. Future plans are outlined to explore ways of improving the influence and usefulness of systematic reviews by providing results in formats suitable to our varied audiences.

Consensus on the Need for a Hierarchical List of Patient-reported Pain Outcomes for Metaanalyses of Knee Osteoarthritis Trials: An OMERACT Objective

Objective. Although protocol registration for systematic reviews is still not mandatory, reviewers should be strongly encouraged to register the protocol to identify the methodological approach, including all outcomes of interest. This will minimize the likelihood of biased decisions in reviews, such as selective outcome reporting. A group of international experts convened to address issues regarding the need to develop hierarchical lists of outcome measurement instruments for a particular outcome for metaanalyses. Methods. Multiple outcome measurement instruments exist to measure the same outcome. Metaanalysis of knee osteoarthritis (OA) trials, and the assessment of pain as an outcome, was used as an exemplar to assess how Outcome Measures in Rheumatology (OMERACT), the Cochrane Collaboration, and other international initiatives might contribute in this area. The meeting began with formal presentations of background topics, empirical evidence from the literature, and a brief introduction to 2 existing hierarchical lists of pain outcome measurement instruments recommended for metaanalyses of knee OA trials. Results. After discussions, most participants agreed that there is a need to develop a methodology for generation of hierarchical lists of outcome measurement instruments to guide metaanalyses. Tools that could be used to steer development of such a prioritized list are the COSMIN checklist (COnsensus-based Standards for the selection of health status Measurement Instruments) and the OMERACT Filter 2.0. Conclusion. We list meta-epidemiological research agenda items that address the frequency of reported outcomes in trials, as well as methodologies to assess the best measurement properties (i.e., truth, discrimination, and feasibility).

Dialogue on Developing Consensus on Measurement and Presentation of Patient-important Outcomes, Using Pain Outcomes as an Exemplar, in Systematic Reviews: A Preconference Meeting at OMERACT 12

Prior to the Outcome Measures in Rheumatology (OMERACT) 12 meeting in Budapest, Hungary, a workshop was held bringing together individuals from a number of international outcome measure organizations to assess how best to further develop consensus on how pain is conceptualized and measured in trials of musculoskeletal conditions, and how the trials should be reported in systematic reviews.

Assessing bias in osteoarthritis trials included in Cochrane reviews: protocol for a meta-epidemiological study.

Introduction The validity of systematic reviews and meta-analysis depends on methodological quality and unbiased dissemination of trials. Our objective is to evaluate the association of estimates of treatment effects with different bias-related study characteristics in meta-analyses of interventions used for treating pain in osteoarthritis (OA). From the findings, we hope to consolidate guidance on interpreting OA trials in systematic reviews based on empirical evidence from Cochrane reviews. Methods and analysis Only systematic reviews that compare experimental interventions with sham, placebo or no intervention control will be considered eligible. Bias will be assessed with the risk of bias tool, used according to the Cochrane Collaboration’s recommendations. Furthermore, center status, trial size and funding will be assessed. The primary outcome (pain) will be abstracted from the first appearing forest plot for overall pain in the Cochrane review. Treatment effect sizes will be expressed as standardised mean differences (SMDs), where the difference in mean values available from the forest plots is divided by the pooled SD. To empirically assess the risk of bias in treatment benefits, we will perform stratified analyses of the trials from the included meta-analyses and assess the interaction between trial characteristics and treatment effect. A relevant study-level covariate is defined as one that decreases the between-study variance (τ2, estimated as Tau-squared) as a consequence of inclusion in the mixed effects statistical model. Ethics and dissemination Meta-analyses and randomised controlled trials provide the most reliable basis for treatment of patients with OA, but the actual impact of bias is unclear. This study will systematically examine the methodological quality in OA Cochrane reviews and explore the effect estimates behind possible bias. Since our study does not collect primary data, no formal ethical assessment and informed consent are required. Trial registration number PROSPERO (CRD42013006924).

Engaging Stakeholders and Promoting Uptake of OMERACT Core Outcome Instrument Sets

Objective. While there has been substantial progress in the development of core outcomes sets, the degree to which these are used by researchers is variable. We convened a special workshop on knowledge translation at the Outcome Measures in Rheumatology (OMERACT) 2016 with 2 main goals. The first focused on the development of a formal knowledge translation framework and the second on promoting uptake of recommended core outcome domain and instrument sets. Methods. We invited all 189 OMERACT 2016 attendees to the workshop; 86 attended, representing patient research partners (n = 15), healthcare providers/clinician researchers (n = 52), industry (n = 4), regulatory agencies (n = 4), and OMERACT fellows (n = 11). Participants were given an introduction to knowledge translation and were asked to propose and discuss recommendations for the OMERACT community to (1) strengthen stakeholder involvement in the core outcome instrument set development process, and (2) promote uptake of core outcome sets with a specific focus on the potential role of post-regulatory decision makers. Results. We developed the novel “OMERACT integrated knowledge translation” framework, which formalizes OMERACT’s knowledge translation strategies. We produced strategies to improve stakeholder engagement throughout the process of core outcome set development and created a list of creative and innovative ways to promote the uptake of OMERACT’s core outcome sets. Conclusion. The guidance provided in this paper is preliminary and is based on the views of the participants. Future work will engage OMERACT groups, “post-regulatory decision makers,” and a broad range of different stakeholders to identify and evaluate the most useful methods and processes, and to revise guidance accordingly.