Methotrexate for juvenile idiopathic arthritis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. Methotrexate has broad immunomodulatory properties and is the most commonly used disease-modifying antirheumatic drug (DMARD). This is an update of a 2001 Cochrane review. It supports a living guideline for children and young people with JIA. OBJECTIVES: To assess the benefits and harms of methotrexate for children and young people with juvenile idiopathic arthritis. SEARCH METHODS: The Australian JIA Living Guideline Working Group created a registry of all randomised controlled trials (RCTs) of JIA by searching CENTRAL, MEDLINE, Embase, and trials registries. The date of the most recent search of online databases was 1 February 2023. SELECTION CRITERIA: We searched for RCTs that compared methotrexate with placebo, no treatment, or another DMARD (with or without concomitant therapies) in children and young people (aged up to 18 years) with JIA. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. The main comparison was methotrexate versus placebo. Our outcomes were treatment response, sustained clinically inactive disease, function, pain, participant global assessment of well-being, serious adverse events, and withdrawals due to adverse events. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We identified three new trials in this update, bringing the total number of included RCTs to five (575 participants). Three trials evaluated oral methotrexate versus placebo, one evaluated methotrexate plus intra-articular glucocorticoid (IAGC) therapy versus IAGC therapy alone, and one evaluated methotrexate versus leflunomide. Doses of methotrexate ranged from 5 mg/m2/week to 15 mg/m2/week in four trials, and participants in the methotrexate group of the remaining trial received 0.5 mg/kg/week. Trial size varied from 31 to 226 participants. The average age of participants ranged from four to 10 years. Most participants were females and most had nonsystemic JIA. The study that evaluated methotrexate plus IAGC therapy versus IAGC therapy alone recruited children and young people with the oligoarticular disease subtype of JIA. Two placebo-controlled trials and the trial of methotrexate versus leflunomide were adequately randomised and blinded, and likely not susceptible to important biases. One placebo-controlled trial may have been susceptible to selection bias due to lack of adequate reporting of randomisation methods. The trial investigating the addition of methotrexate to IAGC therapy was susceptible to performance and detection biases. Methotrexate versus placebo Methotrexate compared with placebo may increase the number of children and young people who achieve treatment response up to six months (absolute difference of 163 more per 1000 people; risk ratio (RR) 1.67, 95% confidence interval (CI) 1.21 to 2.31; I2 = 0%; 3 trials, 328 participants; low-certainty evidence). However, methotrexate compared with placebo may have little or no effect on pain as measured on an increasing scale of 0 to 100 (mean difference (MD) -1.10 points, 95% CI -9.09 to 6.88; 1 trial, 114 participants), improvement in participant global assessment of well-being (absolute difference of 92 more per 1000 people; RR 1.23, 95% CI 0.88 to 1.72; 1 trial, 176 participants), occurrence of serious adverse events (absolute difference of 5 fewer per 1000 people; RR 0.63, 95% CI 0.04 to 8.97; 3 trials, 328 participants), and withdrawals due to adverse events (RR 3.46, 95% CI 0.60 to 19.79; 3 trials, 328 participants) up to six months. We could not estimate the absolute difference for withdrawals due to adverse events because there were no withdrawals in the placebo group. All outcomes were reported within six months of randomisation. We downgraded the certainty of the evidence to low for all outcomes due to indirectness (suboptimal dosing of methotrexate and diverse outcome measures) and imprecision (few participants and low event rates). No trials reported function or the number of participants with sustained clinically inactive disease. Serious adverse events included liver derangement, abdominal pain, and inadvertent overdose. Methotrexate plus intra-articular corticosteroid therapy versus intra-articular corticosteroid therapy alone Methotrexate plus IAGC therapy compared with IAGC therapy alone may have little or no effect on the probability of sustained clinically inactive disease or the rate of withdrawals due to adverse events up to 12 months in children and young people with the oligoarticular subtype of JIA (low-certainty evidence). We could not calculate the absolute difference in withdrawals due to adverse events because there were no withdrawals in the control group. We are uncertain if there is any difference between the interventions in the risk of severe adverse events, because none were reported. The study did not report treatment response, function, pain, or participant global assessment of well-being. Methotrexate versus an alternative disease-modifying antirheumatic drug Methotrexate compared with leflunomide may have little or no effect on the probability of treatment response or on function, participant global assessment of well-being, risk of serious adverse events, and rate of withdrawals due to adverse events up to four months. We downgraded the certainty of the evidence for all outcomes to low due to imprecision. The study did not report pain or sustained clinically inactive disease. AUTHORS' CONCLUSIONS: Oral methotrexate (5 mg/m2/week to 15 mg/m2/week) compared with placebo may increase the number of children and young people achieving treatment response but may have little or no effect on pain or participant global assessment of well-being. Oral methotrexate plus IAGC injections compared to IAGC injections alone may have little or no effect on the likelihood of sustained clinically inactive disease among children and young people with oligoarticular JIA. Similarly, methotrexate compared with leflunomide may have little or no effect on treatment response, function, and participant global assessment of well-being. Serious adverse events due to methotrexate appear to be rare. We will update this review as new evidence becomes available to inform the living guideline.

Crowd-sourcing and automation facilitated the identification and classification of randomized controlled trials in a living review.

OBJECTIVES: To evaluate an approach using automation and crowdsourcing to identify and classify randomized controlled trials (RCTs) for rheumatoid arthritis (RA) in a living systematic review (LSR). METHODS: Records from a database search for RCTs in RA were screened first by machine learning and Cochrane Crowd to exclude non-RCTs, then by trainee reviewers using a Population, Intervention, Comparison, and Outcome (PICO) annotator platform to assess eligibility and classify the trial to the appropriate review. Disagreements were resolved by experts using a custom online tool. We evaluated the efficiency gains, sensitivity, accuracy, and interrater agreement (kappa scores) between reviewers. RESULTS: From 42,452 records, machine learning and Cochrane Crowd excluded 28,777 (68%), trainee reviewers excluded 4,529 (11%), and experts excluded 7,200 (17%). The 1,946 records eligible for our LSR represented 220 RCTs and included 148/149 (99.3%) of known eligible trials from prior reviews. Although excluded from our LSRs, 6,420 records were classified as other RCTs in RA to inform future reviews. False negative rates among trainees were highest for the RCT domain (12%), although only 1.1% of these were for the primary record. Kappa scores for two reviewers ranged from moderate to substantial agreement (0.40-0.69). CONCLUSION: A screening approach combining machine learning, crowdsourcing, and trainee participation substantially reduced the screening burden for expert reviewers and was highly sensitive.

Prioritization of clinical questions for the Australian Living Guideline for the Pharmacological Management of Inflammatory Arthritis.

AIM: Living guidelines aim to reduce delays in translating new knowledge into practice by updating individual recommendations as soon as relevant new evidence emerges. We surveyed members of the Australian Rheumatology Association (ARA) to develop a list of priority questions for the Australian Living Guideline for the Pharmacological Management of Inflammatory Arthritis (ALG) and to explore clinicians' use of clinical practice guidelines. METHODS: An electronic survey of ARA members was performed in two phases. The first survey contained questions about current guideline use and beliefs and invited participants to submit at least three questions relevant to the management of rheumatoid arthritis (RA). In the second round, participants selected 10 questions they considered to be the highest priority from the collated list and ranked them in priority order. The sum of ranks was used to generate a final priority list. RESULTS: There were 115 (21%) and 78 (14%) responses to the first and second survey rounds respectively. 87% of respondents use existing rheumatology guidelines in their usual practice, primarily EULAR guidelines. Most respondents favored the development of Australian rheumatology guidelines. In total, 34 potential recommendation topics were identified and ranked in order of priority. CONCLUSION: A list of 34 clinical questions about RA management, ranked in order of importance by clinicians, has informed the development of the ALG. Similar prioritization exercises in other contexts may permit guidelines to be tailored to the needs of guideline users in their specific context, which may facilitate international collaboration and promote efficient translation of evidence to practice.

Trajectories of self-reported pain-related health outcomes and longitudinal effects on medication use in rheumatoid arthritis: a prospective cohort analysis using the Australian Rheumatology Association Database (ARAD).

OBJECTIVE: To determine distinct trajectories of self-reported pain-related health status in rheumatoid arthritis (RA), their relationship with sociodemographic factors and medication use. METHODS: 988 Australian Rheumatology Association Database participants with RA (71% female, mean age 54 years, mean disease duration 2.3 years) were included. Distinct multi-trajectories over 15-year follow-up for five different self-reported pain-related health outcome measures (Health Assessment Questionnaire Disability Index, visual analogue scores for pain, arthritis, global health and the Assessment of Quality of Life utility index) were identified using latent variable discrete mixture modelling. Random effects models were used to determine associations with medication use and biologic therapy modification during follow-up. RESULTS: Four, approximately equally sized, pain/health status groups were identified, ranging from 'better' to 'poorer', within which changes over time were relatively small. Important determinants of those with poorer pain/health status included female gender, obesity, smoking, socioeconomic indicators and comorbidities. While biologic therapy use was similar between groups during follow-up, biologic therapy modifications (plinear<0.001) and greater tendency of non-tumour necrosis factor inhibitor use (plinear<0.001) were observed in those with poorer pain/health status. Similarly, greater use of opioids, prednisolone and non-steroidal anti-inflammatory drugs was seen in those with poorer pain/health status. CONCLUSION: In the absence of disease activity information, distinct trajectories of varying pain/health status were seen from the outset and throughout the disease course in this RA cohort. More biologic therapy modifications and greater use in anti-inflammatories, opioids and prednisolone were seen in those with poorer pain/health status, reflecting undesirable lived experience of persistent pain in RA.

Australian recommendations on perioperative use of disease-modifying anti-rheumatic drugs in people with inflammatory arthritis undergoing elective surgery.

Disease-modifying anti-rheumatic drugs (DMARDs) are effective treatments for inflammatory arthritis but carry an increased risk of infection. For patients undergoing surgery, there is a need to consider the trade-off between a theoretical increased risk of infection with continuation of DMARDs perioperatively versus an increased risk of disease flare if they are temporarily withheld. We used the Grading of Recommendations Assessment, Development and Evaluation methodology to develop recommendations for perioperative use of DMARDs for people with inflammatory arthritis undergoing elective surgery. The recommendations form part of the National Health and Medical Research Council-endorsed Australian Living Guideline for the Pharmacological Management of Inflammatory Arthritis. Conditional recommendations were made against routinely discontinuing conventional synthetic and biologic (b) DMARDs in the perioperative period but to consider temporary discontinuation of bDMARDs in individuals with a high risk of infection or where the impact of infection would be severe. A conditional recommendation was made in favour of temporary discontinuation of targeted synthetic DMARDs in the perioperative period.

Which clinical research questions are the most important? Development and preliminary validation of the Australia & New Zealand Musculoskeletal (ANZMUSC) Clinical Trials Network Research Question Importance Tool (ANZMUSC-RQIT).

BACKGROUND AND AIMS: High quality clinical research that addresses important questions requires significant resources. In resource-constrained environments, projects will therefore need to be prioritized. The Australia and New Zealand Musculoskeletal (ANZMUSC) Clinical Trials Network aimed to develop a stakeholder-based, transparent, easily implementable tool that provides a score for the 'importance' of a research question which could be used to rank research projects in order of importance. METHODS: Using a mixed-methods, multi-stage approach that included a Delphi survey, consensus workshop, inter-rater reliability testing, validity testing and calibration using a discrete-choice methodology, the Research Question Importance Tool (ANZMUSC-RQIT) was developed. The tool incorporated broad stakeholder opinion, including consumers, at each stage and is designed for scoring by committee consensus. RESULTS: The ANZMUSC-RQIT tool consists of 5 dimensions (compared to 6 dimensions for an earlier version of RQIT): (1) extent of stakeholder consensus, (2) social burden of health condition, (3) patient burden of health condition, (4) anticipated effectiveness of proposed intervention, and (5) extent to which health equity is addressed by the research. Each dimension is assessed by defining ordered levels of a relevant attribute and by assigning a score to each level. The scores for the dimensions are then summed to obtain an overall ANZMUSC-RQIT score, which represents the importance of the research question. The result is a score on an interval scale with an arbitrary unit, ranging from 0 (minimal importance) to 1000. The ANZMUSC-RQIT dimensions can be reliably ordered by committee consensus (ICC 0.73-0.93) and the overall score is positively associated with citation count (standardised regression coefficient 0.33, p<0.001) and journal impact factor group (OR 6.78, 95% CI 3.17 to 14.50 for 3rd tertile compared to 1st tertile of ANZMUSC-RQIT scores) for 200 published musculoskeletal clinical trials. CONCLUSION: We propose that the ANZMUSC-RQIT is a useful tool for prioritising the importance of a research question.

Methods for living guidelines: early guidance based on practical experience. Paper 2: consumer engagement in living guidelines.

OBJECTIVES: To describe and reflect on the consumer engagement approaches used in five living guidelines from the perspectives of consumers (i.e., patients, carers, the public, and their representatives) and guideline developers. STUDY DESIGN AND SETTING: In a descriptive report, we used a template to capture engagement approaches and the experiences of consumers and guideline developers in living guidelines in Australia and the United Kingdom. Responses were summarized using descriptive synthesis. RESULTS: One guideline used a Consumer Panel, three included two to three consumers in the guideline development group, and one did both. Much of our experience was common to all guidelines (e.g., consumers felt welcomed but that their role initially lacked clarity). We identified six challenges and opportunities specific to living guidelines: managing the flow of work; managing engagement in online environments; managing membership of the panel; facilitating more flexibility, variety and depth in engagement; recruiting for specific skills-although these can be built over time; developing living processes to improve; and adapting consumer engagement together. CONCLUSION: Consumer engagement in living guidelines should follow established principles of consumer engagement in guidelines. Conceiving the engagement as living, underpinned by a living process evaluation, allows the approach to be developed with consumers over time.

Vaccination Rates, Perceptions, and Information Sources Used by People With Inflammatory Arthritis.

OBJECTIVE: To determine vaccination rates, perceptions, and information sources in people with inflammatory arthritis. METHODS: Participants enrolled in the Australian Rheumatology Association Database were invited to participate in an online questionnaire, conducted in January 2020, prior to the COVID-19 pandemic. Included questions were about vaccination history, modified World Health Organization Vaccination Hesitancy Scale, views of the information sources consulted, the Beliefs About Medicines Questionnaire, education, and the Single-Item Health Literacy Screener. RESULTS: Response rate was 994 of 1498 (66%). The median age of participants was 62 years, with 67% female. Self-reported adherence was 83% for the influenza vaccine. Participants generally expressed positive vaccination views, particularly regarding safety, efficacy, and access. However, only 43% knew which vaccines were recommended for them. Vaccine hesitancy was primarily attributable to uncertainty and a perceived lack of information about which vaccines were recommended. Participants consulted multiple vaccination information sources (median 3, interquartile range 2-7). General practitioners (89%) and rheumatologists (76%) were the most frequently used information sources and were most likely to yield positive views. Negative views of vaccination were most often from internet chatrooms, social media, and mainstream media. Factors of younger age, male gender, and having more concerns about the harms and overuse of medicines in general were associated with lower adherence and greater uncertainty about vaccinations, whereas education and self-reported literacy were not. CONCLUSION: Participants with inflammatory arthritis generally held positive views about vaccination, although there was considerable uncertainty as to which vaccinations were recommended for them. This study highlights the need for improved consumer information about vaccination recommendations for people with inflammatory arthritis.

Equity Considerations in COVID-19 Vaccination Studies of Individuals With Autoimmune Inflammatory Rheumatic Diseases.

OBJECTIVE: We sought to examine the extent to which populations experiencing inequities were considered in studies of COVID-19 vaccination in individuals with autoimmune inflammatory rheumatic diseases (AIRDs). METHODS: We included all studies (n = 19) from an ongoing Cochrane living systematic review on COVID-19 vaccination in patients with AIRDs. We used the PROGRESS-Plus framework (place of residence, race/ethnicity, occupation, gender/sex, religion, education, socioeconomic status, and social capital, plus: age, multimorbidity, and health literacy) to identify factors that stratify health outcomes. We assessed equity considerations in relation to differences in COVID-19 baseline risk, eligibility criteria, and description of participant characteristics and attrition, controlling for confounding factors, subgroup analyses, and applicability of findings. RESULTS: All 19 studies were cohort studies that followed individuals with AIRDs after vaccination. Three studies (16%) described differences in baseline risk for COVID-19 across age. Two studies (11%) defined eligibility criteria based on occupation and age. All 19 studies described participant age and sex. Twelve studies (67%) controlled for age and/or sex as confounders. Eight studies (47%) conducted subgroup analyses across at least 1 PROGRESS-Plus factor, most commonly age. Ten studies (53%) interpreted applicability in relation to at least 1 PROGRESS-Plus factor, most commonly age (47%), then ethnicity (16%), sex (16%), and multimorbidity (11%). CONCLUSION: Sex and age were the most frequently considered PROGRESS-Plus factors in studies of COVID-19 vaccination in individuals with AIRDs. The generalizability of evidence to populations experiencing inequities is uncertain. Future COVID-19 vaccine studies should report participant characteristics in more detail to inform guideline recommendations.

Using the derived 28-joint disease activity score patient-reported components (DAS28-P) index as a discriminatory measure of response to disease-modifying anti-rheumatic drug therapy in early rheumatoid arthritis.

BACKGROUND: The 28-joint disease activity score (DAS28) is a widely used measure to assess disease activity in rheumatoid arthritis (RA). The DAS28-P index, a derived proportion of the patient-reported components (joint tenderness and patient global assessment) within the DAS28, has been utilized as a discriminatory measure of non-inflammatory pain mechanisms in RA. This study aimed to evaluate the use of the DAS28-P index as a predictor of treatment response in early RA. METHODS: Patients with early RA enrolled in a supplemental fish oil clinical trial received a combination of disease-modifying anti-rheumatic drugs (DMARDs) according to a 'treat-to-target' protocol. First, consecutive measures of the DAS28-P index, derived from the DAS28-erythrocyte sedimentation rate (DAS28-ESR), at each visit over a 1-year period were estimated for each patient. Then, distinct subgroups of treatment responders based on the trajectories of the DAS28-P indices were identified using bivariate k-means cluster analysis. Data on baseline predictors as well as longitudinal outcomes of disease impact and DMARD use over a 1-year period and radiographic progression over a 3-year period were collected and analyzed using a random intercept, population-averaged generalized estimating equation model. RESULTS: 121 patients were included (74% female; mean age of 57; median of 16 weeks of active disease) and a 3-cluster model was identified-the 'Responders' group (n = 58; 48%), the 'Partial Responders' group (n = 32; 26%), and the 'Non-Responders' group (n = 31; 26%). The 'Partial Responders' group had consistently higher proportions of the DAS28-P index throughout the study period and had minimal radiographic progression over time, with the lowest joint erosion score of 0.9 [95% confidence interval (CI) 0.2, 1.6], observed at the 3-year follow-up. At 52 weeks, the methotrexate dose was higher for both 'Partial Responders' and 'Non-Responders' groups (18.5 mg [95% CI 15.5, 21.5] and 18.6 mg [95% CI 15.3, 21.8] respectively), when compared with the 'Responders' group (12.8 mg [95% CI 14.7, 20.9]). CONCLUSIONS: Persistently high DAS28-P index scores are useful to distinguish poor patient global assessment and excessive treatment escalation in early RA, suggestive of underlying non-inflammatory pain contributing to higher disease activity score. Early identification of patients with discordant subjective and objective components of composite disease activity measures may allow better tailoring of treatment in RA.

Australian recommendations on tapering of biologic and targeted synthetic disease-modifying anti-rheumatic drugs in inflammatory arthritis.

Biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARD) have been an important advance in the management of inflammatory arthritis, but are expensive medications, carry a risk of infection and other adverse effects, and are often perceived as a burden by patients. We used GRADE methodology to develop recommendations for dose reduction and discontinuation of b/tsDMARD in people with rheumatoid arthritis (RA), axial spondyloarthritis (AxSpA) and psoriatic arthritis (PsA) who have achieved a low disease activity state or remission. The recommendations form part of the Australian Living Guideline for the Pharmacological Management of Inflammatory Arthritis, an NHMRC-endorsed 'living' guideline, in which recommendations are updated in near real-time as new evidence emerges. Conditional recommendations were made in favour of dose reduction in RA and AxSpA but not in PsA. Abrupt discontinuation of b/tsDMARD is not recommended in any of the three diseases.

Crowdsourcing trainees in a living systematic review provided valuable experiential learning opportunities: a mixed-methods study.

OBJECTIVES: To understand trainee experiences of participating in a living systematic review (LSR) for rheumatoid arthritis and the potential benefits in terms of experiential evidence-based medicine (EBM) education. STUDY DESIGN AND SETTING: We conducted a mixed-methods study with trainees who participated in the LSR and who were recruited broadly from training programs in two countries. Trainees received task-specific training and completed one or more tasks in the review: assessing article eligibility, data extraction, and quality assessment. Trainees completed a survey followed by a one-on-one interview. Data were triangulated to produce broad themes. RESULTS: Twenty one trainees, most of whom had a little prior experience with systematic reviews, reported a positive overall experience. Key benefits included learning opportunities, task segmentation (ability to focus on a single task, as opposed to an entire review), working in a supportive environment, international collaboration, and incentives such as authorship or acknowledgment. Trainees reported improvement in their competency as a Scholar, Collaborator, Leader, and Medical Expert. Challenges included communication and technical difficulties and appropriate matching of tasks to trainee skillsets. CONCLUSION: Participating in an LSR provided benefits to a wide range of trainees and may provide an opportunity for experiential EBM training, while helping LSR sustainability.

Factors influencing clinician prescribing of disease-modifying anti-rheumatic drugs for inflammatory arthritis: A systematic review and thematic synthesis of qualitative studies.

Understanding factors that influence prescribing of disease-modifying anti-rheumatic drugs (DMARDs) will inform strategies to optimise care of people with inflammatory arthritis. We performed a systematic review and thematic synthesis of qualitative studies to explore these factors. Inclusion criteria were: use of qualitative or mixed methods; rheumatologist, nurse or pharmacist perspectives; prescription of any DMARD (conventional [cs], targeted synthetic [ts], biologic [b], biosimilars) and/or glucocorticoids; in any healthcare setting in any country. MEDLINE, Embase and EBSCOhost CINAHL Plus were searched from inception to 15 June 2021. Pairs of review authors independently identified studies for inclusion, assessed methodological quality using the Critical Appraisal Skills Programme checklist, and extracted and thematically synthesised data. Confidence in synthesis themes was evaluated using the GRADE Confidence in Evidence from Reviews of Qualitative research (CERQual) approach. We included 15 studies involving 716 clinicians (683 rheumatologists, 27 nurses, 6 pharmacists) across 10 countries, all focusing on management of patients with rheumatoid arthritis (RA). Six themes were identified: Rheumatologist prescribing is influenced by patients' characteristics, preferences, symptoms and negative responses to medication; Rheumatologist knowledge, experience, habits and subjective judgements are strong drivers of prescribing behaviour; High demands on consultation time impede shared decision-making; Costs and complexity of medication funding arrangements limit prescribing options; Clinicians recognise the importance of providing patient education about medication options; and Clinicians value colleagues' opinions and support to inform prescribing decisions. The majority of themes were graded as moderate confidence (n  =  4), reflecting they are likely to reasonably represent the factors influencing prescribing of DMARDs to people with RA. Quality improvement strategies that address these factors are likely to support best practice pharmacologic management of RA and may be potentially applicable to other types of inflammatory arthritis. High demand on consultation time and complexity of medication funding arrangements are system factors that may or may not be amenable to change. Easily accessible living national guidelines which include lay summaries and treatment algorithms to support prescribing decisions may address some of the themes.

Industry involvement in rheumatology consensus-based recommendations: a systematic review.

Consensus-based recommendations guide standards of care for clinical practice. Pharmaceutical industry involvement in producing such recommendations might undermine their objectivity. We did a systematic review of rheumatology consensus-based recommendations that were published in English from 2000 to 2020. We compared those that were endorsed by major professional societies to those that were sponsored by industry using the validated Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument. Of 234 consensus-based recommendation projects, 51 (22%) were endorsed by major societies and 74 (32%) were sponsored by the pharmaceutical industry. Among industry-sponsored projects, the sponsor was involved in the consensus-based process in 21 (28%), provided a medical writer in 12 (16%), offered honoraria for participation in five (7%), and was allowed to approve the final draft of one project. When compared with projects endorsed by major societies, industry-sponsored projects were less likely to have a high quality assessment on the AGREE II instrument. These results suggest that industry sponsorship of consensus-based recommendations is common in projects that do not receive endorsement by major societies. Such projects are often of lower quality than guidelines endorsed by major professional societies. Medical journals should consider steps to encourage greater rigour of development and to limit undue influence by industry sponsors.

Perspectives of Glucocorticoid Use in Patients with Rheumatoid Arthritis.

OBJECTIVE: Prednisolone is an effective oral glucocorticoid for managing symptoms of rheumatoid arthritis (RA) but has predictable and common adverse effects. We explored patient perspectives of prednisolone use in RA. METHODS: Patients with RA registered with the Australian Rheumatology Association Database (ARAD) who had completed an ARAD questionnaire in the preceding 12 months were invited to participate in an online survey. Responses were linked to already collected respondent demographics, medication use, and patient-reported outcome measures. The Beliefs about Medicine Questionnaire (BMQ) measured patient beliefs on medication necessity and concerns. Free-text responses outlining reasons for stopping or declining prednisolone underwent thematic analysis using NVivo 12. RESULTS: The survey response rate was 79.6% (804/1010), including 251 (31.2%) reporting current prednisolone use and 432 (53.7%) reporting previous use. Compared with previous users, current users were older (P = 0.0002) and had worse self-reported pain, disease activity, health-related quality of life, and function (all P < 0.001). Current users had higher BMQ scores for prednisolone-specific necessity (3.6 versus 1.7; P <0.001) and concerns (2.7 versus 2.3; P <0.001). In previous prednisolone users (n = 432), the most frequent themes identified in free-text responses for cessation were adequate disease control (30.3%), adverse effects (25.2%), and predetermined short courses (21.3%). Of respondents citing adverse effects for cessation (n = 131), weight gain (27.5%), osteoporosis (14.7%), and neuropsychiatric issues (13.8%) were most frequent. CONCLUSIONS: In our cohort, patients with RA taking prednisolone believed it was necessary yet remained concerned about its use. Adequate disease control and adverse effects were important considerations for patients using prednisolone.

Early development of the Australia and New Zealand Musculoskeletal Clinical Trials Network.

The Australia and New Zealand Musculoskeletal (ANZMUSC) Clinical Trials Network was formed to build capacity and infrastructure for high-quality musculoskeletal clinical trials in our region. The purpose of this paper is to describe the steps taken in its formation to help others interested in establishing similar networks. In particular, we describe the steps taken to form the collaboration and our progress in achieving our vision and mission. Our aim is to focus on trials of highest importance and quality to provide definitive answers to the most pressing questions in our field.

Patients' experience of shoulder disorders: a systematic review of qualitative studies for the OMERACT Shoulder Core Domain Set.

OBJECTIVES: To describe the experiences (including symptoms and perceived impacts on daily living) of people with a shoulder disorder. METHODS: Systematic review of qualitative studies. We searched for eligible qualitative studies indexed in Ovid MEDLINE, Ovid Embase, CINAHL (EBSCO), SportDiscus (EBSCO) and Ovid PsycINFO up until November 2017. Two authors independently screened studies for inclusion, appraised their methodological quality using the Critical Appraisal Skills Programme checklist, used thematic synthesis methods to generate themes describing the experiences reported by participants and assessed the confidence in the findings using the Grading of Recommendations Assessment, Development and Evaluation Confidence in Evidence from Reviews of Qualitative research (GRADE-CERQual) approach. RESULTS: The inclusion criteria were met by eight studies, which included 133 participants (49 females and 84 males) with either rotator cuff disease, adhesive capsulitis, proximal humeral fracture, shoulder instability or unspecified shoulder pain. We generated seven themes to describe what people in the included studies reported experiencing: pain; physical function/activity limitations; participation restriction; sleep disruption; cognitive dysfunction; emotional distress; and other pathophysiological manifestations (other than pain). There were interactions between the themes, with particular experiences impacting on others (e.g. pain leading to reduced activities and sleep disruption). Following grading of the evidence, we considered it likely that most of the review findings were a reasonable representation of the experiences of people with shoulder disorders. CONCLUSION: Patients with shoulder disorders contend with considerable disruption to their life. The experiences described should be considered by researchers seeking to select the most appropriate outcomes to measure in clinical trials and other research studies in people with shoulder disorders.

The OMERACT Core Domain Set for Clinical Trials of Shoulder Disorders.

OBJECTIVE: To reach consensus on the core domains to be included in a core domain set for clinical trials of shoulder disorders using the Outcome Measures in Rheumatology (OMERACT) Filter 2.1 Core Domain Set process. METHODS: At OMERACT 2018, the OMERACT Shoulder Working Group conducted a workshop that presented the OMERACT 2016 preliminary core domain set and its rationale based upon a systematic review of domains measured in shoulder trials and international Delphi sessions involving patients, clinicians, and researchers, as well as a new systematic review of qualitative studies on the experiences of people with shoulder disorders. After discussions in breakout groups, the OMERACT core domain set for clinical trials of shoulder disorders was presented for endorsement by OMERACT 2018 participants. RESULTS: The qualitative review (n = 8) identified all domains included in the preliminary core set. An additional domain, cognitive dysfunction, was also identified, but confidence that this represents a core domain was very low. The core domain set that was endorsed by the OMERACT participants, with 71% agreement, includes 4 "mandatory" trial domains: pain, function, patient global - shoulder, and adverse events including death; and 4 "important but optional" domains: participation (recreation/work), sleep, emotional well-being, and condition-specific pathophysiological manifestations. Cognitive dysfunction was voted out of the core domain set. CONCLUSION: OMERACT 2018 delegates endorsed a core domain set for clinical trials of shoulder disorders. The next step includes identification of a core outcome measurement set that passes the OMERACT 2.1 Filter for measuring each domain.

Methotrexate for psoriatic arthritis.

BACKGROUND: Psoriatic arthritis is an inflammatory disease associated with joint damage, impaired function, pain, and reduced quality of life. Methotrexate is a disease-modifying anti-rheumatic drug (DMARD) commonly prescribed to alleviate symptoms, attenuate disease activity, and prevent progression of disease. OBJECTIVES: To assess the benefits and harms of methotrexate for psoriatic arthritis in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, the WHO International Clinical Trials Registry Platform, and www.clinicaltrials.gov for relevant records. We searched all databases from inception to 29 January 2018. We handsearched included articles for additional records and contacted study authors for additional unpublished data. We applied no language restrictions. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) and quasi-RCTs that compared methotrexate versus placebo, or versus another DMARD, for adults with psoriatic arthritis. We reported on the following major outcomes: disease response (measured by psoriatic arthritis response criteria (PsARC)), function (measured by the Health Assessment Questionnaire for Rheumatoid Arthritis (HAQ)), health-related quality of life, disease activity (measured by disease activity score (28 joints) with erythrocyte sedimentation rate (DAS28-ESR)), radiographic progression, serious adverse events, and withdrawals due to adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed search results, assessed risk of bias, extracted trial data, and assessed the quality of evidence using the GRADE approach. We undertook meta-analysis only when this was meaningful. MAIN RESULTS: We included in this review eight RCTs conducted in an outpatient setting, in Italy, the United Kingdom, the United States of America, China, Russia, and Bangladesh. Five studies compared methotrexate versus placebo, and four studies compared methotrexate versus other DMARDs. The average age of participants varied across studies (26 to 52 years), as did the average duration of psoriatic arthritis (one to nine years). Doses of methotrexate varied from 7.5 mg to 25 mg orally per week, but most studies administered approximately 15 mg or less orally per week. Risk of bias was generally unclear or high across most domains for all studies. We considered only one study to have low risk of selection and detection bias. The main study informing results of the primary comparison (methotrexate vs placebo up to six months) was at low risk of bias for all domains except attrition bias and reporting bias.We restricted reporting of results to the comparison of methotrexate versus placebo for up to six months. Low-quality evidence (downgraded due to bias and imprecision) from a single study (221 participants; methotrexate dose 15 mg orally or less per week) informed results for disease response, function, and disease activity. Disease response, measured by the proportion who responded to treatment according to PsARC (response indicates improvement), was 41/109 in the methotrexate group and 24/112 in the placebo group (risk ratio (RR) 1.76, 95% confidence interval (CI) 1.14 to 2.70). This equates to an absolute difference of 16% more responders with methotrexate (4% more to 28% more), and a number needed to treat for an additional beneficial outcome (NNTB) of 6 (95% CI 5 to 25). Mean function, measured by the HAQ (scale 0 to 3; 0 meaning no functional impairment; minimum clinically important difference 0.22), was 1.0 points with placebo and 0.3 points better (95% 0.51 better to 0.09 better) with methotrexate; absolute improvement was 10% (3% better to 17% better), and relative improvement 30% (9% better to 51% better). Mean disease activity as measured by the DAS28-ESR (scale of 0 to 10; lower score means lower disease activity; minimum clinically important difference unknown) was 3.8 points in the methotrexate group and 4.06 points in the placebo group; mean difference was -0.26 points (95% CI -0.65 to 0.13); absolute improvement was 3% (7% better to 1% worse), and relative improvement 6% (16% better to 3% worse).Low-quality evidence (downgraded due to risk of bias and imprecision) from three studies (n = 293) informed our results for serious adverse events and withdrawals due to adverse events. Due to low event rates, we are uncertain if methotrexate results show increased risk of serious adverse events or withdrawals due to adverse events compared to placebo. Results show 1/141 serious adverse events in the methotrexate group and 4/152 in the placebo group: RR 0.26 (95% CI 0.03 to 2.26); absolute difference was 2% fewer events with methotrexate (5% fewer to 1% more). In all, 9/141 withdrawals in the methotrexate group were due to adverse events and 7/152 in the placebo group: RR 1.32 (95% CI 0.51 to 3.42); absolute difference was 1% more withdrawals (4% fewer to 6% more).One study measured health-related quality of life but did not report these results. No study measured radiographic progression. AUTHORS' CONCLUSIONS: Low-quality evidence suggests that low-dose (15 mg or less) oral methotrexate might be slightly more effective than placebo when taken for six months; however we are uncertain if it is more harmful. Effects of methotrexate on health-related quality of life, radiographic progression, enthesitis, dactylitis, and fatigue; its benefits beyond six months; and effects of higher-dose methotrexate have not been measured or reported in a randomised placebo-controlled trial.