Positive and negative controls in rheumatology research.

Observational research from large population databases may be affected by unmeasured confounding and time-related biases, such as immortal time bias. Modern causal inference practice applies propensity score-based methods, new-user designs, and other strategies to mitigate bias. The degree to which these methodologic approaches adequately address bias for any particular study may be difficult to measure. Recently, the incorporation of positive and negative controls has been identified as a means to assess for the impacts of residual confounding and/or time-related biases. The objective of this commentary is to describe the role of positive and negative controls in observational research. We offer recommendations for incorporating controls into critical appraisal and observational research projects.

The State of Patient-Reported Outcome Measures in Rheumatology.

OBJECTIVE: We sought to evaluate the quality and timeliness of patient-reported outcome (PRO) measure reporting, which have not been previously studied. METHODS: Clinical trials that informed new US Food and Drug Administration (FDA) approvals for the first rheumatological indication between 1995 and 2021 were identified. Data were recorded to determine whether collected PROs were published, met minimum clinically important difference (MCID) or statistical significance (P < 0.05) thresholds, and were consistent with Consolidated Standards of Reporting Trials (CONSORT)-PRO standards. Hazard ratios and Kaplan-Meier estimate were used to assess the time from FDA approval to PRO publication. RESULTS: Thirty-one FDA approvals corresponded with 110 pivotal trials and 262 reported PROs. Of the 90 included studies, 1 (1.1%) met all 5 recommended items, 10 (11.1%) met 4 items, 17 (18.9%) met 3 items, 21 (23.3%) met 2 items, 26 (28.9%) met 1 item, and 15 (16.7%) met none of the reporting standards. Most PROs met MCID thresholds (149/262; 56.9%) and were statistically significant (223/262; 85.1%). Of our subset analysis, one-third of PROs were not published upfront (70/212; 33%) and 1 of 9 (22/212; 10.4%) remained unpublished ≥ 4 years after initial trial reporting. Publication rates were highest for the Health Assessment Questionnaire-Disability Index (97.4%) and lowest for the 36-item Short Form Health Survey (81.8%). Less than half of these published PROs met MCID and statistical significance thresholds (94/212; 44.3%). CONCLUSION: One in 9 PROs remained unpublished for ≥ 4 years after initial trial reporting, and compliance with CONSORT-PRO reporting guidelines was poor. Efforts should be made to ensure PROs are adequately reported and expeditiously published.

Recommendations for early referral of individuals with suspected polymyalgia rheumatica: an initiative from the international giant cell arteritis and polymyalgia rheumatica study group.

OBJECTIVE: To develop international consensus-based recommendations for early referral of individuals with suspected polymyalgia rheumatica (PMR). METHODS: A task force including 29 rheumatologists/internists, 4 general practitioners, 4 patients and a healthcare professional emerged from the international giant cell arteritis and PMR study group. The task force supplied clinical questions, subsequently transformed into Population, Intervention, Comparator, Outcome format. A systematic literature review was conducted followed by online meetings to formulate and vote on final recommendations. Levels of evidence (LOE) (1-5 scale) and agreement (LOA) (0-10 scale) were evaluated. RESULTS: Two overarching principles and five recommendations were developed. LOE was 4-5 and LOA ranged between 8.5 and 9.7. The recommendations suggest that (1) each individual with suspected or recently diagnosed PMR should be considered for specialist evaluation, (2) before referring an individual with suspected PMR to specialist care, a thorough history and clinical examination should be performed and preferably complemented with urgent basic laboratory investigations, (3) individuals with suspected PMR with severe symptoms should be referred for specialist evaluation using rapid access strategies, (4) in individuals with suspected PMR who are referred via rapid access, the commencement of glucocorticoid therapy should be deferred until after specialist evaluation and (5) individuals diagnosed with PMR in specialist care with a good initial response to glucocorticoids and a low risk of glucocorticoid related adverse events can be managed in primary care. CONCLUSIONS: These are the first international recommendations for referral of individuals with suspected PMR, which complement the European Alliance of Associations for Rheumatology/American College of Rheumatology management guidelines for established PMR.

Twenty-five years of novel drug approvals in rheumatology.

The field of rheumatology has experienced dozens of novel drug approvals in the past two and a half decades, but the regulatory mechanisms underpinning these decisions are not well understood. In the USA, the Food and Drug Administration (FDA) evaluates the safety and efficacy of novel drugs through the New Drug Application (NDA) process. When additional content expertise is required to evaluate scientific or technical matters, the FDA may convene Human Drug Advisory Committees. To better understand the landscape of rheumatology NDAs and the FDA use of advisory committees, we performed a review of all rheumatic disease drug applications from 1996 to 2021 that were granted approval by the FDA. Our review identified 31 NDAs, seven of which utilized an advisory committee. The indications for using advisory committees and their influence on ultimate approvals was not clear. Recommendations to improve transparency and increase public trust in FDA decisions are provided.

Unpublished clinical trials of common rheumatic diseases.

OBJECTIVES: Randomized controlled trials (RCTs) provide high-quality evidence for treatment efficacy, but many RCTs remain unpublished. The objective of this study was to describe the proportion of unpublished RCTs in five rheumatic diseases and to identify factors associated with publication. METHODS: Registered RCTs for five rheumatic diseases (SLE, vasculitis, spondyloarthritis, SS and PsA) with over 30 months since study completion were identified using ClinicalTrials.gov. Index publications were identified by NCT ID numbers and structured text searches of publication databases. The results of unpublished studies were identified in abstracts and press releases; reasons for non-publication were assessed by surveying corresponding authors. RESULTS: Out of 203 studies that met eligibility criteria, 17.2% remained unpublished, representing data from 4281 trial participants. Higher proportions of published trials were phase 3 RCTs (57.1% vs 28.6% unpublished, P < 0.05) or had a positive primary outcome measure (64.9% vs 25.7% unpublished, P < 0.001). In a multivariable Cox proportional hazards model, a positive outcome was independently associated with publication (hazard ratio 1.55; 95% CI: 1.09, 2.22). Corresponding authors of 10 unpublished trials cited ongoing preparation of the manuscript (50.0%), sponsor/funder issues (40.0%) and unimportant/negative result (20.0%) as reasons for lack of publication. CONCLUSIONS: Nearly one in five RCTs in rheumatology remain unpublished 2 years after trial completion, and publication is associated with positive primary outcome measures. Efforts to encourage universal publication of rheumatology RCTs and reanalysis of previously unpublished trials should be undertaken.

Baseline factors associated with self-reported disease flares following COVID-19 vaccination among adults with systemic rheumatic disease: results from the COVID-19 global rheumatology alliance vaccine survey.

OBJECTIVE: To examine the frequency of, and risk factors for, disease flare following COVID-19 vaccination in patients with systemic rheumatic disease (SRD). METHODS: An international study was conducted from 2 April to 16 August 2021, using an online survey of 5619 adults with SRD for adverse events following COVID-19 vaccination, including flares of disease requiring a change in treatment. We examined risk factors identified a priori based on published associations with SRD activity and SARS-CoV-2 severity, including demographics, SRD type, comorbidities, vaccine type, cessation of immunosuppressive medications around vaccination and history of reactions to non-COVID-19 vaccines, using multivariable logistic regression. RESULTS: Flares requiring a change in treatment following COVID-19 vaccination were reported by 4.9% of patients. Compared with rheumatoid arthritis, certain SRD, including systemic lupus erythematosus (OR 1.51, 95% CI 1.03, 2.20), psoriatic arthritis (OR 1.95, 95% CI 1.20, 3.18) and polymyalgia rheumatica (OR 1.94, 95% CI 1.08, 2.48) were associated with higher odds of flare, while idiopathic inflammatory myopathies were associated with lower odds for flare (OR 0.54, 95% CI 0.31-0.96). The Oxford-AstraZeneca vaccine was associated with higher odds of flare relative to the Pfizer-BioNTech vaccine (OR 1.44, 95% CI 1.07, 1.95), as were a prior reaction to a non-COVID-19 vaccine (OR 2.50, 95% CI 1.76, 3.54) and female sex (OR 2.71, 95% CI 1.55, 4.72). CONCLUSION: SRD flares requiring changes in treatment following COVID-19 vaccination were uncommon in this large international study. Several potential risk factors, as well as differences by disease type, warrant further examination in prospective cohorts.

Tracking clinical resources for coronavirus disease 2019.

PURPOSE OF REVIEW: Assimilating and disseminating information during the novel coronavirus disease 2019 (COVID-19) has been challenging. The purpose of this review is to identify specific threats to the validity of the COVID-19 literature and to recommend resources for practicing rheumatologists and their patients. RECENT FINDINGS: The COVID-19 literature has rapidly expanded and includes 17 998 publications through May of 2020, 1543 of which also address rheumatic disease-related topics. Specific obstacles to acquiring high-quality information have arisen, including 'pandemic research exceptionalism' and a 'parallel pandemic' of misinformation. Unique challenges to rheumatologists include specific interest in antirheumatic disease therapies and a paucity of rheumatology-specific information. Patients with rheumatic diseases have faced shortages of critical medications and a lack of information tailored to their health conditions and medications. SUMMARY: We recommend rheumatologists develop a system to acquire high-quality information and offer guiding principles for triaging specific resources, which include relevance, accessibility, credibility, timeliness, and trustworthiness. The same principles can be applied to selecting patient oriented resources. Specific trustworthy resources are recommended.

Quality of Life and Recommendations for Further Care.

OBJECTIVES: Physician recommendations for further medical treatment or palliative treatment only at the end of life may influence patient decisions. Little is known about the patient characteristics that affect physician-assessed quality of life or how such assessments are related to subsequent recommendations. DESIGN, SETTING, AND SUBJECTS: A 2010 mailed survey of practicing U.S. physicians (1,156/1,878 or 62% of eligible physicians responded). MEASUREMENTS AND MAIN RESULTS: Measures included an end of life vignette with five experimentally varied patient characteristics: setting, alimentation, pain, cognition, and communication. Physicians rated vignette patient quality of life on a scale from 0 to 100 and indicated whether they would recommend continuing full medical treatment or palliative treatment only. Cognitive deficits and alimentation had the greatest impacts on recommendations for further care, but pain and communication were also significant (all p < 0.001). Physicians who recommended continuing full medical treatment rated quality of life three times higher than those recommending palliative treatment only (40.41 vs 12.19; p < 0.01). Religious physicians were more likely to assess quality of life higher and to recommend full medical treatment. CONCLUSIONS: Physician judgments about quality of life are highly correlated with recommendations for further care. Patients and family members might consider these biases when negotiating medical decisions.

Directive counsel and morally controversial medical decision-making: findings from two national surveys of primary care physicians.

BACKGROUND: Because of the potential to unduly influence patients' decisions, some ethicists counsel physicians to be nondirective when negotiating morally controversial medical decisions. OBJECTIVE: To determine whether primary care providers (PCPs) are less likely to endorse directive counsel for morally controversial medical decisions than for typical ones and to identify predictors of endorsing directive counsel in such situations. DESIGN AND PARTICIPANTS: Surveys were mailed to two separate national samples of practicing primary care physicians. Survey 1 was conducted from 2009 to 2010 on 1,504 PCPs; Survey 2 was conducted from 2010 to 2011 on 1,058 PCPs. MAIN MEASURES: Survey 1: After randomization, half of the PCPs were asked if physicians should encourage patients to make the decision that the physician believes is best (directive counsel) with respect to "typical" medical decisions and half were asked the same question with respect to "morally controversial" medical decisions. Survey 2: After reading a vignette in which a patient asked for palliative sedation to unconsciousness, PCPs were asked whether it would be appropriate for the patient's physician to encourage the patient to make the decision the physician believes is best. KEY RESULTS: Of 1,427 eligible physicians, 896 responded to Survey 1 (63 %). Physicians asked about morally controversial decisions were half as likely (35 % vs. 65 % for typical decisions, p < 0.001) to endorse directive counsel. Of 986 eligible physicians, 600 responded to Survey 2 (61 %). Two in five physicians (41 %) endorsed directive counsel after reading a vignette describing a patient requesting palliative sedation to unconsciousness; these physicians tended to be male and more religious. CONCLUSIONS: PCPs are less likely to endorse directive counsel when negotiating morally controversial medical decisions. Male physicians and those who are more religious are more likely to endorse directive counsel in these situations.