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Of our subset analysis, one-third of PROs were not published upfront (70/212; 33%) and 1 of 9 (22/212; 10.4%) remained unpublished ≥ 4 years after initial trial reporting.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 CONCLUSION: One in 9 PROs remained unpublished for ≥ 4 years after initial trial reporting, and compliance with CONSORT-PRO reporting guidelines was poor.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.

Impact of Glucocorticoid Dose on Complete Response, Serious Infections, and Mortality During the Initial Therapy of Lupus Nephritis: A Systematic Review and Meta-Analysis of the Control Arms of Randomized Controlled Trials.

OBJECTIVE: Our objective was to evaluate the effect of glucocorticoid regimens on renal response, infections, and mortality among patients with lupus nephritis (LN). METHODS: We performed a systematic review and meta-analysis of the control arms of randomized clinical trials (RCTs). We included RCTs of biopsy-proven LN that used a protocolized regimen of glucocorticoids in combination with mycophenolic acid analogs or cyclophosphamide and reported the outcomes of complete response (CR), serious infections, and death. The starting dosage of glucocorticoids, tapering method, and administration of glucocorticoid pulses were abstracted. Meta-analysis of proportions, meta-regression, and subgroup meta-analysis were performed at 6 and 12 months for all outcomes. RESULTS: Fifty RCT arms (3,231 patients with LN) were included. The predicted rates of CR, serious infections, and death when starting on oral prednisone at 25 mg/day without pulses were 19.5% (95% confidence interval [CI] 7.3-31.5), 3.2% (95% CI 2.4-4.0), and 0.2% (95% CI 0.0-0.4), respectively. Starting on prednisone at 60 mg/day (without pulses) increased the rates to 34.6% (95% CI 16.9-52.3), 12.1% (95% CI 9.3-14.9), and 2.7% (95% CI 0.0-5.3), respectively. Adding glucocorticoid pulses increased the rates of CR and death but not serious infections. We observed a dose-response gradient between the initial glucocorticoid dosage and all the outcomes at six months after accounting for the administration of glucocorticoid pulses, underlying immunosuppressant, and baseline proteinuria. CONCLUSION: A higher exposure to glucocorticoids during the initial therapy of LN was associated with better renal outcomes at the cost of increased infections and death.

Fragility of randomised controlled trials for systemic lupus erythematosus and lupus nephritis therapies.

OBJECTIVE: We aimed to evaluate the robustness of phase III randomised controlled trials (RCTs) for SLE and lupus nephritis (LN) using the fragility index (FI), the reverse FI (RFI) and the fragility quotient (FQ). METHODS: We searched for phase III RCTs that included patients with active SLE or LN. Data on primary endpoints, total participants and the number of events for each arm were obtained. We calculated the FI score for RCTs with statistically significant results (number of patients required to change from event to non-event to make the study lose statistical significance), the RFI for RCTs without statistically significant results (number of patients required to change from non-event to event to make study gain statistical significance) and the FQ score for both (FI or RFI score divided by the sample size). RESULTS: We evaluated 20 RCTs (16 SLE, four LN). The mean FI/RFI score was 13.6 (SD 6.6). There were nine RCTs with statistically significant results (seven SLE, two LN), and the mean FI score was 10.2 (SD 6.2). The lowest FI was for the ILLUMINATE-2 trial (FI=2), and the highest FI was for the BLISS-52 trial (FI=17).Twelve studies had non-statistically significant results (10 SLE, two LN) with a mean RFI score of 15.6 (SD 6.1). The lowest RFI was for the ILLUMINATE-1 trial (RFI=4), and the highest RFI was for the TULIP-1 trial (RFI=27). The lowest FQ scores were found in the ILLUMINATE trials and the highest in the Rituximab trials (EXPLORER and LUNAR), meaning that the last ones were the most robust results after accounting for sample size. CONCLUSIONS: The evidence of therapies for patients with SLE and LN is derived mostly from fragile RCTs. Clinicians and trialists must be aware of the fragility of these RCTs for clinical decision-making and designing trials for novel therapeutics.

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.