Exploring the effect on primary endpoints in trials testing targeted therapy interventions for rheumatoid arthritis: a meta-epidemiological study on the appropriate use of a core outcome set.

OBJECTIVES: To explore which core domain is best associated with the American College of Rheumatology (ACR) 20% response in trials assessing the effect of targeted interventions in rheumatoid arthritis (RA). METHODS: A meta-epidemiological study was performed on randomised trials investigating biologics and targeted agents compared with placebo or conventional disease-modifying antirheumatic drugs in patients with RA. The main outcome measures were ORs for the ACR 20% response and at least one of the eight core domains according to the existing RA core outcome set (COS) analysed based on standardised mean differences. RESULTS: 115 trials involving 55 422 patients with RA were eligible. The OR for achieving ACR 20% response was 3.19 (95% CI 2.96 to 3.44) for the experimental interventions relative to the comparators. The median number of COS domains reported was 6; 18 trials reported only 1 domain, 17 all 8. Univariable meta-regression analyses indicated that each of the eight core domains was significantly associated with ACR 20% response, yet improvements in physical disability explain a successful ACR 20% response the most. Including only trials reporting on all eight core domains, univariable meta-regression analyses proved improvement in fatigue to explain a successful ACR 20% response the most. CONCLUSIONS: Within this dataset, it is evident that the conclusions concerning our primary objective were significantly influenced by both the amount and characteristics of missing data. Our data suggest that fatigue could be more important for the primary endpoint than previously assumed, but this is based on limited data.

Long-term efficacy of a 2-year MRI treat-to-target strategy on disease activity and radiographic progression in patients with rheumatoid arthritis in clinical remission: 5-year follow-up of the IMAGINE-RA randomised trial.

OBJECTIVE: To investigate whether a 2-year MRI treat-to-target strategy targeting the absence of osteitis combined with clinical remission, compared with a conventional treat-to-target strategy targeting clinical remission only (IMAGINE-rheumatoid arthritis (RA) trial) improves clinical and radiographic outcomes over 5 years in patients with RA in clinical remission. METHODS: IMAGINE-more was an observational extension study of the original 2-year IMAGINE-RA randomised trial (NCT01656278). Clinical examinations and radiographs (hands and feet) were obtained yearly. Prespecified coprimary outcomes at year 5 were Disease Activity Score in 28 joints C reactive protein (DAS28-CRP) remission rate (DAS28-CRP<2.6) and no radiographic progression (van der Heijde-modified Sharp score (vdHSS) ≤0) from baseline. Secondary outcomes included 5-year changes in radiographic, MRI and clinical measures of disease activity and physical function. RESULTS: In total 131 patients, 86 women (67%), mean age 61.2, disease duration 9.5 years, median baseline DAS28-CRP 1.9 (IQR 1.6-2.2) and vdHSS 16.0 (IQR 7.0-36.0) were included in the study; 59 (59%) patients from the original MRI treat-to-target group and 72 (72%) from the conventional group. At year 5, 47 patients (80%) in the MRI treat-to-target group vs 54 patients (75%) in the conventional treat-to-target group were in DAS28-CRP remission (OR 2.00 (95% CI 0.76 to 5.28); p=0.16) while 14 patients (24%) vs 19 patients (26%) had no radiographic progression (OR 0.70, (95% CI 0.28 to 1.71); p=0.43). CONCLUSION: A 2-year combined MRI and clinical treat-to-target strategy, compared with a conventional clinical treat-to-target strategy alone, had no effect on the long-term probability of achieving DAS28-CRP remission and of avoiding radiographic progression.

Navigating the path of progress: The OMERACT 2023 emerging leaders program.

OBJECTIVES: The Outcome Measures in Rheumatology Clinical Trials (OMERACT) Emerging Leaders Program (ELP) aims to cultivate a cohort of skilled leaders within the OMERACT community empowering them with expertise and knowledge to help shape and steer the organization into the future. This publication highlights the significance of the ELP in driving leadership excellence, its impact on OMERACT's evolution, and the outcomes and learnings from the OMERACT 2023 ELP. METHODS: Insights from the 2018 ELP report informed 2023 program improvements. Engagement was measured by attendance and WhatsApp interactions. Positive program aspects, areas for improvement and ideas for enhancing future ELPs were captured via anonymous survey and participant focus groups. RESULTS: Engagement with the ELP was high with 9 participants, 96 % attendance at all workshops, 154 WhatsApp interactions. All program components were highly rated, with the highest being the 'Psychological Safety' and 'Methodology/Process/Politics' workshops. Future enhancements included creating further networking, connection and support activities, practical leadership and methodological skill development opportunities, and a new stream focussing on organisational advancement. CONCLUSIONS: The 2023 OMERACT ELP was well received and successfully addressed areas previously identified as requiring improvement. New educational enhancements were valued, and the importance of fostering psychological safety at all levels was highlighted. The ELP fortifies OMERACT by nurturing a diverse array of skilled leaders who embody OMERACTs core values. Continuing to refine and evolve the ELP over time will help OMERACT sustain its global influence in patient-centered outcome research.

Strategies to promote implementation of core outcomes for medication adherence trials in rheumatology: A report from the OMERACT-Adherence Group.

OBJECTIVES: To identify barriers, facilitators, and strategies for future implementation of the OMERACT-Adherence Core Outcome Set (COS) in medication adherence trials for rheumatic conditions. METHODS: Preliminary Delphi survey findings were discussed at OMERACT 2023, utilising the Consolidated Framework for Implementation Research 2 to identify implementation barriers, facilitators, and solutions. RESULTS: Implementation strategies included simplifying the COS definitions, making it adaptabile for clinical practice and drug trials, adherence trial training workshops, and collaborating with key stakeholders such as payers and other COS developers. CONCLUSION: Ongoing collaboration with individuals and organisations within and beyond rheumatology ensures broader applicability of OMERACT-Adherence COS.

OMERACT Core outcome measurement set for shared decision making in rheumatic and musculoskeletal conditions: a scoping review to identify candidate instruments.

OBJECTIVES: Shared decision making (SDM) is a central tenet in rheumatic and musculoskeletal care. The lack of standardization regarding SDM instruments and outcomes in clinical trials threatens the comparative effectiveness of interventions. The Outcome Measures in Rheumatology (OMERACT) SDM Working Group is developing a Core Outcome Set for trials of SDM interventions in rheumatology and musculoskeletal health. The working group reached consensus on a Core Outcome Domain Set in 2020. The next step is to develop a Core Outcome Measurement Set through the OMERACT Filter 2.2. METHODS: We conducted a scoping review (PRISMA-ScR) to identify candidate instruments for the OMERACT Filter 2.2 We systematically reviewed five databases (Ovid MEDLINE®, Embase, Cochrane Library, CINAHL and Web of Science). An information specialist designed search strategies to identify all measurement instruments used in SDM studies in adults or children living with rheumatic or musculoskeletal diseases or their important others. Paired reviewers independently screened titles, abstracts, and full text articles. We extracted characteristics of all candidate instruments (e.g., measured construct, measurement properties). We classified candidate instruments and summarized evidence gaps with an adapted version of the Summary of Measurement Properties (SOMP) table. RESULTS: We found 14,464 citations, read 239 full text articles, and included 99 eligible studies. We identified 220 potential candidate instruments. The five most used measurement instruments were the Decisional Conflict Scale (traditional and low literacy versions) (n=38), the Hip/Knee-Decision Quality Instrument (n=20), the Decision Regret Scale (n=9), the Preparation for Decision Making Scale (n=8), and the CollaboRATE (n=8). Only 44 candidate instruments (20%) had any measurement properties reported by the included studies. Of these instruments, only 57% matched with at least one of the 7-criteria adapted SOMP table. CONCLUSION: We identified 220 candidate instruments used in the SDM literature amongst people with rheumatic and musculoskeletal diseases. Our classification of instruments showed evidence gaps and inconsistent reporting of measurement properties. The next steps for the OMERACT SDM Working Group are to match candidate instruments with Core Domains, assess feasibility and review validation studies of measurement instruments in rheumatic diseases or other conditions. Development and validation of new instruments may be required for some Core Domains.

Generating a list of potentially important contextual factors covering randomized trials, cohorts, and measurement property studies: An OMERACT initiative.

OBJECTIVES: To generate candidates for contextual factors (CFs) for each CF type (i.e., Effect Modifying Contextual Factors (EM-CFs), Outcome Influencing Contextual Factors (OI-CFs), and Measurement Affecting Contextual Factors (MA-CFs)) considered important within rheumatology. METHODS: We surveyed OMERACT working groups and conducted a Special Interest Group (SIG) session at the OMERACT 2023 meeting, where the results were reviewed, and additional CFs suggested. RESULTS: The working groups suggested 44, 49, and 21 generic EM-CFs, OI-CFs, and MA-CFs, respectively. SIG participants added 49, 44, and 55 factors, respectively. CONCLUSION: Candidate CFs were identified, next step is a consensus-based set of endorsed (important) CFs.

Minor tranquillizers for short-term treatment of newly onset symptoms of anxiety and distress: a systematic review with network meta-analysis of randomized trials.

Unspecific symptoms of anxiety and distress are frequently encountered in patients in both general practice and acute psychiatric services. Minor tranquillizers may be a treatment option when non-pharmacological interventions are insufficient or unavailable. We conducted a systematic review with network meta-analysis of the evidence for short-term (1-4 weeks) pharmacological treatment of newly onset symptoms of anxiety and distress. We searched the PsycInfo, MEDLINE, EMBASE and Cochrane Library databases and extracted data following a predefined hierarchy of outcomes. We assessed risk of bias using the Cochrane Risk of Bias tool and the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation framework (GRADE). We included 34 randomized trials comprising a total of 7044 patients with adjustment disorders or anxiety spectrum disorders. The network meta-analysis showed that regarding the critical outcome symptoms of anxiety within 1-4 weeks benzodiazepines (SMD - 0.58, 95% CI - 0.77 to - 0.40), quetiapine (SMD - 0.51, 95% CI - 0.90 to - 0.13) and pregabalin (SMD - 0.58, 95% CI - 0.87 to - 0.28) all performed better than placebo with no statistically significant difference between the drugs. Data on other important outcomes were inconsistently reported. Adverse effects varied, but overall, it was uncertain whether adverse effects differed between interventions. The evidence regarding the risk of dependence was uncertain, but dependence may be a concern in susceptible individuals even with short-term treatment. Overall, the certainty of the evidence according to GRADE was rated as low to very low across outcomes. Despite the limitations in the evidence, the results of this review can inform treatment guidelines, supporting clinicians in the choice of minor tranquillizer in this prevalent and help-seeking, clinically heterogeneous population.

Do psychotic experiences act as effect modifiers in youths with common mental health problems allocated to transdiagnostic cognitive behavioural therapy versus management as usual? Secondary analyses of the Mind-My-Mind randomized trial.

BACKGROUND: Psychotic experiences (PEs) are common in help-seeking youths with non-psychotic mental health problems, yet the clinical importance of PEs as potential effect modifiers of psychotherapy interventions has been scarcely examined. We examined if PEs were associated with a differential response to transdiagnostic cognitive behavioural therapy (CBT) aimed at common emotional and behavioural problems. METHODS: We present secondary analyses from the Mind My Mind (MMM) trial that randomized 396, 6-16-year-old youths to either 9-13 sessions of transdiagnostic modular community-based CBT (MMM) or community-based management as usual (MAU). MMM was superior to MAU in reducing parent-reported impact of mental health problems according to the Strengths and Difficulties Questionnaire (SDQ). PEs were assessed by semi-structured screening interviews at baseline. The contrast between subgroups (presence/absence of PEs) was calculated to test if PEs are potential effect modifiers regarding the change in parent-reported SDQ-impact (primary outcome, rated 0[low]-10[high]) and other SDQ-related outcomes. RESULTS: Baseline PEs were present in 74 (19%) of youths. The superior effect of MMM on changes in SDQ-impact from baseline to week 18 was not effect modified by the presence of PEs (PEs[yes] -0.89 [95%CI -1.77;-0.01] vs. PEs[no] -1.10 [95%CI -1.52;-0.68], p-value for interaction .68). For secondary outcomes similar patterns were observed. Limitations Statistical power was limited to show if PEs modified treatment response. Replication and meta-analytic evidence are needed. CONCLUSIONS: The beneficial effects of MMM transdiagnostic CBT did not differ by PE-status, indicating that youths with emotional and behavioural problems could be offered such psychotherapy irrespective of co-occurring PEs.

Dose-response association between animal protein sources and risk of gestational diabetes mellitus: a systematic review and meta-analysis.

CONTEXT: There are contradictory findings about the relationship between various animal protein sources and the risk of gestational diabetes mellitus (GDM). OBJECTIVE: The purpose of our study was to understand better the associations between total protein, animal protein, and animal protein sources and the risk of developing GDM. DATA SOURCES: A systematic literature search was conducted in PubMed, Scopus, and Web of Science encompassing the literature up until August 2022. A random-effects model was used to combine the data. For estimating the dose-response curves, a one-stage linear mixed-effects meta-analysis was conducted. DATA EXTRACTION: Data related to the association between animal protein consumption and the risk of GDM in the general population was extracted from prospective cohort studies. DATA ANALYSIS: It was determined that 17 prospective cohort studies with a total of 49 120 participants met the eligibility criteria. It was concluded with high certainty of evidence that there was a significant association between dietary animal protein intake and GDM risk (1.94, 95% CI 1.42 to 2.65, n = 6). Moreover, a higher intake of total protein, total meat, and red meat was positively and significantly associated with an increased risk of GDM. The pooled relative risks of GDM were 1.50 (95% CI: 1.16, 1.94; n = 3) for a 30 g/d increment in processed meat, 1.68 (95% CI: 1.25, 2.24; n = 2) and 1.94 (95% CI: 1.41, 2.67; n = 4) for a 100 g/d increment in total and red meat, and 1.21 (95% CI: 1.10, 1.33; n = 4) and 1.32 (95% CI: 1.15, 1.52; n = 3) for a 5% increment in total protein and animal protein, respectively. GDM had a positive linear association with total protein, animal protein, total meat consumption, and red meat consumption, based on non-linear dose-response analysis. CONCLUSION: Overall, consuming more animal protein-rich foods can increase the risk of GDM. The results from the current study need to be validated by other, well-designed prospective studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42022352303.

Comparative effectiveness of pharmacological interventions for hand osteoarthritis: a systematic review and network meta-analysis of randomised trials.

OBJECTIVE: To explore the comparative effectiveness of pharmacological interventions for hand osteoarthritis (OA). METHODS: We systematically searched Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials from inception until 26 December 2021, for randomised trials of pharmacological interventions for people with hand OA. Two reviewers independently extracted study data and assessed the risk of bias. We calculated the effect sizes for pain (standardised mean differences) using Bayesian random effects models for network meta-analysis (NMA) and pairwise meta-analysis. Based on a pre-specified protocol, we prospectively registered the study at PROSPERO, CRD42021215393. RESULTS: We included 72 trials with 7609 participants. 65 trials (n=5957) were eligible for the quantitative synthesis, investigating 29 pharmacological interventions. Oral non-steroidal anti-inflammatory drugs (NSAIDs) and oral glucocorticoids' NMA effect sizes were -0.18 (95% credible interval -0.36 to 0.02) and -0.54 (-0.83 to -0.24), respectively, compared with placebo, and the result was consistent when limiting evidence to the pairwise meta-analysis of trials without high risk of bias. Intra-articular hyaluronate, intra-articular glucocorticoids, hydroxychloroquine, and topical NSAIDs' NMA effect sizes were 0.22 (-0.08 to 0.51), 0.25 (0.00 to 0.51), -0.01 (-0.19 to 0.18), and -0.14 (-0.33 to 0.08), respectively, compared with placebo. Oral NSAIDs were inferior to oral glucocorticoids with an NMA effect size of 0.36 (0.01 to 0.72). No intervention was superior to placebo when stratifying for thumb and finger OA. CONCLUSION: Oral NSAIDs and glucocorticoids are apparently effective pharmacological interventions in hand OA. Intra-articular therapies and topical NSAIDs were not superior to placebo.

Effect modification of an effective transdiagnostic cognitive behavioral psychotherapy in youths with common mental health problems: Secondary analyses of the randomized mind-my-mind trial.

Mind My Mind (MMM) cognitive behavioral therapy (CBT) manualized treatment is effective in the management of common emotional and behavioral mental health problems in youth, yet not all individuals respond satisfactorily to treatment. This study explored potential effect modifiers, i.e., baseline factors associated with a differential treatment effect. We conducted secondary effect modifier analyses with MMM trial data, which involved randomization of 396 youths aged 6-16 years to either MMM CBT treatment (9-13 sessions) or management as usual in local community settings. We examined sociodemographic- (sex, age, family composition, ethnicity, parental education, and income) and clinical variables (mental disorders and duration of mental health problems) as potential effect modifiers of the a) change in parent-rated impact of mental health problems measured by the Strengths and Difficulties Questionnaire (SDQ) or b) response (reduction of ≥1 on SDQ-impact). In intention-to-treat analyses, superior treatment (net) benefits from the MMM intervention were found among youths who met criteria for any mental disorder at baseline (-1.25 [95%CI: -1.67;-0.82]) compared to youths that did not meet diagnostic criteria (-0.22 [95%CI:-1.09;0.65]). Comorbidity vs no comorbidity (-1.84 [95%CI:-2.58;-1.10] vs -0.72 [95%CI:-1.15;-0.29]) and longer duration of untreated mental health problems, i.e., more vs less than 6 months (-1.16 [95%CI:-1.55;-0.78] vs 0.43 [95%CI:-1.01;1.86]) were also associated with superior treatment benefits. The sociodemographic factors were not associated with differential treatment effects in the intention-to-treat analyses. These findings suggest that community-based programs like the MMM are well-suited for youths with substantial mental health problems. Clinical Trials Identifier: NCT03535805.

Fracture risk reduction and safety by osteoporosis treatment compared with placebo or active comparator in postmenopausal women: systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials.

OBJECTIVE: To review the comparative effectiveness of osteoporosis treatments, including the bone anabolic agents, abaloparatide and romosozumab, on reducing the risk of fractures in postmenopausal women, and to characterise the effect of antiosteoporosis drug treatments on the risk of fractures according to baseline risk factors. DESIGN: Systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials. DATA SOURCES: Medline, Embase, and Cochrane Library to identify randomised controlled trials published between 1 January 1996 and 24 November 2021 that examined the effect of bisphosphonates, denosumab, selective oestrogen receptor modulators, parathyroid hormone receptor agonists, and romosozumab compared with placebo or active comparator. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials that included non-Asian postmenopausal women with no restriction on age, when interventions looked at bone quality in a broad perspective. The primary outcome was clinical fractures. Secondary outcomes were vertebral, non-vertebral, hip, and major osteoporotic fractures, all cause mortality, adverse events, and serious cardiovascular adverse events. RESULTS: The results were based on 69 trials (>80 000 patients). For clinical fractures, synthesis of the results showed a protective effect of bisphosphonates, parathyroid hormone receptor agonists, and romosozumab compared with placebo. Compared with parathyroid hormone receptor agonists, bisphosphonates were less effective in reducing clinical fractures (odds ratio 1.49, 95% confidence interval 1.12 to 2.00). Compared with parathyroid hormone receptor agonists and romosozumab, denosumab was less effective in reducing clinical fractures (odds ratio 1.85, 1.18 to 2.92 for denosumab v parathyroid hormone receptor agonists and 1.56, 1.02 to 2.39 for denosumab v romosozumab). An effect of all treatments on vertebral fractures compared with placebo was found. In the active treatment comparisons, denosumab, parathyroid hormone receptor agonists, and romosozumab were more effective than oral bisphosphonates in preventing vertebral fractures. The effect of all treatments was unaffected by baseline risk indicators, except for antiresorptive treatments that showed a greater reduction of clinical fractures compared with placebo with increasing mean age (number of studies=17; ß=0.98, 95% confidence interval 0.96 to 0.99). No harm outcomes were seen. The certainty in the effect estimates was moderate to low for all individual outcomes, mainly because of limitations in reporting, nominally indicating a serious risk of bias and imprecision. CONCLUSIONS: The evidence indicated a benefit of a range of treatments for osteoporosis in postmenopausal women for clinical and vertebral fractures. Bone anabolic treatments were more effective than bisphosphonates in the prevention of clinical and vertebral fractures, irrespective of baseline risk indicators. Hence this analysis provided no clinical evidence for restricting the use of anabolic treatment to patients with a very high risk of fractures. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019128391.

Effect of probiotic supplementation on chemotherapy- and radiotherapy-related diarrhoea in patients with cancer: an umbrella review of systematic reviews and meta-analyses.

To date, several systematic reviews and meta-analyses (SRMA) have investigated the effects of probiotics, but the certainty of the evidence for an effect on chemotherapy and radiotherapy-related diarrhoea has not been assessed. We conducted an overview of SRMA, searching MEDLINE, Scopus, and ISI Web of Science from inception up to February 2022. We summarised the findings of eligible SRMA. Subsequently, we included randomised clinical trials (RCT) from the SRMA in meta-analyses, using a quality effects model to calculate the OR and 95 % CI for each outcome. We used 'A Measurement Tool to Assess Systematic Reviews' and the Cochrane risk of bias tool to assess the methodological quality of the SRMA and their RCT, respectively. We used the 'Grading of Recommendations Assessment, Development, and Evaluation'.We included thirteen SRMA, which reported pooled effect sizes for chemotherapy and radiotherapy-related diarrhoea based on a total of eighteen RCT. Our meta-analyses demonstrated statistically significant beneficial effects from probiotics on all outcomes, except stool consistency; diarrhoea (any grade) OR 0·35 (95 % CI 0·22, 0·54), grade ≥ 2 diarrhoea 0·43 (0·25, 0·74), grade ≥ 3 diarrhoea 0·30 (0·15, 0·59), use of medication 0·49 (0·27, 0·88), soft stool 1·10 (0·44, 2·76) and watery stool 0·52 (0·29, 1·29). Probiotics use can reduce the incidence of diarrhoea in cancer patients in chemotherapy and radiotherapy, but the certainty of evidence for significant outcomes was very low and low.

Early vs delayed enteral nutrition or parenteral nutrition in hospitalized patients: An umbrella review of systematic reviews and meta-analyses of randomized trials.

We conducted an umbrella review to summarize the existing evidence on the effect of early enteral nutrition (EEN) compared with other approaches, including delayed enteral nutrition (DEN), parenteral nutrition (PN), and oral feeding (OF) on clinical outcomes in hospitalized patients. We performed a systematic search up to December 2021, in MEDLINE (via PubMed), Scopus, and Institute for Scientific Information Web of Science. We included systematic reviews with meta-analyses (SRMAs) of randomized trials investigating EEN compared with DEN, PN, or OF for any clinical outcomes in hospitalized patients. We used "A Measurement Tool to Assess Systematic Reviews" (AMSTAR2) and the Cochrane risk-of-bias tool for assessing the methodological quality of the systematic reviews and their included trial, respectively. The certainty of the evidence was rated using the "Grading of Recommendations Assessment, Development, and Evaluation" (GRADE) approach. We included 45 eligible SRMAs contributing with a total of 103 randomized controlled trials. The overall meta-analyses showed that patients who received EEN had statistically significant beneficial effects on most outcomes compared with any control (ie, DEN, PN, or OF), including mortality, sepsis, overall complications, infection complications, multiorgan failure, anastomotic leakage, length of hospital stay, time to flatus, and serum albumin levels. No statistically significant beneficial effects were found for risk of pneumonia, noninfectious complications, vomiting, wound infection, as well as number of days of ventilation, intensive care unit days, serum protein, and pre-serum albumin levels. Our results indicate that EEN may be preferred over DEN, PN, and OF because of the beneficial effects on many clinical outcomes.

Colchicine twice a day for hand osteoarthritis (COLOR): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Colchicine has been suggested for osteoarthritis treatment, but evidence is contradictory. We aimed to investigate colchicine's efficacy and safety compared with placebo in people with hand osteoarthritis. METHODS: In this single-centre, double-blind, randomised, placebo-controlled trial we recruited adults with symptomatic hand osteoarthritis and finger pain of at least 40 mm on a 100 mm visual analogue scale from an outpatient clinic in Denmark. The hand with the most severe finger pain at inclusion was the target hand. Participants were randomly assigned (1:1) to 0·5 mg colchicine or placebo taken orally twice a day for 12 weeks, stratified by BMI (≥30 kg/m2), sex, and age (≥75 years). Participants, outcome assessors, and data analysts were masked to treatment allocation. The primary endpoint was change from baseline to week 12 in target hand finger pain, assessed on a 100 mm visual analogue scale with a pre-specified minimal clinically important difference of 15 mm, in the intention-to-treat population. Safety was assessed at week 12 in the intention-to-treat population. The study was registered with ClinicalTrials.gov, NCT04601883, and with EudraCT, 2020-002803-20. FINDINGS: Between Jan 15, 2021, and March 3, 2022, 186 people were screened for eligibility, and 100 were randomly assigned to receive colchicine (n=50) or placebo (n=50). Participants had a mean age of 70·9 (SD 7·5) years, 69 (69%) of 100 were women and 31 (31%) were men. All participants completed the study. The mean change from baseline to week 12 in finger pain were -13·9 mm (SE 2·8) in the colchicine group and -13·5 mm (2·8) in the placebo group, with a between-group difference (colchicine vs placebo) of -0·4 mm (95% CI -7·6 to 6·7; p=0·90). In the colchicine group, there were 76 adverse events in 36 (72%) of 50 participants and one serious adverse advent (migraine attack leading to hospital admission). In the placebo group, there were 42 adverse events in 22 (44%) of 50 participants and two serious adverse events (cholecystitis and elevated alanine aminotransferase concentrations, in the same patient). INTERPRETATION: In people with painful hand osteoarthritis, treatment with 0·5 mg of colchicine twice day for 12 weeks did not effectively relieve pain, and treatment with colchicine was associated with more adverse events. FUNDING: The Oak Foundation, IMK Almene Fond, Minister Erna Hamilton's Scholarship for Science and Art, AP Moller and Wife Chastine McKinney Moller's Foundation for Medical Science Advancement, The Danish Medical Association, the Velux Foundation, Aase and Ejnar Danielsen's Foundation, and Director Emil C Hertz and Wife Inger Hertz's foundation.

Effect modification by contextual factors of urate-lowering therapy on serum urate in people with gout: A systematic review with meta-regression analysis.

OBJECTIVE: To synthesize evidence of the effect of contextual factors (CFs) on efficacy of urate-lowering therapy (ULT) on serum urate (SU) as outcome in gout patients. METHODS: Randomised controlled trials (RCTs) from (updated) Cochrane reviews were the starting point. RCTs were included if they explored the role of any CF on efficacy of ULT on SU in gout patients. For CFs with sufficient data (i.e. ≥3 trials), a mixed-effects meta-regression analysis was performed with trial and comparison as random effects, whereas specific CFs were modelled as fixed factors. RESULTS: Eight RCTs were included. Effect modification by CFs was explored for age, sex, race, renal function, cardiovascular comorbidity, tophi, thiazide-diuretic use, and previous ULT use. Crude data stratified by renal function were available for four trials (36 randomised comparisons), and suitable for meta-analysis. Pooled estimates revealed that gout patients with a normal, mildly-, or moderately impaired renal function were consistently more likely to achieve SU target with ULT compared to control. Among RCTs comparing ULT to placebo (30 comparisons), effects of ULT on achieving SU target were not statistically different for those with normal (OR:66.87;[11.39-392.75]) compared to mildly (OR:28.54;[5.11-159.46]) and moderately (OR:21.45;[3.20-143.64]) impaired renal function, but seemed lower in those with severely impaired (OR:9.13;[0.96-86.97]) renal function. Data were insufficient to draw conclusions on effect modification by other CFs. CONCLUSION: Few RCTs report stratified analyses exploring the role of CFs. ULT seemed effective in reaching the SU target in all levels of renal function, though severely impaired renal function appeared to render a slight disadvantage.

Serum urate as a proposed surrogate outcome measure in gout trials: From the OMERACT working group.

Serum urate (SU) is the most common primary efficacy outcome in trials of urate-lowering therapies for gout. Despite this, it is not formally considered a validated surrogate outcome. In this paper we will outline the definitions of biomarkers and surrogate outcome measures, respectively as well as the available frameworks and challenges in the assessment of the validity of serum urate as a surrogate in gout (i.e. a reasonable replacement for gout symptoms).

Risk of harm in synthetic and biological intervention trials in patients with inflammatory arthritis: protocol for a metaepidemiological study focusing on contextual factors.

INTRODUCTION: Inflammatory arthritis (IA) conditions, including rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis, are characterised by inflammatory infiltration of the joints. Biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), respectively, reduce the effects of proinflammatory cytokines and immune cells to ameliorate disease. However, immunosuppression can be associated with high rates of serious adverse events (SAEs), including serious infections, and maybe an increased risk of malignancies and cardiovascular events. Currently, there is no empirical evidence on the extent to which contextual factors and risk of bias (RoB) domains may modify these harm signals in randomised trials. METHODS AND ANALYSIS: We will search MEDLINE (via PubMed) for systematic reviews published since April 2015 and all Cochrane reviews. From these reviews, randomised trials will be eligible if they include patients with an IA condition with at least one group randomly allocated to bDMARD and/or tsDMARD treatments. A predefined form will be used for extracting data on population characteristics (eg, baseline characteristics or eligibility criteria, such as medication background) and specific harm outcome measures, such as number of withdrawals, numbers of patients discontinuing due to adverse events and number of patients having SAEs. RoB in individual trials will be assessed using a modified Cochrane RoB tool. We will estimate the potentially causal harm effects related to the experimental intervention compared with control comparator as risk ratios, and heterogeneity across randomised comparisons will be assessed statistically and evaluated as inconsistency using the I2 Index. Our metaregression analyses will designate population and trial characteristics and each RoB domain as independent variables, whereas the three harm domains will serve as dependent variables. ETHICS AND DISSEMINATION: Ethics approval is not required for this study. Results will be disseminated through publication in international peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42020171124.

A systematic review and meta-analysis of observational studies on the association between animal protein sources and risk of rheumatoid arthritis.

OBJECTIVE: The aim of this study was to investigate the linear and nonlinear dose-response associations of animal-based dietary protein intake and risk of developing rheumatoid arthritis (RA). METHODS: A systematic search of MEDLINE, Scopus and Embase was conducted up to October 2020. Observational studies that report risk estimates of RA for animal-based protein consumption were included. We calculated pooled relative risks (RRs) by using a random-effects model. Linear and non-linear dose-response analyses were performed to examine the dose-response relations between animal-based protein consumption and RA. RESULTS: Seven cohort studies (n = 457,554) with 3545 incident cases and six case-control studies with 3994 cases and 5252 controls were identified. Highest compared with the lowest category of fish consumption was inversely associated with risk of RA (RR: 0.89; 95% CI, 0.80 to 0.99; I2 = 0%, n = 10). Also, a 100 g/day increment in fish intake was associated with a 15% decreased risk of RA. Dose-response analysis showed a modest U-shaped association between fish consumption and incidence of RA, with the lowest risk at a fish intake of 20-30 g/day (Pnon-linearity = 0.04). We found no significant association between consumption of red meat, poultry or dairy and the risk of RA. CONCLUSION: The present study revealed a significant reverse association between fish consumption and risk of RA. While we observed no association between red meat, dairy or poultry consumption and risk of RA. Further well-designed prospective studies are needed to support our findings.