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Objective: To examine the association between study characteristics and the harms reported in randomised controlled trials (RCTs) on biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients with inflammatory arthritis (IA)., Methods: We searched MEDLINE for all Cochrane reviews and for systematic reviews published since April 2015. RCTs were eligible if they included patients with IA receiving b/tsDMARD, compared with any comparator arm. Harms were evaluated based on number of withdrawals due to adverse events (WDdtAEs), total withdrawals (WDs), serious adverse events (SAEs) and deaths. Data were extracted for 48 trial/patient characteristics and meta-regression analyses were performed to relate the relative risk ratio (RRR) of harms to the trial characteristics., Results: A total of 284 trials (from 245 reviews) with 97 607 patients were included, contributing 490 comparisons for the primary analysis. Overall, the relative risk of WDdtAEs was lower when trials used active comparators (RRR, 0.74 (95% CI 0.58 to 0.94)) and higher when requiring raised inflammatory markers at enrolment (RRR, 1.25 (1.01 to 1.55)). Our meta-regression analyses suggested that trials with eligibility criteria for minimum tender/swollen joint count and maximum disease duration decreased the risk of WDs, while previous b/tsDMARDs use at the time of enrolment increased the risk of SAEs., Conclusions: Most study characteristics do not affect the reported harm measures. However, a trend was observed where trials selecting patients with higher baseline disease activity found a higher risk ratio of WDdtAEs and SAEs, but also a lower risk of WDs, compared with trials not selecting patients with a high disease activity., Prospero Registration Number: CRD42020171124., Competing Interests: Competing interests: All authors have completed the ICMJE (International Committee of Medical Journal Editors) uniform disclosure form www.icmje.org/disclosure-of-interest/ and declare they received no financial support from any industry for the submitted work. However, DEF has received Grants and/or research support from Amgen, Corbus, CSL Behring, Galapagos, Gilead, GSK, Horizon, Kadmon, Novartis, Pfizer, Roche/Genetech, Talaris; Consulting fees from Amgen, Corbus, Galapagos, Horizon, Kadmon, Pfizer, Talaris and payment or honoraria from CME. JSS has received institution grants or contracts from Abbvie, Astra-Zeneca, Eli Lilly and Company, Galapagos; Consultant fees from AbbVie, Amgen, Ananda, Astro, BMS, Celltrion, Chugai, Eli Lilly and Company, Gilead, Immunovant, MSD, Novartis, Pfizer, Roche, R-Pharma, Samsung, Sanofi, UCB; Payment or honoraria from Eli Lilly, UCB, Chugai, Sandoz. PCT has received institution grants or contracts from Galapagos; Consulting fees from AbbVie, Biogen, Galapagos, Gilead Sciences, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Inc, UCB, Eli Lilly, Fresenius, Acelyrin; Payment or honoraria from AbbVie; support for attending meetings and/or travel from Lilly; Participation on a Data Safety Monitoring Board or Advisory Board for Sanofi, Kymab, Immunovant. LEK has received consultant fees and payment or honoraria from AbbVie, Amgen, Biogen, BMS, Eli Lilly, Gilead, Janssen pharmaceuticals, MSD, Novartis, Pfizer, and UCB Pharma; has stock options in Novartis, Merck, Eli Lilly, Novo Nordisk, UCB and is employed at Leo Pharmaceutical from 1 June 2024. RC has received consulting fees from Image Analysis, trading as IAG, Image Analysis Group (UK) and Compass Communications; Payment or honoraria from Osteoarthritis and Cartilage, Acta Orthopaedica and Frontiers in Drug Safety and Regulation; A Leading member of OMERACT (Outcome Measures in Rheumatology), a member of the GRADE Working Group and editor for Cochrane Collaboration., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objective: To examine the pain relief effects of comparators (placebos and untreated control groups) in hand osteoarthritis trials and the impact of contextual factors., Methods: We systematically searched PubMed, EMBASE and CENTRAL from inception to December 26, 2021. We included randomised controlled trials of people with hand osteoarthritis with a placebo or an untreated control group. We assessed the Risk of Bias with Cochrane Risk-of-Bias tool version 2. Each comparator was contrasted with a null-arm, imputed as having a zero change from baseline with the same standard deviation as the comparator. We combined the standardised mean differences with a random effects meta-analysis. The contextual factors' effect was explored in meta-regression and stratified models with pain as the dependent variable., Results: 84 trials (7262 participants) were eligible for quantitative synthesis, of which 76 (6462 participants) were eligible for the stratified analyses. Placebos were superior to their matched null-arms in relieving pain with an effect size of -0.51 (95% confidence interval -0.61 to -0.42), while untreated control groups were not. When analysing all comparators, blinded trial designs and low risk of bias were associated with higher pain relief compared to an open-label trial design and some concern or high risk of bias., Conclusion: The placebo response on pain for people with hand osteoarthritis was increased by appropriate blinding and a lower risk of bias assessment. Placebos were superior to a null-arm, while untreated control groups were not. Results emphasise the importance of using appropriate comparators in clinical trials., Prospero Registration Id: CRD42022298984., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., (© 2023. The Author(s).)

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., Competing Interests: Competing interests: This study had no competing financial interests. Interests disclosed in the International Committee of Medical Journal Editors (ICMJE) conflict of interest forms are as follows: LKS has received grants from the Health Research Council of New Zealand, royalties/licenses from UpToDate and consulting fees from Pharmac NZ. AD has received grants for the research project disclosed as funding. IKH has received consulting fees from Novartis and GSK and is a member of the OARSI executive committee. MK has received grants from IMI APPROACH and the Dutch Arthritis Society, royalties/licences from Wolters Kluwer and Springer Verlag, and consulting fees from Abbvie, Pfizer, Kiniksa Flexion, Galapagos, CHDR, Novartis and UCB, and she is a member of the OARSI board, the EULAR council and President of the Dutch Society for Rheumatology., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Melatonin has become a widely used sleeping aid for young individuals currently not included in existing guidelines. The aim was to develop a recommendation on the use of melatonin in children and adolescents aged 2-20 years, with chronic insomnia due to disorders beyond indication., Methods: We performed a systematic search for guidelines, systematic reviews, and randomised trials (RCTs) in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A separate search for adverse events was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 17, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (2-20 years of age) with chronic insomnia due to underlying disorders, in whom sleep hygiene practices have been inadequate and melatonin was tested. Studies exclusively on autism spectrum disorders or attention deficit hyperactive disorder were excluded. There were no restrictions on dosage, duration of treatment, time of consumption or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events, assessed at 2-4 weeks post-treatment. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, non-serious adverse events, and all-cause dropouts (assessed at 2-4 weeks post-treatment), plus quality of sleep and daytime functioning (assessed at 3-6 months post-treatment). Pooled estimates were calculated using inverse variance random effects model. Statistical heterogeneity was calculated using I 2 statistics. Risk of bias was assessed using Cochrane risk of bias tool. Publication bias was assessed using funnel plots. A multidisciplinary guideline panel constructed the recommendation using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was used to discuss the feasibility and acceptance of the constructed recommendation and its impact on resources and equity. The protocol is registered with the Danish Health Authority., Findings: We identified 13 RCTs, including 403 patients with a wide range of conditions. Melatonin reduced sleep latency by 14.88 min (95% CI 23.42-6.34, 9 studies, I 2  = 60%) and increased total sleep time by 18.97 min (95% CI 0.37-37.57, 10 studies, I 2  = 57%). The funnel plot for total sleep time showed no apparent indication of publication bias. No other clinical benefits were found. The number of patients experiencing adverse events was not statistically increased however, safety data was scarce. Certainty of evidence was low., Interpretation: Low certainty evidence supports a moderate effect of melatonin in treating sleep continuity parameters in children and adolescents with chronic insomnia due to primarily medical disorders beyond indication. The off-label use of melatonin for these patients should never be the first choice of treatment, but may be considered by medical specialists with knowledge of the underlying disorder and if non-pharmacological interventions are inadequate. If treatment with melatonin is initiated, adequate follow-up to evaluate treatment effect and adverse events is essential., Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation., Competing Interests: LB is a member of the Danish medication Reimbursement Committee. AV has previously received honoraria for lectures at AGB pharma, Takeda & Medice and holds stocks at Novo Nordisk. All other authors declare no competing interests. Statements of conflicts of interests can be found for all members of the guideline panel, the external reviewer of the national clinical guideline, the reference–and project group at the Danish Health Authority website (www.sst.dk)., (© 2023 The Authors.)

Background: Currently, melatonin is used to treat children and adolescents with insomnia without knowing the full extent of the short-term and long-term consequences. Our aim was to provide clinicians and guideline panels with a systematic assessment of serious-and non-serious adverse events seen in continuation of melatonin treatment and the impact on pubertal development and bone health following long-term administration in children and adolescents with chronic insomnia., Methods: We searched PubMed, Embase, Cinahl and PsycINFO via Ovid, up to March 17, 2023, for studies on melatonin treatment among children and adolescents (aged 5-20 years) with chronic insomnia. The language was restricted to English, Danish, Norwegian, and Swedish. Outcomes were non-serious adverse events and serious adverse events assessed 2-4 weeks after initiating treatment and pubertal development and bone health, with no restriction on definition or time of measurement. Observational studies were included for the assessment of long-term outcomes, and serious and non-serious adverse events were assessed via randomised studies. The certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The protocol is registered with the Danish Health Authority., Findings: We identified 22 randomised studies with 1350 patients reporting on serious-and non-serious adverse events and four observational studies with a total of 105 patients reporting on pubertal development. Melatonin was not associated with serious adverse events, yet the number of patients experiencing non-serious adverse events was increased (Relative risk 1.56, 95% CI 1.01-2.43, 17 studies, I 2  = 47%). Three studies reported little or no influence on pubertal development following 2-4 years of treatment, whereas one study registered a potential delay following longer treatment durations (>7 years). These findings need further evaluation due to several methodological limitations., Interpretation: Children who use melatonin are likely to experience non-serious adverse events, yet the actual extent to which melatonin leads to non-serious adverse events and the long-term consequences remain uncertain. This major gap of knowledge on safety calls for caution against complacent use of melatonin in children and adolescents with chronic insomnia and for more research to inform clinicians and guideline panels on this key issue., Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation., Competing Interests: LB is a member of the Danish medication reimbursement committee. AV has previously received honoraria for lectures at AGB pharma, Takeda & Medice, and holds stocks at Novo Nordisk. All other authors declare no competing interests. Statements of conflicts of interests can be found for all members of the guideline panel, the external reviewer of the national clinical guideline, the reference–and project group at the Danish Health Authority website (www.sst.dk)., (© 2023 The Authors.)

Background: Melatonin prescriptions for children and adolescents have increased substantially during the last decade. Existing clinical recommendations focus on melatonin as a treatment for insomnia related to neurodevelopmental disorders. To help guide clinical decision-making, we aimed to construct a recommendation on the use of melatonin in children and adolescents aged 5-20 years with idiopathic chronic insomnia., Methods: A systematic search for guidelines, systematic reviews and randomised controlled trials (RCT) were performed in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A search for adverse events in otherwise healthy children and adolescents was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 18, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (5-20 years of age) with idiopathic chronic insomnia, in whom sleep hygiene practices have been inadequate and melatonin was tested. There were no restrictions on dosage, duration of treatment, time of consumption, or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, all-cause dropouts, and non-serious adverse events. Outcomes were assessed at different time points to assess short-term and long-term effects. Meta-analysis was performed using inverse variance random-effects model and risk of bias was assessed using Cochrane risk of bias tool. If possible, funnel plots would be constructed to investigate publication bias. Heterogeneity was calculated via I 2 statistics. A multidisciplinary guideline panel formulated the recommendation according to Grading of Recommendations Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was subsequently used to discuss the feasibility and acceptance of the constructed recommendation alongside the impact on resources and equity. The protocol is registered with the Danish Health Authority., Findings: We included eight RCTs with 419 children and adolescents with idiopathic chronic insomnia. Melatonin led to a moderate increase in total sleep time by 30.33 min (95% confidence interval (CI) 18.96-41.70, 4 studies, I 2  = 0%) and a moderate reduction in sleep latency by 18.03 min (95% CI -26.61 to -9.44, 3 studies, I 2  = 0%), both as assessed by sleep diary. No other beneficial effects were found. None of the studies provided information on serious adverse events, yet the number of participants experiencing non-serious adverse events was increased (Relative risk 3.44, 95% CI 1.25-9.42, 4 studies, I 2  = 0%). Funnel plots were not constructed due to the low number of studies. The certainty of evidence was very low on the quality of sleep and low for daytime functioning., Interpretation: Evidence of very low certainty shows that benefits are limited and unwanted events are likely when melatonin is used to treat otherwise healthy children and adolescents with chronic insomnia. Melatonin should never be the first choice of treatment for this particular population, yet carefully monitored short-term use may be considered if sleep hygiene practices and non-pharmacological interventions have proven inadequate, and only if daytime function is compromised., Funding: The Danish Health Authority and the Parker Institute, Bispebjerg and Frederiksberg Hospital supported by the Oak Foundation., Competing Interests: LB is a member of the Danish medication reimbursement committee. AV has previously received honoraria for lectures at AGB pharma, Takeda & Medice and holds stocks at Novo Nordisk. All other authors declare no competing interests. Statements of conflicts of interests can be found for all members of the guideline panel, the external reviewer of the national clinical guideline, the reference–and project group at the Danish Health Authority website (www.sst.dk)., (© 2023 The Authors.)

Background and Purpose: Hip precautions are routinely prescribed to patients with osteoarthritis to decrease dislocation rates after total hip arthroplasty (THA) using a posterior approach. However, recommendations have been based on very low certainty of evidence. We updated the evidence on the influence of hip precautions on early recovery following THA by this systematic review., Materials and Methods: We performed systematic searches for randomized controlled trials (RCT) and non-randomized (NRS) studies in MEDLINE, Embase, PEDro, and CINAHL published from 2016 to July 2022. 2 reviewers independently included studies comparing postoperative precautions with minimal or no precautions, extracted data, and assessed the risk of bias. Random effects meta-analyses were used to synthesize the results. The certainty of the evidence was rated by the Grading of Recommendations Assessment and Evaluation approach. The critical outcome was the risk of hip dislocations within 3 months of surgery. Other outcomes were long-term risk of dislocation and reoperation, self-reported and performance-based assessment of function, quality of life, pain, and time to return to work., Results: 4 RCTs and 5 NRSs, including 8,835 participants, were included. There may be no or negligible difference in early hip dislocations (RCTs: risk ratio [RR] 1.8, 95% confidence interval [CI] 0.6-5.2; NRS: RR 0.9, CI 0.3-2.5). Certainty in the evidence was low for RCTs and very low for NRSs. Finally, precautions may reduce the performance-based assessment of function slightly, but the evidence was very uncertain. For all other outcomes, no differences were found (moderate to very low certainty evidence)., Conclusion: The current evidence does not support routinely prescribing hip precautions post-surgically for patients undergoing THA to prevent hip dislocations. However, the results might change with high-quality studies.

Objective: To assess the benefits and harms associated with biopsychosocial rehabilitation in patients with inflammatory arthritis and osteoarthritis (OA)., Methods: We performed a systematic review and meta-analysis. Data were collected through electronic searches of Cochrane CENTRAL, MEDLINE, Embase, PsycInfo, and CINAHL databases up to March 2019. Trials examining the effect of biopsychosocial rehabilitation in adults with inflammatory arthritis and/or OA were considered eligible, excluding rehabilitation adjunct to surgery. The primary outcome for benefit was pain and total withdrawals for harm., Results: Of the 27 trials meeting the eligibility criteria, 22 trials (3,750 participants) reported sufficient data to be included in the quantitative synthesis. For patient-reported outcome measures, biopsychosocial rehabilitation was slightly superior to control for pain relief (standardized mean difference [SMD] -0.19 [95% confidence interval (95% CI) -0.31, -0.07]), had a small effect on patient global assessment score (SMD -0.13 [95% CI -0.26, -0.00]), with no apparent effect on health-related quality of life, fatigue, self-reported disability/physical function, mental well-being, and reduction in pain intensity ≥30%. Clinician-measured outcomes displayed a small effect on observed disability/physical function (SMD -0.34 [95% CI -0.57, -0.10]), a large effect on physician global assessment score (SMD -0.72 [95% CI -1.18, -0.26]), and no effect on inflammation. No difference in harms existed in terms of the number of withdrawals, adverse events, or serious adverse events., Conclusion: Biopsychosocial rehabilitation produces a significant but clinically small beneficial effect on patient-reported pain among patients with inflammatory arthritis and OA, with no difference in harm. Methodologic weaknesses were observed in the included trials, suggesting low-to-moderate confidence in the estimates of effect., (© 2021 American College of Rheumatology.)

Objective: To gauge the evidence of periodontal therapy's impact on measures of disease activity and systemic inflammatory burden in individuals with rheumatoid arthritis (RA)., Methods: A search for randomized trials and controlled cohort studies of RA patients with periodontitis was conducted on April 7, 2019, with an update on December 17, 2020 in PubMed, Cochrane Library (CENTRAL), Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trial Registry Platform portal. Two reviewers screened titles and abstracts and selected papers for full-text review. We used Outcome Measures in Rheumatology (OMERACT)-endorsed outcome domains for RA trials and summarized continuous outcomes using standardized mean differences (SMDs) with 95% confidence intervals (95% CIs). We evaluated inconsistency using the I 2 statistic and combined SMDs using random-effects models for the meta-analyses; fixed-effect meta-analyses were used for sensitivity analysis. To explore heterogeneity, we added stratified/meta-regression analyses, expressed in T 2 ., Results: Of the 1,909 studies identified, 9 (including 10 comparisons) were eligible for quantitative synthesis (n = 388). Evidence suggested a favorable effect of periodontal treatment on disease activity (SMD -0.88 [95% CI -1.38, -0.38]; n = 311). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to judge the estimates' certainty; evidence rated as having low or very low certainty indicated that any possible effect of periodontal treatment in RA is likely to change as more evidence is provided. Selection bias and RA medication stability were highlighted as sources of heterogeneity between studies., Conclusion: There is an urgent need for a well-designed prospective cohort study (preferably a randomized controlled trial) of patients with RA and periodontitis using rigorous protocols, standardized diagnostic criteria, data collection, and adequate duration of follow-up., (© 2021 American College of Rheumatology.)

Objective: Antipsychotic-related prolactin changes may expose children and adolescents to severe adverse reactions (ARs) related to pubertal development and growth. We therefore aimed to assess the effects of antipsychotics on prolactin levels and associated somatic ARs in children and adolescents. Methods: We systematically searched PubMed and CENTRAL for placebo-controlled randomized trials of antipsychotics in children and adolescents aged ≤18 years, reporting prolactin levels and related ARs. We conducted a random-effect meta-analysis and assessed risk of bias version 2 (ROB2). Results: Thirty-two randomized controlled trials with an average trial duration of 6 weeks, covering 4643 participants with an average age of 13 years and a male majority of 65.3%. Risk of bias across domains was low or unclear. The following antipsychotic compounds: aripiprazole ( n  = 810), asenapine ( n  = 506), lurasidone ( n  = 314), olanzapine ( n  = 179), paliperidone ( n  = 149), quetiapine ( n  = 381), risperidone ( n  = 609), and ziprasidone ( n  = 16) were compared with placebo ( n  = 1658). Compared with placebo, statistically significant higher prolactin increase occurred with risperidone (mean difference [MD] = 28.24 ng/mL), paliperidone (20.98 ng/mL), and olanzapine (11.34 ng/mL). Aripiprazole significantly decreased prolactin (MD = -4.91 ng/mL), whereas quetiapine, lurasidone, and asenapine were not associated with significantly different prolactin levels than placebo. Our results on ziprasidone are based on a single study, making it insufficient to draw strong conclusions. On average, 20.8% of patients treated with antipsychotic developed levels of prolactin that were too high (hyperprolactinemia), whereas only 1.03% of patients reported prolactin-related ARs. Data were highly limited for long-term effects. Conclusions: In children and adolescents, risperidone, paliperidone, and olanzapine are associated with significant prolactin increase, whereas aripiprazole is associated with significant decrease. Despite the significant changes in prolactin level, few ARs were reported. Study protocol on PROSPERO: CRD42018116451.

The Danish Health Authority develops clinical practice guidelines to support clinical decision-making based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system and prioritizes using Cochrane reviews. The objective of this study was to explore the usefulness of Cochrane reviews as a source of evidence in the development of clinical recommendations. Evidence-based recommendations in guidelines published by the Danish Health Authority between 2014 and 2021 were reviewed. For each recommendation, it was noted if and how Cochrane reviews were utilized. In total, 374 evidence-based recommendations and 211 expert consensus recommendations were published between 2014 and 2021. Of the 374 evidence-based recommendations, 106 included evidence from Cochrane reviews. In 28 recommendations, all critical and important outcomes included evidence from Cochrane reviews. In 36 recommendations, a minimum of all critical outcomes included evidence from Cochrane reviews, but not all important outcomes. In 33 recommendations, some but not all critical outcomes included evidence from Cochrane reviews. Finally, in nine recommendations, some of the important outcomes included evidence from Cochrane reviews. In almost one-third of the evidence-based recommendations, Cochrane reviews were used to inform clinical recommendations. This evaluation should inform future evaluations of Cochrane review uptake in clinical practice guidelines concerning outcomes important for clinical decision-making.

Objective: To study the effects of supervised training in adults with subacromial pain syndrome., Data Sources: Embase, MEDLINE, Cochrane Library, Cumulative Index to Nursing and Allied Health, and Physiotherapy Evidence Database were searched from inception to March 2020., Study Selection: Independent reviewers selected randomized controlled trials comparing supervised training with (1) no training or (2) self-training in adults with subacromial pain syndrome lasting for at least 1 month. Critical outcomes were shoulder pain, function, and patient-perceived effect. Important outcomes included other potential benefits and adverse events at 3-month follow-up., Data Extraction: Two independent reviewers extracted data for the meta-analysis. Risk of bias was assessed using the Cochrane Risk of Bias tool 1, and certainty of evidence was evaluated using the Grades of Recommendation Assessment, Development, and Evaluation (GRADE)., Data Synthesis: Ten studies (n=597, 43% female) were included. Supervised training resulted in larger improvements than no training on pain (at rest: n=286; mean difference [MD], 1.68; 95% confidence interval [CI], 0.31-3.06 on 0-10 scale; during movement: n=353; MD, 1.84; 95% CI,0.91-2.76), function (n=396; standardized MD, 0.30; 95% CI, 0.07-0.52), and patient-perceived effect (n=118; risk ratio, 1.43; 95% CI, 0.87-2.34). Supervised training had potential benefits regarding quality of life, return to work, dropout, and training adherence, albeit more patients reported mild, transient pain after training. Supervised training and self-training showed equal improvements on pain (n=44) and function (n=76), with no data describing patient-perceived effect. Certainty of evidence was low for critical outcomes and low-moderate for other outcomes., Conclusions: Supervised training might be superior to no training and equally effective as self-training on critical and important outcomes. Based on low-moderate certainty of evidence, these findings support a weak recommendation for supervised training in adults with subacromial pain syndrome., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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 I 2 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

There has been a growing interest in the gastrointestinal system and its significance for autism spectrum disorder (ASD), including the significance of adopting a gluten-free and casein-free (GFCF) diet. The objective was to investigate beneficial and safety of a GFCF diet among children with a diagnosis of ASD. We performed a systematic literature search in Medline, Embase, Cinahl, and the Cochrane Library up to January 2020 for existing systematic reviews and individual randomized controlled trials (RCTs). Studies were included if they investigated a GFCF diet compared to a regular diet in children aged 3 to 17 years diagnosed with ASD, with or without comorbidities. The quality of the identified existing reviews was assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR). The risk of bias in RCTs was assessed using the Cochrane Risk of Bias Tool, and overall quality of evidence was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). We identified six relevant RCTs, which included 143 participants. The results from a random effect model showed no effect of a GFCF diet on clinician-reported autism core symptoms (standardized mean difference (SMD) -0.31 (95% Cl. -0.89, 0.27)), parent-reported functional level (mean difference (MD) 0.61 (95% Cl -5.92, 7.14)) or behavioral difficulties (MD 0.80 (95% Cl -6.56, 10.16)). On the contrary, a GFCF diet might trigger gastrointestinal adverse effects (relative risk (RR) 2.33 (95% Cl 0.69, 7.90)). The quality of evidence ranged from low to very low due to serious risk of bias, serious risk of inconsistency, and serious risk of imprecision. Clinical implications of the present findings may be careful consideration of introducing a GFCF diet to children with ASD. However, the limitations of the current literature hinder the possibility of drawing any solid conclusion, and more high-quality RCTs are needed. The protocol is registered at the Danish Health Authority website.

Introduction: Pain assessment in people with dementia is difficult, and withdrawal of analgesics may allow for assessment of treatment efficacy whilst decreasing pill burden, adverse events and interactions. We aimed to describe the use of analgesics among elderly in Denmark and to compile the evidence for withdrawal of analgesics among people with dementia., Methods: With respect to analgesics use, we employed data from national registries on the analgesic prescription use (opioids, nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen) in 2017 among elderly people with and without dementia. Trial evidence was produced by performing a systematic search in MEDLINE, Embase and Cinahl for trials evaluating withdrawal of analgesics in people with dementia., Results: Opioids were prescribed more frequently (p = 0.026) and NSAIDs less frequently (p = 0.026) to people with dementia. With respect to trial evidence, we identified two studies: An observational cross-over study (n = 3) reporting acetaminophen withdrawal leading to increases in pain frequency and duration, and a cluster-randomised clinical trial (n = 352) reporting changes in mobilization-observation-behaviour-intensity-dementia-2 (MOBID-2) pain score during a four-week withdrawal period (acetaminophen, opioids and/or pregabaline) from a mean ± standard deviation of 2.3 ± 2.1 to 2.9 ± 2.6 compared with 3.5 ± 2.6 to 3.5 ± 2.5 in the control group., Conclusions: In Denmark, use of opioids is higher in elderly with dementia compared to elderly without dementia. The evidence suggests that withdrawal of analgesics may aggravate pain but increases in pain scores may be of little clinical relevance in most people. Clinical trials investigating analgesics withdrawal are warranted., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Objectives: To assess the efficacy and safety of methotrexate (MTX) in combination with an approved biological agent compared to biological monotherapy, in the management of patients with rheumatoid arthritis (RA)., Methods: MEDLINE, EMBASE, CENTRAL and other sources were searched for randomised trials evaluating a biological agent plus MTX versus the same biological agent in monotherapy. Co-primary outcomes were ACR50 and the number of patients who discontinued due to adverse events (AEs). Random-effects models were applied for meta-analyses with risk ratio and 95% confidence intervals and the GRADE approach was used to assess confidence in the estimates., Results: The analysis comprised 16 trials (4965 patients), including all biological agents approved for RA except anakinra and certolizumab. The overall likelihood of responding to therapy (i.e. ACR50) after 6 months was 32% better when MTX was given concomitantly with biological agents (1.32 [1.20-1.45]; P < 0.001) corresponding to 11 more out of 100 patients (7-16 more); Moderate Quality Evidence. Discontinuing due to AEs from concomitant use of MTX was potentially 20% increased (1.21 [0.97-1.50]; P = 0.09) compared to biological monotherapy corresponding to 1 more out of 100 patients (0-3 more); Moderate Quality Evidence., Conclusions: Randomised trials provide Moderate Quality Evidence for a favourable benefit-harm balance supporting concomitant use of MTX rather than monotherapy when prescribing a biological agent in patients with RA although in absolute terms only 7-16 more out of 100 patients will achieve an ACR50 response after 6 months of this combination therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: The role of glucocorticoids in the treatment of rheumatoid arthritis (RA) is widely debated. Impairment of bone formation may be counter-balanced by reduced systemic inflammation. This review aims to assess the effect of prednisolone/prednisone on bone mineral density (BMD) in patients with RA analyzed in randomized, controlled trials., Methods: We performed a systematic literature search and identified randomized, double-blinded placebo-controlled studies including patients with RA and using prednisolone or prednisone as the intervention. We selected studies that measured BMD by DXA at baseline and at least once thereafter. Two authors independently performed reference review, data extraction and risk of bias assessment. Primary outcome was mean change in BMD from baseline to follow-up. Secondary endpoints included radiographic scores, RA disease activity indices and fractures. We rated the quality of evidence using the GRADE approach. Outcomes were standardized for meta-analyses and 95% confidence intervals (95% CI) were calculated., Results: We identified 7 studies and included previously unpublished data. Studies were similar regarding study population and intervention. Standard mean difference (SMD) in change in BMD from 0 to 24 months was -0.02 (95%CI -0.16, 0.12) at the lumbar spine and -0.11 (95% CI -0.25, 0.02) at the hip (both high quality evidence) between patients treated with prednisolone/prednisone or not. Data completeness was low in some studies, concomitant treatment of RA differed between studies and differences in use of anti-osteoporotic medication may have influenced the results. However, sensitivity analyses excluding studies in which participants used either the most or the least potent concomitant RA treatment or used anti-osteoporotic therapies did not alter the estimates., Conclusions: In patients with early and active RA, we found no difference in change in BMD between patients treated with prednisone/prednisolone versus placebo, suggesting that at least through 24 months, the suppression of inflammation by glucocorticoids may counterbalance their adverse effects on bone remodeling., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To assess the importance of trial characteristics as contextual factors when evaluating the treatment effect of targeted therapies for patients with psoriatic disease., Methods: We identified randomized controlled trials (RCTs) evaluating targeted therapies approved for psoriatic arthritis (PsA) and psoriasis (8 biologics and apremilast). The effect of targeted therapies was analyzed in the 2 psoriatic conditions combined by using drug retention as a common outcome, and separately by using the American College of Rheumatology 20% improvement criteria (ACR20) for PsA and the Psoriasis Area Severity Index 75% improvement score (PASI75) for psoriasis. We explored potential effect modification of trial characteristics in stratified and meta-regression analyses. Odds ratios (ORs) were calculated and compared among the trial eligibility criteria via the ratio of ORs., Results: Forty-eight PsA and psoriasis trials (51 comparisons; 17,737 patients) were eligible. Overall retention was OR 2.16 (95% confidence interval [95% CI] 1.70-2.75) with higher odds for PsA trials compared with psoriasis trials (ratio of ORs 2.55 [95% CI 1.64-3.97]). The eligibility criteria "targeted therapy history," "minimum required disease duration," "required negative rheumatoid factor," and "required Classification Criteria for Psoriatic Arthritis criteria" were of importance for achieving ACR20 in PsA. The eligibility criterion "minimum required disease duration" was of importance for achieving PASI75 in psoriasis. A total of 7 PsA trials had rescue before time-point-of-retention reporting (adaptive trials)., Conclusion: From this exploratory meta-epidemiologic study, we now have evidence from RCTs to support the notion that patients with PsA are more likely to adhere to targeted therapies compared to patients with psoriasis. Furthermore, we identified a few contextual factors of importance in regard to achieving ACR20 in PsA trials and PASI75 in psoriasis trials., (© 2017, American College of Rheumatology.)

Objective: The objective of this population-based cohort study was to investigate the impact of comorbidities on disease activity, treatment response, and persistence with the first-tried tumor necrosis factor inhibitor (TNFi) in patients with psoriatic arthritis (PsA)., Methods: Data on patient characteristics, disease activity, and treatment response and persistence were obtained from the DANBIO registry. Information on comorbidities according to the Charlson Comorbidity Index (CCI) was obtained through linkage with the Danish National Patient Register. Kaplan-Meier plots and Cox proportional hazard regression analyses were performed. Percentages of patients achieving relevant clinical responses were calculated., Results: We identified 1,750 patients eligible for analyses. Patients with higher CCI scores had higher disease activity measures at baseline and increased occurrence of depression and/or anxiety. Kaplan-Meier curves showed shorter persistence with treatment for patients with a CCI score ≥2 (log-rank P < 0.001) and for patients with depression and/or anxiety (P = 0.027) compared to patients without comorbidities. In multivariate analysis, a CCI score ≥2 was associated with reduced TNFi persistence compared with patients without comorbidities (hazard ratio 1.72 [95% confidence interval 1.26-2.37]; P = 0.001). A smaller proportion of patients with a CCI score ≥2 achieved European League Against Rheumatism (EULAR) good response (P < 0.001) and EULAR good-or-moderate response (P < 0.001) at 6 months compared with patients without comorbidities., Conclusion: The presence of comorbidities was associated with higher baseline disease activity, shorter TNFi persistence, and reduced clinical response rates in a cohort of Danish patients with PsA., (© 2017, American College of Rheumatology.)

Purpose: To summarise recommendations about 20 non-surgical interventions for recent onset (<12 weeks) non-specific low back pain (LBP) and lumbar radiculopathy (LR) based on two guidelines from the Danish Health Authority., Methods: Two multidisciplinary working groups formulated recommendations based on the GRADE approach., Results: Sixteen recommendations were based on evidence, and four on consensus. Management of LBP and LR should include information about prognosis, warning signs, and advise to remain active. If treatment is needed, the guidelines suggest using patient education, different types of supervised exercise, and manual therapy. The guidelines recommend against acupuncture, routine use of imaging, targeted treatment, extraforaminal glucocorticoid injection, paracetamol, NSAIDs, and opioids., Conclusion: Recommendations are based on low to moderate quality evidence or on consensus, but are well aligned with recommendations from international guidelines. The guideline working groups recommend that research efforts in relation to all aspects of management of LBP and LR be intensified.

Importance: Nalmefene is a newly approved drug for alcohol use disorder, but the risk of harms has not been evaluated from empirical trial evidence., Objective: To assess the harm of nalmefene administered to individuals diagnosed with substance use or impulse control disorders by performing a systematic review and meta-analysis of randomised controlled trials., Data Sources: A search was performed in Cochrane Central Register of Controlled Trials (CENTRAL, 2014), MEDLINE via PubMed (1950), EMBASE via Ovid (1974), and Clinicaltrials.gov through December 2014., Study Selection: This study included only randomised controlled trials with placebo or active controls that administered nalmefene to adult individuals for treating impulse control and/or substance use disorders. Both published and unpublished randomised controlled trials were eligible for inclusion., Data Extraction and Synthesis: Internal validity was assessed using the Cochrane risk-of-bias tool. Published information from the trials was supplemented by contact between reviewers and industry sponsor. Data were combined using two meta-approaches in fixed effects models; Peto Odds Ratios and risk differences were reported with 95% confidence intervals (95%CIs)., Main Outcomes and Measures: Number of patients with serious adverse events, including specific psychiatric serious adverse events and withdrawals due to adverse events., Results: Of 20 potentially relevant studies, 15 randomised controlled trials met the inclusion criteria, and 8 of these provided data enabling the meta-analysis. Overall, serious adverse events did not occur more often in the nalmefene group than in the placebo group (Peto Odds Ratio = 0.97 [95% CI 0.64-1.44]; P = 0.86). Risk of psychiatric serious adverse events was slightly elevated, albeit not at a statistically significant level (Peto Odds Ratio = 1.32 [95% CI 0.62, 2.83]; P = 0.47). Withdrawals due to adverse events were significantly more likely to occur with nalmefene compared to placebo (Peto Odds Ratio = 3.22 [95% CI 2.46-4.22]; P<0.001)., Conclusions and Relevance: The three-fold increased risk of withdrawal from treatment on nalmefene due to adverse events is a matter of safety concern. The nature of these adverse events cannot be elucidated further without access to individual patients data.

Objectives: To summarize and compare the benefits and harms of biological agents used as monotherapy for rheumatoid arthritis (RA) in order to inform decisions for patients who are intolerant to conventional DMARD therapy., Methods: We searched MEDLINE, EMBASE, CENTRAL, and other sources for randomised trials that compared biological monotherapy with methotrexate, placebo, or other biological monotherapies. Primary outcomes were ACR50 and the number of patients who discontinued due to adverse events. Our network meta-analysis was based on mixed-effects logistic regression, including both direct and indirect comparisons of the treatment effects, while preserving the randomised comparisons within each trial. PROSPERO identifier: CRD42012002800., Results: The analysis comprises 28 trials (8602 patients), including all nine biological agents approved for RA. Eight trials included "DMARD-naïve", and 20 "DMARD-Inadequate responder" (DMARD-IR) patients. All agents except anakinra and infliximab were superior (p < 0.05) to placebo (i.e., no DMARD treatment) with regard to ACR50. Etanercept and rituximab were superior to anakinra (p = 0.018 and p = 0.049, respectively). Tocilizumab was superior to adalimumab (p = 0.0082), anakinra (p = 0.0083), certolizumab (p = 0.037), and golimumab (p = 0.049). No differences among etanercept, tocilizumab, and rituximab were found (p > 0.52). However, because rituximab was evaluated in just 40 patients, our confidence in the estimates is limited. When including only DMARD-IR trials, the same statistical pattern emerged; in addition etanercept and tocilizumab were superior to abatacept. At recommended doses, both etanercept and tocilizumab were superior to adalimumab and certolizumab. No statistically significant differences among biological agents were found with respect to discontinuation due to adverse events (p > 0.068)., Conclusions: Evidence from randomised trials suggests that most biological agents are effective as monotherapy. Although our confidence in the estimates is limited, etanercept or tocilizumab may be the optimal choice for most patients who need treatment with biological monotherapy. However, given our limited confidence in the estimates including possibility of bias, it is appropriate to strongly weight patients׳ preferences and values in the final treatment choice., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Spinal manipulative therapy (SMT) is a widely used manual treatment, but many reviews exist with conflicting conclusions about the safety of SMT. We performed an overview of reviews to elucidate and quantify the risk of serious adverse events (SAEs) associated with SMT., Methods: We searched five electronic databases from inception to December 8, 2015. We included reviews on any type of studies, patients, and SMT technique. Our primary outcome was SAEs. Quality of the included reviews was assessed using a measurement tool to assess systematic reviews (AMSTAR). Since there were insufficient data for calculating incidence rates of SAEs, we used an alternative approach; the conclusions regarding safety of SMT were extracted for each review, and the communicated opinion were judged by two reviewers independently as safe, harmful, or neutral/unclear. Risk ratios (RRs) of a review communicating that SMT is safe and meeting the requirements for each AMSTAR item, were calculated., Results: We identified 283 eligible reviews, but only 118 provided data for synthesis. The most frequently described adverse events (AEs) were stroke, headache, and vertebral artery dissection. Fifty-four reviews (46%) expressed that SMT is safe, 15 (13%) expressed that SMT is harmful, and 49 reviews (42%) were neutral or unclear. Thirteen reviews reported incidence estimates for SAEs, roughly ranging from 1 in 20,000 to 1 in 250,000,000 manipulations. Low methodological quality was present, with a median of 4 of 11 AMSTAR items met (interquartile range, 3 to 6). Reviews meeting the requirements for each of the AMSTAR items (i.e. good internal validity) had a higher chance of expressing that SMT is safe., Conclusions: It is currently not possible to provide an overall conclusion about the safety of SMT; however, the types of SAEs reported can indeed be significant, sustaining that some risk is present. High quality research and consistent reporting of AEs and SAEs are needed., Systematic Review Registration: PROSPERO CRD42015030068 .

Objective: To determine the comparative efficacy and safety of antipsychotics for youth with early-onset schizophrenia using network meta-analytic methods combining direct and indirect trial data., Method: The authors systematically searched MEDLINE, the Cochrane Library, and clinicaltrials.gov and selected randomized controlled trials allocating youth with schizophrenia spectrum disorders to a (non-clozapine) antipsychotic versus placebo or another antipsychotic. Major efficacy outcomes were Positive and Negative Syndrome Scale (PANSS) total and positive symptoms. Major safety outcomes were weight, plasma triglyceride levels, extrapyramidal symptoms, akathisia, and all-cause discontinuation. Sixteen additional outcomes were analyzed. A random-effects arm-based network meta-analysis was applied, and consistency was assessed by pairwise meta-analysis. Confidence in PANSS total estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach., Results: Twelve 6- to 12-week trials (N = 2,158; 8-19 years old; 61% boys) involving 8 antipsychotics (aripiprazole, asenapine, paliperidone, risperidone, quetiapine, olanzapine, molindone, and ziprasidone) were analyzed. PANSS total symptom change was comparable among antipsychotics (low- to moderate-quality evidence), except ziprasidone (very low- to low-quality evidence), and all antipsychotics were superior to placebo (low- to high-quality evidence), except ziprasidone and asenapine (low- to moderate-quality evidence). PANSS positive changes and additional efficacy outcomes were comparable among antipsychotics. Weight gain was primarily associated with olanzapine; extrapyramidal symptoms and akathisia were associated with molindone; and prolactin increased with risperidone, paliperidone, and olanzapine. Serious adverse events, discontinuation of treatment, sedation, insomnia, or change in triglycerides did not differ among antipsychotics., Conclusion: This network meta-analysis showed comparable efficacy among antipsychotics for early-onset schizophrenia, except that efficacy appeared inferior for ziprasidone and unclear for asenapine. Adverse reaction profiles varied substantially among the investigated antipsychotics and were largely consistent with prior findings in adults. Protocol registration information-Antipsychotic Treatment for Children With Schizophrenia Spectrum Disorders: Network Meta-Analysis of Randomised Trials; https://www.crd.york.ac.uk/PROSPERO/; CRD42013006676., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine possible differences in serious adverse effects among the 10 currently approved biological and targeted synthetic DMARDs (b/ts-DMARDs) for RA., Methods: Systematic review in bibliographic databases, trial registries and websites of regulatory agencies identified randomized trials of approved b/ts-DMARDs for RA. Network meta-analyses using mixed-effects Poisson regression models were conducted to calculate rate ratios for serious adverse events (SAEs) and deaths between each of the 10 drugs and control (i.e. no b/ts-DMARD treatment), based on subjects experiencing an event in relation to person-years. Confidence in the estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE)., Results: A total of 117 trials (47 615 patients) were included. SAEs were more common with certolizumab compared with abatacept (rate ratio = 1.58, 95% CI: 1.18, 2.14), adalimumab (1.36, 95% CI: 1.02, 1.81), etanercept (1.60, 95% CI: 1.18, 2.17), golimumab (1.45, 95% CI: 1.00, 2.08), rituximab (1.63, 95% CI: 1.16, 2.30), tofacitinib (1.44, 95% CI: 1.03, 2.02) and control (1.45, 95% CI: 1.13, 1.87); and tocilizumab compared with abatacept (1.30, 95% CI: 1.03, 1.65), etanercept (1.31, 95% CI: 1.04, 1.67) and rituximab (1.34, 95% CI: 1.01, 1.78). No other comparisons were statistically significant. Accounting for study duration confirmed our findings for up to 6 months' treatment but not for longer-term treatment (6-24 months). No differences in mortality between b/ts-DMARDs and control were found. Based on the GRADE approach, confidence in the estimates was low due to lack of head-to-head comparison trials and imprecision in indirect estimates., Conclusion: Despite low confidence in the estimates, our analysis found potential differences in rates of SAEs. Our data suggest caution should be taken when deciding among available drugs., Systematic Review Registration Number: PROSPERO CRD42014014842., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Arthritis patients often take fish oil supplements to alleviate symptoms, but limited evidence exists regarding their efficacy. The objective was to evaluate whether marine oil supplements reduce pain and/or improve other clinical outcomes in patients with arthritis. Six databases were searched systematically (24 February 2015). We included randomized trials of oral supplements of all marine oils compared with a control in arthritis patients. The internal validity was assessed using the Cochrane Risk of Bias tool and heterogeneity was explored using restricted maximum of likelihood (REML)-based meta-regression analysis. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to rate the overall quality of the evidence. Forty-two trials were included; 30 trials reported complete data on pain. The standardized mean difference (SMD) suggested a favorable effect (-0.24; 95% confidence interval, CI, -0.42 to -0.07; heterogeneity, I ² = 63%. A significant effect was found in patients with rheumatoid arthritis (22 trials; -0.21; 95% CI, -0.42 to -0.004) and other or mixed diagnoses (3 trials; -0.63; 95% CI, -1.20 to -0.06), but not in osteoarthritis patients (5 trials; -0.17; 95% CI, -0.57-0.24). The evidence for using marine oil to alleviate pain in arthritis patients was overall of low quality, but of moderate quality in rheumatoid arthritis patients., Competing Interests: The authors declare no conflict of interest.

Background and Objective: Although various biological agents are in use for polyarticular juvenile idiopathic arthritis (pJIA), head-to-head trials comparing the efficacy and safety among them are lacking. We aimed to compare the efficacy and safety of biological agents in pJIA using all currently available randomized withdrawal trials (wRCTs)., Methods: A systematic search of MEDLINE, EMBASE, CENTRAL, and clinicaltrials.gov was performed. Eligible wRCTs: patients with pJIA where a biological agent was compared with another biological agent or placebo. Efficacy was evaluated using disease flare as a measure. Adverse events (AEs) and serious AEs were evaluated. Network meta-analysis compared biological agents based on a (empirical Bayes) mixed-effects logistic regression model that combines statistical inference from both direct and indirect comparisons of the treatment effects between biological agents., Results: Of 496 references identified, five wRCTs were included-abatacept, adalimumab, anakinra, etanercept, and tocilizumab, one trial each, all vs. placebo. There were no differences in efficacy among biological agents and most showed statistically significant efficacy compared with placebo (nearly all exceptions were in agreement with the original study data). Serious AEs occurred very infrequently (0-8%) and an analysis was not possible. There were no differences for AEs when compared among biological agents or to placebo., Conclusion: There were no statistical differences among biological agents for efficacy or safety. Overall, biological agents were effective and safe when compared to placebo. Based on these data, other considerations such as price and availability may need to be used to decide among biological agents when treating pJIA patients., (Copyright © 2016. Published by Elsevier Inc.)

Objectives: To empirically assess the clinical effects of physiotherapy on pain in adults., Design: Using meta-epidemiology, we report on the effects of a 'physiotherapy' intervention on self-reported pain in adults. For each trial, the group difference in the outcome 'pain intensity' was assessed as standardised mean differences (SMD) with 95% CIs. Stratified analyses were conducted according to patient population (International Classification of Diseases-10 classes), type of physiotherapy intervention, their interaction, as well as type of comparator group and risks of bias. The quality of the body of evidence was assessed based on GRADE methodology., Data Sources: Systematic searches were carried out in MEDLINE and PEDro from 1 January 2004-31 December 2013. 174 trials (224 comparisons) met the inclusion criteria for the meta-analysis., Eligibility Criteria for Selecting Studies: Randomised trials using 'no intervention' or of a sham-controlled design were selected. Only articles written in English were eligible., Results: An overall moderate effect of physiotherapy on pain corresponding to 0.65 SD-units (95% CI 0.57 to 0.73) was found based on a moderate inconsistency (I(2)=51%). Stratified exploration showed that therapeutic exercise for musculoskeletal diseases tended to be more beneficial than multimodal interventions (difference 0.30 95% CI 0.03 to 0.57; p=0.03). Trials with a 'no intervention' comparator tended to have a higher overall effect size than trials with a sham comparator (difference 0.25; 95% CI 0.09 to 0.41; p=0.004). In general, our confidence in the estimates was low, mainly due to high risk of performance biases and between-study heterogeneity., Conclusions: Physiotherapy reduces pain in adults, but standardisation of interventions and focus on trial research with low risks of bias and reproducible treatment modalities are needed., Trial Registration Number: CRD42014008754., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

There is convincing evidence for the known and unambiguously accepted beneficial effects of glucocorticoids at low dosages. However, the implementation of existing recommendations and guidelines on the management of glucocorticoid therapy in rheumatic diseases is lagging behind. As a first step to improve implementation, we aimed at defining conditions under which long-term glucocorticoid therapy may have an acceptably low level of harm. A multidisciplinary European League Against Rheumatism task force group of experts including patients with rheumatic diseases was assembled. After a systematic literature search, breakout groups critically reviewed the evidence on the four most worrisome adverse effects of glucocorticoid therapy (osteoporosis, hyperglycaemia/diabetes mellitus, cardiovascular diseases and infections) and presented their results to the other group members following a structured questionnaire for final discussion and consensus finding. Robust evidence on the risk of harm of long-term glucocorticoid therapy was often lacking since relevant study results were often either missing, contradictory or carried a high risk of bias. The group agreed that the risk of harm is low for the majority of patients at long-term dosages of ≤5 mg prednisone equivalent per day, whereas at dosages of >10 mg/day the risk of harm is elevated. At dosages between >5 and ≤10 mg/day, patient-specific characteristics (protective and risk factors) determine the risk of harm. The level of harm of glucocorticoids depends on both dose and patient-specific parameters. General and glucocorticoid-associated risk factors and protective factors such as a healthy lifestyle should be taken into account when evaluating the actual and future risk., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: To define the optimal biologic agent for systemic JIA (sJIA) based on safety and efficacy data from a randomized controlled trial (RCT)., Methods: Through a systematic literature search, sJIA RCTs evaluating biologic agents were identified. The primary efficacy outcome was defined as a 30% improvement according to the modified American College of Rheumatology Paediatric 30 response criteria (JIA ACR30). The primary safety outcome was defined as serious adverse events (SAEs). Outcomes were analysed by pairwise and network meta-analyses. The quality of evidence between biologic agents was assessed by applying the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology., Results: From the 493 citations originally identified, 5 RCTs were eligible for inclusion-one each for anakinra, canakinumab and tocilizumab and two for rilonacept: all vs placebo. While all were effective, the network meta-analysis indicated with low-quality evidence (due to indirect comparison and inconsistency) that rilonacept-treated patients were less likely to respond than those treated with canakinumab [odds ratio (OR) 0.10 (95% CI 0.02, 0.38), P = 0.001] or tocilizumab [OR 0.12 (95% CI 0.03, 0.44), P = 0.001]. Risks of SAEs were similar among the biologic agents (supported by very low-quality evidence) and not different from placebo., Conclusion: Despite heterogeneous eligibility criteria and study designs across the five studies and different modified JIA ACR30 criteria, this meta-analysis of short-term RCTs presents empirical evidence that canakinumab and tocilizumab are more effective than rilonacept. Biologic agents in sJIA seem safe and comparable with respect to SAE risk in the short term., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To investigate whether analysis of the modified intention-to-treat (mITT) population with postrandomization exclusion of patients from analysis is associated with biased estimates of treatment effect compared to the conservative intention-to-treat (ITT) population., Study Design and Setting: Placebo-controlled, blinded randomized trials on biological or targeted interventions for rheumatoid arthritis were identified through a systematic search. Two authors independently extracted data. A random-effects meta-analysis was used to combine odds ratios as an expression of treatment effect and stratify according to the different analysis populations., Results: Seventy-two randomized trials were included and analyzed (23,842 patients). Thirty trials analyzed the ITT population, 37 analyzed an mITT population, and 5 trials had an unclear analysis population. The treatment effect of active intervention compared to control, when based on mITT, was comparable to ITT (odds ratio 3.76 [95% confidence interval 3.09, 4.57], and 3.47 [2.77, 4.34]; comparison P = 0.60)., Conclusion: We found no difference in the treatment effect between randomized trials using ITT and mITT analyses populations. This suggests that the mITT approach in rheumatoid arthritis trials investigating biological or targeted interventions does not introduce bias compared to ITT., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Sponsors that seek to commercialize new drugs apply to the Food and Drug Administration (FDA) which independently analyzes the raw data and reports the results on its website., Objectives: This study sought to determine if there are differences between the FDA assessments and journal reports on biologic agents developed for the treatment of rheumatoid arthritis., Methods: Available data on FDA-approved drugs were extracted from the website, and a systematic literature search was conducted to identify matching studies in peer-reviewed medical journals. Outcome measures were the American College of Rheumatology response criteria ACR20 (efficacy) and withdrawal due to adverse events (safety). As effect size odds ratios were estimated for each active trial arm vs. control arm (i.e. for both sources: FDA and journal report), followed by calculation of the ratios of the FDA and journal report odds ratios. A ratio of odds ratios not equal to 1 was categorized as a discrepancy., Results: FDA reports were available for 8 of 9 FDA-approved biologic agents for rheumatoid arthritis; all identified trials (34) except one were published in peer-reviewed journals. Overall, discrepancies were noted for 20 of the 33 evaluated trials. Differences in the apparent benefit reporting were found in 39% (24/61) pairwise comparisons and in 11 cases these were statistically significant; the FDA report showed greater benefit than the journal publication in 15 comparisons and lesser benefit in 9. Differences in the reported harms were found in 51% (28/55) pairwise comparisons and were statistically significant in 5. The "signal" in FDA reports showed a less harmful effect than the journal publication in 17 comparisons whereas a more harmful effect in 11. The differences were attributed to differences in analytic approach, patient inclusion, rounding effect, and counting discrepancies. However, no differences were categorized as critical., Conclusion: There was no empirical evidence to suggest biased estimates between the two sources. Increased and detailed transparency in publications would improve the understanding and credibility of published results. Further, the FDA report was found to be a useful source when data are missing in the published report (i.e. reporting bias).

Objective: To determine if variations in trial eligibility criteria and patient baseline characteristics could be considered effect modifiers of the treatment response when testing targeted therapies (biological agents and targeted synthetic disease modifying antirheumatic drugs (DMARDs)) for rheumatoid arthritis (RA)., Methods: We conducted a meta-epidemiological study of all trials evaluating a targeted therapy approved by regulatory authorities for treating RA. The database search was completed on December 11th 2013. Eligible trials reported ACR20 data at months 3-6 and used an add-on design. Odds ratios (ORs) were calculated from the response rates and compared among the trial eligibility criteria/patient baseline characteristics of interest. Comparisons are presented as the Ratio of Odds Ratios (ROR)., Results: Sixty-two trials (19,923 RA patients) were included in the primary analyses using ACR20 response. Overall, targeted therapies constituted an effective treatment (OR 3.96 95% confidence interval (CI) 3.41 to 4.60). The majority of the trial eligibility criteria and patient baseline characteristics did not modify treatment effect. The added benefit of targeted therapies was lower in trials including "DMARD-naïve" patients compared with trials including "DMARD inadequate responders" (ROR = 0.45, 95%CI 0.31 to 0.66) and trials including "targeted therapy inadequate responders" (0.50, 95%CI 0.29 to 0.87), test for interaction: p = 0.0002. Longer mean disease duration was associated with a higher likelihood of responding to treatment (β = 1.05, 95%CI 1.00 to 1.11 OR's per year; p = 0.03). Analyses conducted using DAS28-remission as the outcome supported the above-mentioned findings., Conclusion: Our results suggest that a highly selective inclusion is not associated with greater treatment effect, as might otherwise be expected. The added benefit of a targeted therapy was lower in trials including patients who were DMARD-naïve and trials including patients with shorter disease durations.

A taskforce comprised of an expert group of 21 rheumatologists, radiologists and methodologists from 11 countries developed evidence-based recommendations on the use of imaging in the clinical management of both axial and peripheral spondyloarthritis (SpA). Twelve key questions on the role of imaging in SpA were generated using a process of discussion and consensus. Imaging modalities included conventional radiography, ultrasound, magnetic resonance imaging, computed tomography (CT), positron emission tomography, single photon emission CT, dual-emission x-ray absorptiometry and scintigraphy. Experts applied research evidence obtained from systematic literature reviews using MEDLINE and EMBASE to develop a set of 10 recommendations. The strength of recommendations (SOR) was assessed by taskforce members using a visual analogue scale. A total of 7550 references were identified in the search process, from which 158 studies were included in the systematic review. Ten recommendations were produced using research-based evidence and expert opinion encompassing the role of imaging in making a diagnosis of axial SpA or peripheral SpA, monitoring inflammation and damage, predicting outcome, response to treatment, and detecting spinal fractures and osteoporosis. The SOR for each recommendation was generally very high (range 8.9-9.5). These are the first recommendations which encompass the entire spectrum of SpA and evaluate the full role of all commonly used imaging modalities. We aimed to produce recommendations that are practical and valuable in daily practice for rheumatologists, radiologists and general practitioners., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

The aim of this study was to assess the clinical efficacy and safety of oral ginger for symptomatic treatment of osteoarthritis (OA) by carrying out a systematic literature search followed by meta-analyses on selected studies. Inclusion criteria were randomized controlled trials (RCTs) comparing oral ginger treatment with placebo in OA patients aged >18 years. Outcomes were reduction in pain and reduction in disability. Harm was assessed as withdrawals due to adverse events. The efficacy effect size was estimated using Hedges' standardized mean difference (SMD), and safety by risk ratio (RR). Standard random-effects meta-analysis was used, and inconsistency was evaluated by the I-squared index (I(2)). Out of 122 retrieved references, 117 were discarded, leaving five trials (593 patients) for meta-analyses. The majority reported relevant randomization procedures and blinding, but an inadequate intention-to-treat (ITT) analysis. Following ginger intake, a statistically significant pain reduction SMD = -0.30 ([95% CI: [(-0.50, -0.09)], P = 0.005]) with a low degree of inconsistency among trials (I(2) = 27%), and a statistically significant reduction in disability SMD = -0.22 ([95% CI: ([-0.39, -0.04)]; P = 0.01; I(2) = 0%]) were seen, both in favor of ginger. Patients given ginger were more than twice as likely to discontinue treatment compared to placebo ([RR = 2.33; 95% CI: (1.04, 5.22)]; P = 0.04; I(2) = 0%]). Ginger was modestly efficacious and reasonably safe for treatment of OA. We judged the evidence to be of moderate quality, based on the small number of participants and inadequate ITT populations. Prospero: CRD42011001777., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Introduction: Antipsychotic treatment in early-onset schizophrenia (EOS) lacks a rich evidence base, and efforts to rank different drugs concerning their efficacy have not proven any particular drug superior. In contrast to the literature regarding adult-onset schizophrenia (AOS), comparative effectiveness studies in children and adolescents are limited in number and size, and only a few meta-analyses based on conventional methodologies have been conducted., Methods and Analyses: We will conduct a network meta-analysis of all randomised controlled trials (RCTs) that evaluate antipsychotic therapies for EOS to determine which compounds are efficacious, and to determine the relative efficacy and safety of these treatments when compared in a network meta-analysis. Unlike a contrast-based (standard) meta-analysis approach, an arm-based network meta-analysis enables statistical inference from combining both direct and indirect comparisons within an empirical Bayes framework. We will acquire eligible studies through a systematic search of MEDLINE, the Cochrane Central Registry of Controlled Trials, Clinicaltrials.gov and Centre for Reviews and Dissemination databases. Eligible studies should randomly allocate children and adolescents presenting with schizophrenia or a related non-affective psychotic condition to an intervention group or to a control group. Two reviewers will-independently and in duplicate-screen titles and abstracts, complete full text reviews to determine eligibility, and subsequently perform data abstraction and assess risk of bias of eligible trials. We will conduct meta-analyses to establish the effect of all reported therapies on patient-relevant efficacy and safety outcomes when possible., Ethics and Dissemination: No formal ethical procedures regarding informed consent are required as no primary data collection is undertaken. The review will help facilitate evidence-based management, identify key areas for future research, and provide a framework for conducting large systematic reviews combining direct and indirect comparisons. The study will be disseminated by peer-reviewed publication and conference presentation., Trial Registration Number: PROSPERO CRD42013006676., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Introduction: When participants drop out of randomised clinical trials, as frequently happens, the intention-to-treat (ITT) principle does not apply, potentially leading to attrition bias. Data lost from patient dropout/lack of follow-up are statistically addressed by imputing, a procedure prone to bias. Deviations from the original definition of ITT are referred to as modified intention-to-treat (mITT). As yet, the impact of the potential bias associated with mITT has not been assessed. Our objective is to investigate potential bias and disadvantages of performing mITT and evaluate possible concerns when executing different mITT approaches in meta-analyses., Methods and Analysis: Using meta-epidemiology on randomised trials considered less prone to bias (ie, good internal validity) and assessing biological or targeted agents in patients with rheumatoid arthritis, we will meta-analyse data from 10 biological and targeted drugs based on collections of trials that would correspond to 10 individual meta-analyses., Ethics and Dissemination: This study will enhance transparency for evaluating mITT treatment effects described in meta-analyses. The intended audience will include healthcare researchers, policymakers and clinicians. Results of the study will be disseminated by peer-review publication., Protocol Registration: In PROSPERO CRD42013006702, 11. December 2013., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Despite significant cost differences, the comparative effect of combination treatments of disease modifying anti-rheumatic drugs (DMARDs) with and without biologic agents has rarely been examined. Thus we performed a network meta-analysis on the effect of combination therapies on progression of radiographic joint erosions in patients with rheumatoid arthritis (RA)., Methods and Findings: The following combination drug therapies compared versus single DMARD were investigated: Double DMARD: 2 DMARDs (methotrexate, sulfasalazine, leflunomide, injectable gold, cyclosporine, chloroquine, azathioprin, penicillamin) or 1 DMARD plus low dose glucocorticoid (LDGC); triple DMARD: 3 DMARDs or 2 DMARDs plus LDGC; biologic combination: 1 DMARD plus biologic agent (tumor necrosis factor α inhibitor (TNFi) or abatacept or tocilizumab or CD20 inhibitor (CD20i)). Randomized controlled trials were identified in a search of electronic archives of biomedical literature and included in a star-shaped network meta-analysis and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol. Effects are reported as standardized mean differences (SMD). The effects of data from 39 trials published in the period 1989-2012 were as follows: Double DMARD: -0.32 SMD (CI: -0.42, -0.22); triple DMARD: -0.46 SMD (CI: -0.60, -0.31); 1 DMARD plus TNFi: -0.30 SMD (CI: -0.36, -0.25); 1 DMARD plus abatacept: -0.20 SMD (CI: -0.33, -0.07); 1 DMARD plus tocilizumab: -0.34 SMD (CI: -0.48, -0.20); 1 DMARD plus CD20i: -0.32 SMD (CI: -0.40, -0.24). The indirect comparisons showed similar effects between combination treatments apart from triple DMARD being significantly better than abatacept plus methotrexate (-0.26 SMD (CI: -0.45, -0.07)) and TNFi plus methotrexate (-0.16 SMD (CI: -0.31, -0.01))., Conclusion: Combination treatment of a biologic agent with 1 DMARD is not superior to 2-3 DMARDs including or excluding LDGC in preventing structural joint damage. Future randomized studies of biologic agents should be compared versus a combination of DMARDs.

This article is based on a systematic literature search and meta-analyses of clinical data regarding effects of bisphosphonates (BP) and denosumab (DS) on preventing skeletal related events (SRE) in patients with bone metastases from solid tumours. Although there are pharmacological differences between the different types of BP no major differences were observed between BP in preventing SRE or in adverse events. Treatment with DS has in three randomised trials showed a greater effect than BP in preventing SRE. The optimal choice of bone-anti-resorptive agent should depend on the patient's general condition, renal function and treatment logistics.

Objective: To evaluate the effects of oral nonsteroidal antiinflammatory drugs (NSAIDs) on C-reactive protein (CRP) levels in rheumatoid arthritis (RA) patients, with a prespecified focus on the different NSAIDs., Methods: We performed a systematic search in Medline via PubMed, the Cochrane Central Register of Controlled Trials, EMBase via OVID, the Institute for Scientific Information Web of Science, and other sources. Eligible trials were parallel-group, randomized, placebo-controlled trials of oral NSAID therapy in RA patients for which there were extractable CRP data. Standardized mean differences (SMDs) with 95% confidence intervals (95% CIs) were calculated from the differences in means of CRP levels between groups (active treatment minus placebo) divided by the pooled SDs. For the meta-analysis, a random-effects model was used to estimate the overall change in CRP level, and stratified analysis was used to examine differences among NSAIDs., Results: We included 19 trials of 10 different NSAIDs. Overall, NSAIDs showed no effect on the CRP level (SMD 0.01 [95% CI -0.03, 0.06], P = 0.62). However, the prespecified stratified analysis indicated varying effects on the CRP level according to the different NSAIDs; lumiracoxib caused a statistically significant and consistent (I(2) = 0%) increase in the CRP level (SMD 0.13 [95% CI 0.01, 0.25], P = 0.037), whereas naproxen caused a statistically significant and consistent (I(2) = 0%) decrease in the CRP level (SMD -0.11 [95% CI -0.20, -0.02], P = 0.022)., Conclusion: Overall, NSAIDs have no effect on the CRP level. However, the nonselective NSAID naproxen was associated with a significant decrease in the CRP level, whereas the cyclooxygenase 2-selective NSAID lumiracoxib was associated with a significant increase in the CRP level. This finding is interesting considering the suspected influence of NSAIDs on cardiovascular complications., (Copyright © 2012 by the American College of Rheumatology.)