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.

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.

Use of melatonin for children and adolescents with chronic insomnia attributable to disorders beyond indication: a systematic review, meta-analysis and clinical recommendation.

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 I2 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, I2 = 60%) and increased total sleep time by 18.97 min (95% CI 0.37-37.57, 10 studies, I2 = 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.

Use of melatonin in children and adolescents with idiopathic chronic insomnia: a systematic review, meta-analysis, and clinical recommendation.

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 I2 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, I2 = 0%) and a moderate reduction in sleep latency by 18.03 min (95% CI -26.61 to -9.44, 3 studies, I2 = 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, I2 = 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.

The short-term and long-term adverse effects of melatonin treatment in children and adolescents: a systematic review and GRADE assessment.

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, I2 = 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.

Hip precautions after posterior-approach total hip arthroplasty among patients with primary hip osteoarthritis do not influence early recovery: a systematic review and meta-analysis of randomized and non-randomized studies with 8,835 patients.

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.

Biopsychosocial Rehabilitation for Inflammatory Arthritis and Osteoarthritis Patients: A Systematic Review and Meta-Analysis of Randomized Trials.

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.

A Meta-Analysis of Antipsychotic-Induced Hypo- and Hyperprolactinemia in Children and Adolescents.

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.

Usefulness of Cochrane Reviews in Clinical Guideline Development-A Survey of 585 Recommendations.

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.

Evidence-Based Research on Effectiveness of Periodontal Treatment in Rheumatoid Arthritis Patients: A Systematic Review and Meta-Analysis.

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 I2 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 T2 . 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.

Parent-Mediated Interventions for Children and Adolescents With Autism Spectrum Disorders: A Systematic Review and Meta-Analysis.

There has been increasing interest in parent-mediated interventions (PMIs) for children with autism spectrum disorders (ASDs). The objective of this systematic review and meta-analysis was to examine the effect of PMIs compared to no PMI for children with ASD aged 2-17 years. The primary outcome was adaptive functioning rated by a parent or clinician. The secondary outcomes were long-term adaptive functioning rated by the parents, adverse events, core symptoms of ASD, disruptive behavior, parental well-being, quality of life of the child rated by the parents and anxiety. The MEDLINE, PsycInfo, Embase, and CINAHL databases were searched in March 2020. The Cochrane Risk of Bias Tool was used to rate the individual studies, and the certainty in the evidence was evaluated using GRADE. We identified 30 relevant randomized controlled trials (RCTs), including 1,934 participants. A clinically relevant effect of PMIs on parent-rated adaptive functioning was found with a low certainty of evidence [Standard mean difference (SMD): 0.28 (95% CI: -0.01, 0.57)] on Vineland Adaptive Behavior Scales (VABS), whereas no clinically relevant effect was seen for clinician-rated functional level, with a very low certainty of evidence [SMD on Clinical Global Impressions (CGI)-severity scale: SMD -0.45 [95% CI: -0.87, -0.03)]. PMIs may slightly improve clinician-rated autism core symptoms [SMD: -0.35 (95% CI: -0.71, 0.02)]. Additionally, no effect of PMIs on parent-rated core symptoms of ASD, parental well-being or adverse effects was identified, all with a low certainty of evidence. There was a moderate certainty of evidence for a clinically relevant effect on disruptive behavior [SMD: 0.55 (95% Cl: 0.36, 0.74)]. The certainty in the evidence was downgraded due to serious risk of bias, lack of blinding, and serious risk of imprecision due to few participants included in meta-analyses. The present findings suggest that clinicians may consider introducing PMIs to children with ASD, but more high-quality RCTs are needed because the effects are not well-established, and the results are likely to change with future studies. The protocol for the systematic review is registered at the Danish Health Authority website (www.sst.dk).

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.

Supervised Training Compared With No Training or Self-training in Patients With Subacromial Pain Syndrome: A Systematic Review and Meta-analysis.

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.

The Effect of a Combined Gluten- and Casein-Free Diet on Children and Adolescents with Autism Spectrum Disorders: A Systematic Review and Meta-Analysis.

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.

Analgesics use and withdrawal in people with dementia - a register-based Danish study and a systematic review.

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.

Added value of combining methotrexate with a biological agent compared to biological monotherapy in rheumatoid arthritis patients: A systematic review and meta-analysis of randomised trials.

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.

The effect of glucocorticoids on bone mineral density in patients with rheumatoid arthritis: A systematic review and meta-analysis of randomized, controlled trials.

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.

Trial Characteristics as Contextual Factors When Evaluating Targeted Therapies in Patients With Psoriatic Disease: A Meta-Epidemiologic Study.

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.

Impact of Comorbidities on Tumor Necrosis Factor Inhibitor Therapy in Psoriatic Arthritis: A Population-Based Cohort Study.

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.

National Clinical Guidelines for non-surgical treatment of patients with recent onset low back pain or lumbar radiculopathy.

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.