Improving social justice in observational studies: protocol for the development of a global and Indigenous STROBE-equity reporting guideline.

BACKGROUND: Addressing persistent and pervasive health inequities is a global moral imperative, which has been highlighted and magnified by the societal and health impacts of the COVID-19 pandemic. Observational studies can aid our understanding of the impact of health and structural oppression based on the intersection of gender, race, ethnicity, age and other factors, as they frequently collect this data. However, the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline, does not provide guidance related to reporting of health equity. The goal of this project is to develop a STROBE-Equity reporting guideline extension. METHODS: We assembled a diverse team across multiple domains, including gender, age, ethnicity, Indigenous background, disciplines, geographies, lived experience of health inequity and decision-making organizations. Using an inclusive, integrated knowledge translation approach, we will implement a five-phase plan which will include: (1) assessing the reporting of health equity in published observational studies, (2) seeking wide international feedback on items to improve reporting of health equity, (3) establishing consensus amongst knowledge users and researchers, (4) evaluating in partnership with Indigenous contributors the relevance to Indigenous peoples who have globally experienced the oppressive legacy of colonization, and (5) widely disseminating and seeking endorsement from relevant knowledge users. We will seek input from external collaborators using social media, mailing lists and other communication channels. DISCUSSION: Achieving global imperatives such as the Sustainable Development Goals (e.g., SDG 10 Reduced inequalities, SDG 3 Good health and wellbeing) requires advancing health equity in research. The implementation of the STROBE-Equity guidelines will enable a better awareness and understanding of health inequities through better reporting. We will broadly disseminate the reporting guideline with tools to enable adoption and use by journal editors, authors, and funding agencies, using diverse strategies tailored to specific audiences.

Phosphodiesterase 5 inhibitors (PDE5i) for the treatment of Raynaud's phenomenon.

BACKGROUND: Raynaud's phenomenon is a vasodilatory phenomenon characterised by digital pallor, cyanosis, and pain of the extremities. Primary Raynaud's phenomenon has no underlying disease associated with it, while secondary Raynaud's phenomenon is associated with connective tissue disorders such as systemic sclerosis. Systemic sclerosis causes fibrosis and commonly affects the skin and internal organs such as the gastrointestinal tract, lungs, kidney, and heart. Phosphodiesterase 5 inhibitors (PDE5i) are a class of drugs that increases blood flow to the extremities and may be beneficial in the treatment of Raynaud's phenomenon. OBJECTIVES: To assess the benefits and harms of PDE5i compared to placebo for the treatment of Raynaud's phenomenon. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and clinical trial registries up to June 2022. We did not apply any language restrictions. We searched the bibliographies of retrieved articles and contacted key experts in the field for additional and unpublished data. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing PDE5i to placebo in people with primary and secondary Raynaud's phenomenon. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: This review included nine RCTs which ranged in duration from four to eight weeks and included a total of 411 participants. The majority had Raynaud's phenomenon secondary to systemic sclerosis. Tadalafil was assessed in four studies, sildenafil in three studies, vardenafil in one study, and a new PDE5 inhibitor known as "PF-00489791" in one study. Three studies were parallel design and six studies were cross-over. The frequency of attacks per week was 24 with placebo and PDE5i reduced the frequency of attacks by an average of three attacks per week (mean difference (MD) -3.07, 95% confidence interval (CI) -5.15 to -1.00; 8 studies; low-certainty evidence). The duration of attacks per day was 55 minutes with placebo and PDE5i reduced the duration of attacks by an average of five minutes (MD -5.31, 95% CI -8.90 to -1.71; 8 studies; low-certainty evidence). Very low-certainty evidence from one study with eight participants showed severity of Raynaud's attacks (assessed on a 10 cm visual analogue scale with lower scores indicating less severity) was 20% lower with a PDE5i (3.7 with placebo compared to 1.6 with treatment; MD -2.1, 95% CI -2.7 to 1.4; very low-certainty evidence). Pain and patient global assessment were assessed on a 10 cm visual analogue scale with lower scores indicating improvement. Low-certainty evidence showed that the use of PDE5i may result in little to no difference compared to placebo in reducing the average pain of Raynaud's attacks (3 to 2.9; MD -0.10, 95% CI -0.78 to 0.57; 4 studies). Global scores were 36% lower with the use of a PDE5i compared to placebo (9.2 to 5.6; MD -3.59, 95% CI -4.45 to -2.73; 1 study, 24 participants; low-certainty evidence). The rate of withdrawals during treatment with PDE5i ranged from 4% to 20% compared with 2% in the placebo group in five studies. Four studies reported no withdrawals due to adverse events. Seven studies reported no serious adverse events. The rate of serious adverse events reported in two studies ranged from 2% during treatment to 4% with placebo. The majority of the studies were judged as low or unclear risk of bias for selection, performance, and detection bias. Almost half were judged at high risk of attrition bias and unclear risk for selective reporting bias. We downgraded frequency of attacks, duration of attacks, pain intensity, and patient global assessment for small sample sizes and concerns about inconsistency and graded each as low certainty of evidence. We downgraded severity of attacks to very low certainty due to serious concerns about imprecision and publication bias. We downgraded withdrawals due to adverse events and serious adverse events to moderate certainty of evidence due to a low number of reported events. AUTHORS' CONCLUSIONS: Based on low-certainty evidence, PDE5i may reduce the frequency of attacks of Raynaud's phenomenon by a small amount per week, result in a small reduction in the duration of attack, improve patients' global assessment of their disease, and result in little to no difference in pain. PDE5i probably result in little or no difference in serious adverse events but slightly increase the likelihood of withdrawing from treatment due to an adverse event.

How effects on health equity are assessed in systematic reviews of interventions.

BACKGROUND: Enhancing health equity is endorsed in the Sustainable Development Goals. The failure of systematic reviews to consider potential differences in effects across equity factors is cited by decision-makers as a limitation to their ability to inform policy and program decisions.  OBJECTIVES: To explore what methods systematic reviewers use to consider health equity in systematic reviews of effectiveness. SEARCH METHODS: We searched the following databases up to 26 February 2021: MEDLINE, PsycINFO, the Cochrane Methodology Register, CINAHL, Education Resources Information Center, Education Abstracts, Criminal Justice Abstracts, Hein Index to Foreign Legal Periodicals, PAIS International, Social Services Abstracts, Sociological Abstracts, Digital Dissertations and the Health Technology Assessment Database. We searched SCOPUS to identify articles that cited any of the included studies on 10 June 10 2021. We contacted authors and searched the reference lists of included studies to identify additional potentially relevant studies. SELECTION CRITERIA: We included empirical studies of cohorts of systematic reviews that assessed methods for measuring effects on health inequalities. We define health inequalities as unfair and avoidable differences across socially stratifying factors that limit opportunities for health. We operationalised this by assessing studies which evaluated differences in health across any component of the PROGRESS-Plus acronym, which stands for Place of residence, Race/ethnicity/culture/language, Occupation, Gender or sex, Religion, Education, Socioeconomic status, Social capital. "Plus" stands for other factors associated with discrimination, exclusion, marginalisation or vulnerability such as personal characteristics (e.g. age, disability), relationships that limit opportunities for health (e.g. children in a household with parents who smoke) or environmental situations which provide limited control of opportunities for health (e.g. school food environment). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a pre-tested form. Risk of bias was appraised for included studies according to the potential for bias in selection and detection of systematic reviews.  MAIN RESULTS: In total, 48,814 studies were identified and the titles and abstracts were screened in duplicate. In this updated review, we identified an additional 124 methodological studies published in the 10 years since the first version of this review, which included 34 studies. Thus, 158 methodological studies met our criteria for inclusion. The methods used by these studies focused on evidence relevant to populations experiencing health inequity (108 out of 158 studies), assess subgroup analysis across PROGRESS-Plus (26 out of 158 studies), assess analysis of a gradient in effect across PROGRESS-Plus (2 out of 158 studies) or use a combination of subgroup analysis and focused approaches (20 out of 158 studies). The most common PROGRESS-Plus factors assessed were age (43 studies), socioeconomic status in 35 studies, low- and middle-income countries in 24 studies, gender or sex in 22 studies, race or ethnicity in 17 studies, and four studies assessed multiple factors across which health inequity may exist. Only 16 studies provided a definition of health inequity. Five methodological approaches to consider health equity in systematic reviews of effectiveness were identified: 1) descriptive assessment of reporting and analysis in systematic reviews (140 of 158 studies used a type of descriptive method); 2) descriptive assessment of reporting and analysis in original trials (50 studies); 3) analytic approaches which assessed differential effects across one or more PROGRESS-Plus factors (16 studies); 4) applicability assessment (25 studies) and 5) stakeholder engagement (28 studies), which is a new finding in this update and examines the appraisal of whether relevant stakeholders with lived experience of health inequity were included in the design of systematic reviews or design and delivery of interventions. Reporting for both approaches (analytic and applicability) lacked transparency and was insufficiently detailed to enable the assessment of credibility. AUTHORS' CONCLUSIONS: There is a need for improvement in conceptual clarity about the definition of health equity, describing sufficient detail about analytic approaches (including subgroup analyses) and transparent reporting of judgments required for applicability assessments in order to consider health equity in systematic reviews of effectiveness.

Is equity considered in systematic reviews of interventions for mitigating social isolation and loneliness in older adults?

BACKGROUND: Social isolation and loneliness affect one in four older adults in many regions around the world. Social isolation and loneliness are shown to be associated with declines in physical and mental health. Intersecting social determinants of health influence both the risk of being socially isolated and lonely as well as the access and uptake of interventions. Our objective is to evaluate what evidence is available within systematic reviews on how to mitigate inequities in access to and effectiveness of interventions. METHODS: We performed an overview of reviews following methods of the Cochrane Handbook for Overviews of Reviews. We selected systematic reviews of effectiveness of interventions aimed at mitigating social isolation and loneliness in older adults (aged 60 or above) published in the last 10 years. In addition, we assessed all primary studies from the most recent systematic review with a broad intervention focus. We searched MEDLINE, EMBASE, PsycINFO, CINAHL, and Scopus in collaboration with a librarian scientist. We used a structured framework called PROGRESS-Plus to assess the reporting and consideration of equity. PROGRESS-Plus stands for place of residence, race/ethnicity/culture/language, occupation, gender or sex, religion, education, socioeconomic status (SES), social capital, while "plus" stands for additional factors associated with discrimination and exclusion such as age, disability, and sexual orientation. We assessed whether PROGRESS-Plus factors were reported in description of the population, examination of differential effects, or discussion of applicability or limitations. RESULTS: We identified and assessed 17 eligible systematic reviews. We assessed all 23 primary studies from the most recent systematic review with a broad intervention focus. All systematic reviews and primary studies described the population by one or more PROGRESS-Plus factor, most commonly across place of residence and age, respectively. None of the reviews and five primary studies examined differential effects across one or more PROGRESS-Plus dimension. Nine reviews and four primary studies discussed applicability or limitations of their findings by at least one PROGRESS-Plus factor. CONCLUSIONS: Although we know that social isolation and loneliness are worse for the poorest and most socially disadvantaged older adults, the existing evidence base lacks details on how to tailor interventions for these socially disadvantaged older people.

Shoe Lifts for Leg Length Discrepancy in Adults With Common Painful Musculoskeletal Conditions: A Systematic Review of the Literature.

OBJECTIVE: To determine whether shoe lifts effectively treat leg length discrepancy (LLD)-associated morbidities in adults with common painful musculoskeletal conditions. DATA SOURCES: Trip database, Cochrane Central Register of Controlled Trials database, PubMed database, Physiotherapy Evidence Database, and National Guideline Clearinghouse database. The search was performed in September 2017, was limited to English only, and had no time constraints. STUDY SELECTION: Two reviewers independently determined study eligibility. Inclusion criteria were (1) participants ≥18 years old with musculoskeletal-related complaints and LLD; (2) a shoe lift intervention was used; and (3) the study reported on pain, function, range of motion, patient satisfaction, quality of life, or adverse events. Randomized controlled trials (RCTs) and controlled intervention, cohort, before-and-after, case series, and case report studies were included. Three-hundred and nineteen articles were screened, and 9 guidelines were reviewed. DATA EXTRACTION: We extracted data pertaining to participant demographic characteristics, study setting, recruitment, randomization, method of LLD measurement, shoe lift characteristics, treatment duration, and outcome measures. We included 10 studies, including 1 RCT. DATA SYNTHESIS: LLD was associated with low back pain, scoliosis, and osteoarthritis of the hip and knee. Description of LLD correction strategy was often inadequate. Study quality was very low or poor. In non-RCT studies reporting on the proportion of participants who improved with a shoe lift, 88%±3% of 349 participants treated had partial or complete pain relief (effect size range, 66.7%-100%). All 22 RCT participants receiving treatment experienced pain relief (mean pain reduction, 27±9mm on a 150-mm visual analog scale). Two of 9 guidelines recommended shoe lift use based on consensus and were of moderate-to-high quality. CONCLUSIONS: There is low-quality evidence that shoe lifts reduce pain and improve function in patients with LLD and common painful musculoskeletal conditions. High-quality research evaluating a threshold LLD to correct and a strategy to do so is necessary. Developing an appropriate comparison group to test clinically relevant outcome measures would make a valuable contribution in this regard.

Biologics or tofacitinib for people with rheumatoid arthritis naive to methotrexate: a systematic review and network meta-analysis.

BACKGROUND: Biologic disease-modifying anti-rheumatic drugs (biologics) are highly effective in treating rheumatoid arthritis (RA), however there are few head-to-head biologic comparison studies. We performed a systematic review, a standard meta-analysis and a network meta-analysis (NMA) to update the 2009 Cochrane Overview. This review is focused on the adults with RA who are naive to methotrexate (MTX) that is, receiving their first disease-modifying agent. OBJECTIVES: To compare the benefits and harms of biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib versus comparator (methotrexate (MTX)/other DMARDs) in people with RA who are naive to methotrexate. METHODS: In June 2015 we searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE and Embase; and trials registers. We used standard Cochrane methods. We calculated odds ratios (OR) and mean differences (MD) along with 95% confidence intervals (CI) for traditional meta-analyses and 95% credible intervals (CrI) using a Bayesian mixed treatment comparisons approach for network meta-analysis (NMA). We converted OR to risk ratios (RR) for ease of interpretation. We also present results in absolute measures as risk difference (RD) and number needed to treat for an additional beneficial or harmful outcome (NNTB/H). MAIN RESULTS: Nineteen RCTs with 6485 participants met inclusion criteria (including five studies from the original 2009 review), and data were available for four TNF biologics (adalimumab (six studies; 1851 participants), etanercept (three studies; 678 participants), golimumab (one study; 637 participants) and infliximab (seven studies; 1363 participants)) and two non-TNF biologics (abatacept (one study; 509 participants) and rituximab (one study; 748 participants)).Less than 50% of the studies were judged to be at low risk of bias for allocation sequence generation, allocation concealment and blinding, 21% were at low risk for selective reporting, 53% had low risk of bias for attrition and 89% had low risk of bias for major baseline imbalance. Three trials used biologic monotherapy, that is, without MTX. There were no trials with placebo-only comparators and no trials of tofacitinib. Trial duration ranged from 6 to 24 months. Half of the trials contained participants with early RA (less than two years' duration) and the other half included participants with established RA (2 to 10 years). Biologic + MTX versus active comparator (MTX (17 trials (6344 participants)/MTX + methylprednisolone 2 trials (141 participants))In traditional meta-analyses, there was moderate-quality evidence downgraded for inconsistency that biologics with MTX were associated with statistically significant and clinically meaningful benefit versus comparator as demonstrated by ACR50 (American College of Rheumatology scale) and RA remission rates. For ACR50, biologics with MTX showed a risk ratio (RR) of 1.40 (95% CI 1.30 to 1.49), absolute difference of 16% (95% CI 13% to 20%) and NNTB = 7 (95% CI 6 to 8). For RA remission rates, biologics with MTX showed a RR of 1.62 (95% CI 1.33 to 1.98), absolute difference of 15% (95% CI 11% to 19%) and NNTB = 5 (95% CI 6 to 7). Biologics with MTX were also associated with a statistically significant, but not clinically meaningful, benefit in physical function (moderate-quality evidence downgraded for inconsistency), with an improvement of HAQ scores of -0.10 (95% CI -0.16 to -0.04 on a 0 to 3 scale), absolute difference -3.3% (95% CI -5.3% to -1.3%) and NNTB = 4 (95% CI 2 to 15).We did not observe evidence of differences between biologics with MTX compared to MTX for radiographic progression (low-quality evidence, downgraded for imprecision and inconsistency) or serious adverse events (moderate-quality evidence, downgraded for imprecision). Based on low-quality evidence, results were inconclusive for withdrawals due to adverse events (RR of 1.32, but 95% confidence interval included possibility of important harm, 0.89 to 1.97). Results for cancer were also inconclusive (Peto OR 0.71, 95% CI 0.38 to 1.33) and downgraded to low-quality evidence for serious imprecision. Biologic without MTX versus active comparator (MTX 3 trials (866 participants)There was no evidence of statistically significant or clinically important differences for ACR50, HAQ, remission, (moderate-quality evidence for these benefits, downgraded for imprecision), withdrawals due to adverse events,and serious adverse events (low-quality evidence for these harms, downgraded for serious imprecision). All studies were for TNF biologic monotherapy and none for non-TNF biologic monotherapy. Radiographic progression was not measured. AUTHORS' CONCLUSIONS: In MTX-naive RA participants, there was moderate-quality evidence that, compared with MTX alone, biologics with MTX was associated with absolute and relative clinically meaningful benefits in three of the efficacy outcomes (ACR50, HAQ scores, and RA remission rates). A benefit regarding less radiographic progression with biologics with MTX was not evident (low-quality evidence). We found moderate- to low-quality evidence that biologic therapy with MTX was not associated with any higher risk of serious adverse events compared with MTX, but results were inconclusive for withdrawals due to adverse events and cancer to 24 months.TNF biologic monotherapy did not differ statistically significantly or clinically meaningfully from MTX for any of the outcomes (moderate-quality evidence), and no data were available for non-TNF biologic monotherapy.We conclude that biologic with MTX use in MTX-naive populations is beneficial and that there is little/inconclusive evidence of harms. More data are needed for tofacitinib, radiographic progression and harms in this patient population to fully assess comparative efficacy and safety.

Calcium channel blockers for primary and secondary Raynaud's phenomenon.

BACKGROUND: Raynaud's phenomenon is a vasospastic disease characterized by digital pallor, cyanosis, and extremity pain. Primary Raynaud's phenomenon is not associated with underlying disease, but secondary Raynaud's phenomenon is associated with connective tissue disorders such as systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease. Calcium channel blockers promote vasodilation and are commonly used when drug treatment for Raynaud's phenomenon is required. OBJECTIVES: To assess the benefits and harms of calcium channel blockers (CCBs) versus placebo for treatment of individuals with Raynaud's phenomenon with respect to Raynaud's type (primary vs secondary) and type and dose of CCBs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (May 19, 2017), MEDLINE (1946 to May 19, 2017), Embase (1947 to May 19, 2017), clinicaltrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Portal. We applied no language restrictions. We also searched bibliographies of retrieved articles and contacted key experts for additional and unpublished data. SELECTION CRITERIA: All randomized controlled trials (RCTs) comparing calcium channel blockers versus placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed search results and risk of bias and extracted trial data. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: This review contains 38 RCTs (33 cross-over RCTs) with an average duration of 7.4 weeks and 982 participants; however, not all trials reported all outcomes of interest. Nine of the identified trials studied patients with primary Raynaud's phenomenon (N = 365), five studied patients with secondary Raynaud's phenomenon (N = 63), and the rest examined a mixture of patients with primary and secondary Raynaud's phenomenon (N = 554). The most frequently encountered risk of bias types were incomplete outcome data and poor reporting of randomization and allocation methods.When researchers considered both primary and secondary Raynaud's phenomenon, evidence of moderate quality (downgraded for inconsistency) from 23 trials with 528 participants indicates that calcium channel blockers (CCBs) were superior to placebo in reducing the frequency of attacks. CCBs reduced the average number of attacks per week by six ( weighted mean difference (WMD) -6.13, 95% confidence interval (CI) -6.60 to - 5.67; I² = 98%) compared with 13.7 attacks per week with placebo. When review authors excluded Kahan 1985C, a trial showing a very large reduction in the frequency of attacks, data showed that CCBs reduced attack frequency by 2.93 per week (95% CI -3.44 to -2.43; I² = 77%).Low-quality evidence (downgraded for imprecision and inconsistency) from six trials with 69 participants suggests that the average duration of attacks did not differ in a statistically significant or clinically meaningful way between CCBs and placebo (WMD -1.67 minutes, 95% CI -3.29 to 0); this is equivalent to a -9% difference (95% CI -18% to 0%).Moderate-quality evidence (downgraded for inconsistency) based on 16 trials and 415 participants showed that CCBs reduced attack severity by 0.62 cm (95% CI -0.72 to - 0.51) on a 10-cm visual analogue scale (lower scores indicate less severity); this was equivalent to absolute and relative percent reductions of 6% (95% CI -11% to -8%) and 9% (95% CI -11% to -8%), respectively, which may not be clinically meaningful.Improvement in Raynaud's pain (low-quality evidence; downgraded for imprecision and inconsistency) and in disability as measured by a patient global assessment (moderate-quality evidence; downgraded for imprecision) favored CCBs (pain: WMD -1.47 cm, 95% CI -2.21 to -0.74; patient global: WMD -0.37 cm, 95% CI -0.73 to 0, when assessed on a 0 to 10 cm visual analogue scale, with lower scores indicating less pain and less disability). However, these effect estimates were likely underpowered, as they were based on limited numbers of participants, respectively, 62 and 92. For pain assessment, absolute and relative percent improvements were 15% (95% -22% to -7%) and 47% (95% CI -71% to -24%), respectively. For patient global assessment, absolute and relative percent improvements were 4% (95% CI -7% to 0%) and 9% (95% CI -19% to 0%), respectively.Subgroup analyses by Raynaud's type, CCB class, and CCB dose suggest that dihydropyridine CCBs in higher doses may be more effective for primary Raynaud's than for secondary Raynaud's, and CCBs likely have a greater effect in primary than in secondary Raynaud's. However, differences were small and were not found for all outcomes. Dihydropyridine CCBs were studied as they are the subgroup of CCBs that are not cardioselective and are traditionally used in RP treatment whereas other CCBs such as verapamil are not routinely used and diltiazem is not used as first line subtype of CCBs. Most trial data pertained to nifedipine.Withdrawals from studies due to adverse effects were inconclusive owing to a wide CI (risk ratio [RR] 1.30, 95% CI 0.51 to 3.33) from two parallel studies with 63 participants (low-quality evidence downgraded owing to imprecision and a high attrition rate); absolute and relative percent differences in withdrawals were 6% (95% CI -14% to 26%) and 30% (95% CI -49% to 233%), respectively. In cross-over trials, although a meta-analysis was not performed, withdrawals were more common with CCBs than with placebo. The most common side effects were headache, dizziness, nausea, palpitations, and ankle edema. However, in all trials, no serious adverse events (death or hospitalization) were reported. AUTHORS' CONCLUSIONS: Randomized controlled trials with evidence of low to moderate quality showed that CCBs (especially the dihydropyridine class) may be useful in reducing the frequency, duration, severity of attacks, pain and disability associated with Raynaud's phenomenon. Higher doses may be more effective than lower doses and these CCBs may be more effective in primary RP. Although there were more withdrawals due to adverse events in the treatment groups, no serious adverse events were reported.

Biologics or tofacitinib for people with rheumatoid arthritis unsuccessfully treated with biologics: a systematic review and network meta-analysis.

BACKGROUND: Biologic disease-modifying anti-rheumatic drugs (DMARDs: referred to as biologics) are effective in treating rheumatoid arthritis (RA), however there are few head-to-head comparison studies. Our systematic review, standard meta-analysis and network meta-analysis (NMA) updates the 2009 Cochrane overview, 'Biologics for rheumatoid arthritis (RA)' and adds new data. This review is focused on biologic or tofacitinib therapy in people with RA who had previously been treated unsuccessfully with biologics. OBJECTIVES: To compare the benefits and harms of biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib versus comparator (placebo or methotrexate (MTX)/other DMARDs) in people with RA, previously unsuccessfully treated with biologics. METHODS: On 22 June 2015 we searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE, and Embase; and trials registries (WHO trials register, Clinicaltrials.gov). We carried out article selection, data extraction, and risk of bias and GRADE assessments in duplicate. We calculated direct estimates with 95% confidence intervals (CI) using standard meta-analysis. We used a Bayesian mixed treatment comparison (MTC) approach for NMA estimates with 95% credible intervals (CrI). We converted odds ratios (OR) to risk ratios (RR) for ease of understanding. We have also presented results in absolute measures as risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB). Outcomes measured included four benefits (ACR50, function measured by Health Assessment Questionnaire (HAQ) score, remission defined as DAS < 1.6 or DAS28 < 2.6, slowing of radiographic progression) and three harms (withdrawals due to adverse events, serious adverse events, and cancer). MAIN RESULTS: This update includes nine new RCTs for a total of 12 RCTs that included 3364 participants. The comparator was placebo only in three RCTs (548 participants), MTX or other traditional DMARD in six RCTs (2468 participants), and another biologic in three RCTs (348 participants). Data were available for four tumor necrosis factor (TNF)-biologics: (certolizumab pegol (1 study; 37 participants), etanercept (3 studies; 348 participants), golimumab (1 study; 461 participants), infliximab (1 study; 27 participants)), three non-TNF biologics (abatacept (3 studies; 632 participants), rituximab (2 studies; 1019 participants), and tocilizumab (2 studies; 589 participants)); there was only one study for tofacitinib (399 participants). The majority of the trials (10/12) lasted less than 12 months.We judged 33% of the studies at low risk of bias for allocation sequence generation, allocation concealment and blinding, 25% had low risk of bias for attrition, 92% were at unclear risk for selective reporting; and 92% had low risk of bias for major baseline imbalance. We downgraded the quality of the evidence for most outcomes to moderate or low due to study limitations, heterogeneity, or rarity of direct comparator trials. Biologic monotherapy versus placeboCompared to placebo, biologics were associated with clinically meaningful and statistically significant improvement in RA as demonstrated by higher ACR50 and RA remission rates. RR was 4.10 for ACR50 (95% CI 1.97 to 8.55; moderate-quality evidence); absolute benefit RD 14% (95% CI 6% to 21%); and NNTB = 8 (95% CI 4 to 23). RR for RA remission was 13.51 (95% CI 1.85 to 98.45, one study available; moderate-quality evidence); absolute benefit RD 9% (95% CI 5% to 13%); and NNTB = 11 (95% CI 3 to 136). Results for withdrawals due to adverse events and serious adverse events did not show any statistically significant or clinically meaningful differences. There were no studies available for analysis for function measured by HAQ, radiographic progression, or cancer outcomes. There were not enough data for any of the outcomes to look at subgroups. Biologic + MTX versus active comparator (MTX/other traditional DMARDs)Compared to MTX/other traditional DMARDs, biologic + MTX was associated with a clinically meaningful and statistically significant improvement in ACR50, function measured by HAQ, and RA remission rates in direct comparisons. RR for ACR50 was 4.07 (95% CI 2.76 to 5.99; high-quality evidence); absolute benefit RD 16% (10% to 21%); NNTB = 7 (95% CI 5 to 11). HAQ scores showed an improvement with a mean difference (MD) of 0.29 (95% CI 0.21 to 0.36; high-quality evidence); absolute benefit RD 9.7% improvement (95% CI 7% to 12%); and NNTB = 5 (95% CI 4 to 7). Remission rates showed an improved RR of 20.73 (95% CI 4.13 to 104.16; moderate-quality evidence); absolute benefit RD 10% (95% CI 8% to 13%); and NNTB = 17 (95% CI 4 to 96), among the biologic + MTX group compared to MTX/other DMARDs. There were no studies for radiographic progression. Results were not clinically meaningful or statistically significantly different for withdrawals due to adverse events or serious adverse events, and were inconclusive for cancer. Tofacitinib monotherapy versus placeboThere were no published data. Tofacitinib + MTX versus active comparator (MTX)In one study, compared to MTX, tofacitinib + MTX was associated with a clinically meaningful and statistically significant improvement in ACR50 (RR 3.24; 95% CI 1.78 to 5.89; absolute benefit RD 19% (95% CI 12% to 26%); NNTB = 6 (95% CI 3 to 14); moderate-quality evidence), and function measured by HAQ, MD 0.27 improvement (95% CI 0.14 to 0.39); absolute benefit RD 9% (95% CI 4.7% to 13%), NNTB = 5 (95% CI 4 to 10); high-quality evidence). RA remission rates were not statistically significantly different but the observed difference may be clinically meaningful (RR 15.44 (95% CI 0.93 to 256.1; high-quality evidence); absolute benefit RD 6% (95% CI 3% to 9%); NNTB could not be calculated. There were no studies for radiographic progression. There were no statistically significant or clinically meaningful differences for withdrawals due to adverse events and serious adverse events, and results were inconclusive for cancer. AUTHORS' CONCLUSIONS: Biologic (with or without MTX) or tofacitinib (with MTX) use was associated with clinically meaningful and statistically significant benefits (ACR50, HAQ, remission) compared to placebo or an active comparator (MTX/other traditional DMARDs) among people with RA previously unsuccessfully treated with biologics.No studies examined radiographic progression. Results were not clinically meaningful or statistically significant for withdrawals due to adverse events and serious adverse events, and were inconclusive for cancer.

Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis.

BACKGROUND: Serious infections are a major concern for patients considering treatments for rheumatoid arthritis. Evidence is inconsistent as to whether biological drugs are associated with an increased risk of serious infection compared with traditional disease-modifying antirheumatic drugs (DMARDs). We did a systematic review and meta-analysis of serious infections in patients treated with biological drugs compared with those treated with traditional DMARDs. METHODS: We did a systematic literature search with Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to Feb 11, 2014. Search terms included "biologics", "rheumatoid arthritis" and their synonyms. Trials were eligible for inclusion if they included any of the approved biological drugs and reported serious infections. We assessed the risk of bias with the Cochrane Risk of Bias Tool. We did a Bayesian network meta-analysis of published trials using a binomial likelihood model to assess the risk of serious infections in patients with rheumatoid arthritis who were treated with biological drugs, compared with those treated with traditional DMARDs. The odds ratio (OR) of serious infection was the primary measure of treatment effect and calculated 95% credible intervals using Markov Chain Monte Carlo methods. FINDINGS: The systematic review identified 106 trials that reported serious infections and included patients with rheumatoid arthritis who received biological drugs. Compared with traditional DMARDs, standard-dose biological drugs (OR 1.31, 95% credible interval [CrI] 1.09-1.58) and high-dose biological drugs (1.90, 1.50-2.39) were associated with an increased risk of serious infections, although low-dose biological drugs (0.93, 0.65-1.33) were not. The risk was lower in patients who were methotrexate naive compared with traditional DMARD-experienced or anti-tumour necrosis factor biological drug-experienced patients. The absolute increase in the number of serious infections per 1000 patients treated each year ranged from six for standard-dose biological drugs to 55 for combination biological therapy, compared with traditional DMARDs. INTERPRETATION: Standard-dose and high-dose biological drugs (with or without traditional DMARDs) are associated with an increase in serious infections in rheumatoid arthritis compared with traditional DMARDs, although low-dose biological drugs are not. Clinicians should discuss the balance between benefit and harm with the individual patient before starting biological treatment for rheumatoid arthritis. FUNDING: Rheumatology Division at the University of Alabama at Birmingham.

Biologic or tofacitinib monotherapy for rheumatoid arthritis in people with traditional disease-modifying anti-rheumatic drug (DMARD) failure: a Cochrane Systematic Review and network meta-analysis (NMA).

BACKGROUND: We performed a systematic review, a standard meta-analysis and network meta-analysis (NMA), which updates the 2009 Cochrane Overview, 'Biologics for rheumatoid arthritis (RA)'. This review is focused on biologic monotherapy in people with RA in whom treatment with traditional disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX) had failed (MTX/other DMARD-experienced). OBJECTIVES: To assess the benefits and harms of biologic monotherapy (includes anti-tumor necrosis factor (TNF) (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) or non-TNF (abatacept, anakinra, rituximab, tocilizumab)) or tofacitinib monotherapy (oral small molecule) versus comparator (placebo or MTX/other DMARDs) in adults with RA who were MTX/other DMARD-experienced. METHODS: We searched for randomized controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2015, Issue 6, June), MEDLINE (via OVID 1946 to June 2015), and Embase (via OVID 1947 to June 2015). Article selection, data extraction and risk of bias and GRADE assessments were done in duplicate. We calculated direct estimates with 95% confidence intervals (CI) using standard meta-analysis. We used a Bayesian mixed treatment comparisons (MTC) approach for NMA estimates with 95% credible intervals (CrI). We converted odds ratios (OR) to risk ratios (RR) for ease of understanding. We calculated absolute measures as risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB). MAIN RESULTS: This update includes 40 new RCTs for a total of 46 RCTs, of which 41 studies with 14,049 participants provided data. The comparator was placebo in 16 RCTs (4,532 patients), MTX or other DMARD in 13 RCTs (5,602 patients), and another biologic in 12 RCTs (3,915 patients). Monotherapy versus placeboBased on moderate-quality direct evidence, biologic monotherapy (without concurrent MTX/other DMARDs) was associated with a clinically meaningful and statistically significant improvement in American College of Rheumatology score (ACR50) and physical function, as measured by the Health Assessment Questionnaire (HAQ) versus placebo. RR was 4.68 for ACR50 (95% CI, 2.93 to 7.48); absolute benefit RD 23% (95% CI, 18% to 29%); and NNTB = 5 (95% CI, 3 to 8). The mean difference (MD) was -0.32 for HAQ (95% CI, -0.42 to -0.23; a negative sign represents greater HAQ improvement); absolute benefit of -10.7% (95% CI, -14% to -7.7%); and NNTB = 4 (95% CI, 3 to 5). Direct and NMA estimates for TNF biologic, non-TNF biologic or tofacitinib monotherapy showed similar results for ACR50 , downgraded to moderate-quality evidence. Direct and NMA estimates for TNF biologic, anakinra or tofacitinib monotherapy showed a similar results for HAQ versus placebo with mostly moderate quality evidence.Based on moderate-quality direct evidence, biologic monotherapy was associated with a clinically meaningful and statistically significant greater proportion of disease remission versus placebo with RR 1.12 (95% CI 1.03 to 1.22); absolute benefit 10% (95% CI, 3% to 17%; NNTB = 10 (95% CI, 8 to 21)).Based on low-quality direct evidence, results for biologic monotherapy for withdrawals due to adverse events and serious adverse events were inconclusive, with wide confidence intervals encompassing the null effect and evidence of an important increase. The direct estimate for TNF monotherapy for withdrawals due to adverse events showed a clinically meaningful and statistically significant result with RR 2.02 (95% CI, 1.08 to 3.78), absolute benefit RD 3% (95% CI,1% to 4%), based on moderate-quality evidence. The NMA estimates for TNF biologic, non-TNF biologic, anakinra, or tofacitinib monotherapy for withdrawals due to adverse events and for serious adverse events were all inconclusive and downgraded to low-quality evidence. Monotherapy versus active comparator (MTX/other DMARDs)Based on direct evidence of moderate quality, biologic monotherapy (without concurrent MTX/other DMARDs) was associated with a clinically meaningful and statistically significant improvement in ACR50 and HAQ scores versus MTX/other DMARDs with a RR of 1.54 (95% CI, 1.14 to 2.08); absolute benefit 13% (95% CI, 2% to 23%), NNTB = 7 (95% CI, 4 to 26) and a mean difference in HAQ of -0.27 (95% CI, -0.40 to -0.14); absolute benefit of -9% (95% CI, -13.3% to -4.7%), NNTB = 2 (95% CI, 2 to 4). Direct and NMA estimates for TNF monotherapy and NMA estimate for non-TNF biologic monotherapy for ACR50 showed similar results, based on moderate-quality evidence. Direct and NMA estimates for non-TNF biologic monotherapy, but not TNF monotherapy, showed similar HAQ improvements , based on mostly moderate-quality evidence.There were no statistically significant or clinically meaningful differences for direct estimates of biologic monotherapy versus active comparator for RA disease remission. NMA estimates showed a statistically significant and clinically meaningful difference versus active comparator for TNF monotherapy (absolute improvement 7% (95% CI, 2% to 14%)) and non-TNF monotherapy (absolute improvement 19% (95% CrI, 7% to 36%)), both downgraded to moderate quality.Based on moderate-quality direct evidence from a single study, radiographic progression (scale 0 to 448) was statistically significantly reduced in those on biologic monotherapy versus active comparator, MD -4.34 (95% CI, -7.56 to -1.12), though the absolute reduction was small, -0.97% (95% CI, -1.69% to -0.25%). We are not sure of the clinical relevance of this reduction.Direct and NMA evidence (downgraded to low quality), showed inconclusive results for withdrawals due to adverse events, serious adverse events and cancer, with wide confidence intervals encompassing the null effect and evidence of an important increase. AUTHORS' CONCLUSIONS: Based mostly on RCTs of six to 12-month duration in people with RA who had previously experienced and failed treatment with MTX/other DMARDs, biologic monotherapy improved ACR50, function and RA remission rates compared to placebo or MTX/other DMARDs.Radiographic progression was reduced versus active comparator, although the clinical significance was unclear.Results were inconclusive for whether biologic monotherapy was associated with an increased risk of withdrawals due to adverse events, serious adverse events or cancer, versus placebo (no data on cancer) or MTX/other DMARDs.

Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis.

BACKGROUND: This is an update of the 2009 Cochrane overview and network meta-analysis (NMA) of biologics for rheumatoid arthritis (RA). OBJECTIVES: To assess the benefits and harms of nine biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib, versus comparator (MTX, DMARD, placebo (PL), or a combination) in adults with rheumatoid arthritis who have failed to respond to methotrexate (MTX) or other disease-modifying anti-rheumatic drugs (DMARDs), i.e., MTX/DMARD incomplete responders (MTX/DMARD-IR). METHODS: We searched for randomized controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (via The Cochrane Library Issue 6, June 2015), MEDLINE (via OVID 1946 to June 2015), and EMBASE (via OVID 1947 to June 2015). Data extraction, risk of bias and GRADE assessments were done in duplicate. We calculated both direct estimates using standard meta-analysis and used Bayesian mixed treatment comparisons approach for NMA estimates to calculate odds ratios (OR) and 95% credible intervals (CrI). We converted OR to risk ratios (RR) which are reported in the abstract for the ease of interpretation. MAIN RESULTS: This update included 73 new RCTs for a total of 90 RCTs; 79 RCTs with 32,874 participants provided usable data. Few trials were at high risk of bias for blinding of assessors/participants (13% to 21%), selective reporting (4%) or major baseline imbalance (8%); a large number had unclear risk of bias for random sequence generation (68%) or allocation concealment (74%).Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a statistically significant and clinically meaningful improvement in ACR50 versus comparator (RR 2.71 (95% confidence interval (CI) 2.36 to 3.10); absolute benefit 24% more patients (95% CI 19% to 29%), number needed to treat for an additional beneficial outcome (NNTB) = 5 (4 to 6). NMA estimates for ACR50 in tumor necrosis factor (TNF) biologic+MTX/DMARD (RR 3.23 (95% credible interval (Crl) 2.75 to 3.79), non-TNF biologic+MTX/DMARD (RR 2.99; 95% Crl 2.36 to 3.74), and anakinra + MTX/DMARD (RR 2.37 (95% Crl 1.00 to 4.70) were similar to the direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a clinically and statistically important improvement in function measured by the Health Assessment Questionnaire (0 to 3 scale, higher = worse function) with a mean difference (MD) based on direct evidence of -0.25 (95% CI -0.28 to -0.22); absolute benefit of -8.3% (95% CI -9.3% to -7.3%), NNTB = 3 (95% CI 2 to 4). NMA estimates for TNF biologic+MTX/DMARD (absolute benefit, -10.3% (95% Crl -14% to -6.7%) and non-TNF biologic+MTX/DMARD (absolute benefit, -7.3% (95% Crl -13.6% to -0.67%) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with clinically and statistically significantly greater proportion of participants achieving remission in RA (defined by disease activity score DAS < 1.6 or DAS28 < 2.6) versus comparator (RR 2.81 (95% CI, 2.23 to 3.53); absolute benefit 18% more patients (95% CI 12% to 25%), NNTB = 6 (4 to 9)). NMA estimates for TNF biologic+MTX/DMARD (absolute improvement 17% (95% Crl 11% to 23%)) and non-TNF biologic+MTX/DMARD (absolute improvement 19% (95% Crl 12% to 28%) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), radiographic progression (scale 0 to 448) was statistically significantly reduced in those on biologics + MTX/DMARDs versus comparator, MD -2.61 (95% CI -4.08 to -1.14). The absolute reduction was small, -0.58% (95% CI -0.91% to -0.25%) and we are unsure of the clinical relevance of this reduction. NMA estimates of TNF biologic+MTX/DMARD (absolute reduction -0.67% (95% Crl -1.4% to -0.12%) and non-TNF biologic+MTX/DMARD (absolute reduction, -0.68% (95% Crl -2.36% to 0.92%)) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for imprecision), results for withdrawals due to adverse events were inconclusive, with wide confidence intervals encompassing the null effect and evidence of an important increase in withdrawals, RR 1.11 (95% CI 0.96 to 1.30). The NMA estimates of TNF biologic+MTX/DMARD (RR 1.24 (95% Crl 0.99 to 1.57)) and non-TNF biologic+MTX/DMARD (RR 1.20 (95% Crl 0.87 to 1.67)) were similarly inconclusive and downgraded to low for both imprecision and indirectness.Based on direct evidence of high quality, biologic+MTX/DMARD was associated with clinically significantly increased risk (statistically borderline significant) of serious adverse events on biologic+MTX/DMARD (Peto OR [can be interpreted as RR due to low event rate] 1.12 (95% CI 0.99 to 1.27); absolute risk 1% (0% to 2%), As well, the NMA estimate for TNF biologic+MTX/DMARD (Peto OR 1.20 (95% Crl 1.01 to 1.43)) showed moderate quality evidence of an increase in the risk of serious adverse events. The other two NMA estimates were downgraded to low quality due to imprecision and indirectness and had wide confidence intervals resulting in uncertainty around the estimates: non-TNF biologics + MTX/DMARD: 1.07 (95% Crl 0.89 to 1.29) and anakinra: RR 1.06 (95% Crl 0.65 to 1.75).Based on direct evidence of low quality (downgraded for serious imprecision), results were inconclusive for cancer (Peto OR 1.07 (95% CI 0.68 to 1.68) for all biologic+MTX/DMARD combinations. The NMA estimates of TNF biologic+MTX/DMARD (Peto OR 1.21 (95% Crl 0.63 to 2.38) and non-TNF biologic+MTX/DMARD (Peto OR 0.99 (95% Crl 0.58 to 1.78)) were similarly inconclusive and downgraded to low quality for both imprecision and indirectness.Main results text shows the results for tofacitinib and differences between medications. AUTHORS' CONCLUSIONS: Based primarily on RCTs of 6 months' to 12 months' duration, there is moderate quality evidence that the use of biologic+MTX/DMARD in people with rheumatoid arthritis who have failed to respond to MTX or other DMARDs results in clinically important improvement in function and higher ACR50 and remission rates, and increased risk of serious adverse events than the comparator (MTX/DMARD/PL; high quality evidence). Radiographic progression is slowed but its clinical relevance is uncertain. Results were inconclusive for whether biologics + MTX/DMARDs are associated with an increased risk of cancer or withdrawals due to adverse events.

TNF-alpha inhibitors for ankylosing spondylitis.

BACKGROUND: TNF (tumor necrosis factor)-alpha inhibitors block a key protein in the inflammatory chain reaction responsible for joint inflammation, pain, and damage in ankylosing spondylitis. OBJECTIVES: To assess the benefit and harms of adalimumab, etanercept, golimumab, and infliximab (TNF-alpha inhibitors) in people with ankylosing spondylitis. SEARCH METHODS: We searched the following databases to January 26, 2009: MEDLINE (from 1966); EMBASE (from 1980); the Cochrane Central Register of Controlled Trials (CENTRAL; 2008, Issue 4); ACP Journal Club; CINAHL (from 1982); and ISI Web of Knowledge (from 1900). We ran updated searches in May 2012, October 2013, and in June 2014 for McMaster PLUS. We searched major regulatory agencies for safety warnings and clinicaltrials.gov for registered trials. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing adalimumab, etanercept, golimumab and infliximab to placebo, other drugs or usual care in patients with ankylosing spondylitis, reported in abstract or full-text. DATA COLLECTION AND ANALYSIS: Two authors independently assessed search results, risk of bias, and extracted data. We conducted Bayesian mixed treatment comparison (MTC) meta-analyses using WinBUGS software. To investigate a class-effect of harms across biologics, we pooled harms data using Review Manager 5. MAIN RESULTS: We included twenty-one, short-term (24 weeks or less) RCTs with a total of 3308 participants; 18 contributed data to the MTC analysis: adalimumab (4 studies), etanercept (8 studies), golimumab (2 studies), infliximab (3 studies), and one head-to-head study (etanercept versus infliximab) which was unblinded and considered at a higher risk of bias. The risk of selection and detection bias was low or unclear for most of the studies. The risk of selective outcome reporting was low for most studies as they reported on outcomes recommended by the Assessment of SpondyloArthritis international Society. We found little heterogeneity and no significant inconsistency in the MTC analyses. The majority of the studies were funded by pharmaceutical companies. Most studies permitted concomitant therapy of stable doses of disease-modifying anti-rheumatic drugs, non-steroidal anti-inflammatory drugs, or corticosteroids, but allowances varied across studies.Compared with placebo, there was high quality evidence that patients on an anti-TNF agent were three to four times more likely to achieve an ASAS40 response (assessing spinal pain, function, and inflammation, as measured by the mean of intensity and duration of morning stiffness, and patient global assessment) by six months (adalimumab: risk ratio (RR) 3.53, 95% credible interval (Crl) 2.49 to 4.91; etanercept: RR 3.31, 95% Crl 2.38 to 4.53; golimumab: RR 2.90, 95% Crl 1.90 to 4.23; infliximab: RR 4.07, 95% Crl 2.80 to 5.74, with a 25% to 40% absolute difference between treatment and placebo groups. The number needed to treat (NNT) to achieve an ASAS 40 response ranged from 3 to 5.There was high quality evidence of improvement in physical function on a 0 to 10 scale (adalimumab: mean difference (MD) -1.6, 95% Crl -2.2 to -0.9; etanercept: MD -1.1, 95% CrI -1.6 to -0.6; golimumab: MD -1.5, 95% Crl -2.3 to -0.7; infliximab: MD -2.1, 95% Crl -2.7 to -1.4, with an 11% to 21% absolute difference between treatment and placebo groups. The NNT to achieve the minimally clinically important difference of 0.7 points ranged from 2 to 4.Compared with placebo, there was moderate quality evidence (downgraded for imprecision) that patients on an anti-TNF agent were more likely to achieve an ASAS partial remission by six months (adalimumab: RR 6.28, 95% Crl 3.13 to 12.78; etanercept: RR 4.24, 95% Crl 2.31 to 8.09; golimumab: RR 5.18, 95% Crl 1.90 to 14.79; infliximab: RR 15.41, 95% Crl 5.09 to 47.98 with a 10% to 44% absolute difference between treatment and placebo groups. The NNT to achieve an ASAS partial remission response ranged from 3 to 11.There was low to moderate level evidence of a greater reduction in spinal inflammation as measured by magnetic resonance imaging though the absolute differences were small and the clinical relevance of the difference was unclear: adalimumab (1 trial; -6% (95% confidence interval (CI) -12% to 0.05%); 1 trial: 53.6% mean decrease from baseline versus 9.4% mean increase in the placebo group), golimumab (1 trial; -2.5%, (95% CI -5.6% to -0.7%)), and infliximab (1 trial; -3% (95% CI -4% to -2.4%)).Radiographic progression was measured in one trial (N = 60) of etanercept versus placebo and it found that radiologic changes were similar in both groups (detailed data not provided).There were few events of withdrawals due to adverse events leading to imprecision around the estimates. When all the anti-TNF agents were combined against placebo, there was moderate quality evidence from 16 studies of an increased risk of withdrawals due to adverse events in the anti-TNF group (Peto odds ratio (OR) 2.44, 95% CI 1.26 to 4.72; total events: 38/1637 in biologic group; 7/986 in placebo) though the absolute increase in harm was small (1%; 95% CI 0% to 2%).Due to low event rates, evidence of the effect of individual TNF-inhibitors against placebo or for all four biologics pooled together versus placebo on serious adverse events is inconclusive (moderate quality; downgraded for imprecision). For all anti-TNF pooled versus placebo based on 16 studies: Peto OR 1.45, 95% CI 0.85 to 2.48; 51/1530 in biologic group; 18/878 in placebo; absolute difference: 1% (95% CI 0% to 2%).Using indirect comparison methodology, and one head-to-head study of etanercept versus infliximab, wide confidence intervals meant that results were inconclusive for evidence of differences in the major outcomes between different anti-TNF agents. Regulatory agencies have published warnings about rare adverse events of serious infections, including tuberculosis, malignancies and lymphoma. AUTHORS' CONCLUSIONS: There is moderate to high quality evidence that anti-TNF agents improve clinical symptoms in the treatment of ankylosing spondylitis. More participants withdrew due to adverse events when on an anti-TNF agent but we did not find evidence of an increase in serious adverse events, though event rates were low and trials had a short duration. The short-term toxicity profile appears acceptable. Based on indirect comparison methodology, we are uncertain whether there are differences between anti-TNF agents in terms of the key benefit or harm outcomes.

Strategies to increase the ownership and use of insecticide-treated bednets to prevent malaria.

BACKGROUND: Malaria is a life-threatening parasitic disease and 40% of the world's population lives in areas affected by malaria. Insecticide-treated bednets (ITNs) effectively prevent malaria, however, barriers to their use have been identified. OBJECTIVES: To assess the evidence on the effectiveness of available strategies that focus on delivery and appropriate use of ITNs. SEARCH METHODS: We searched the EPOC Register of Studies, CENTRAL, MEDLINE, EMBASE, HealthStar, CINAHL, PubMed, Science Citation Index, ProQuest Dissertations and Theses, African Index Medicus (AIM), World Health Organization Library and Information Networks for Knowledge (WHOLIS), LILACS, Virtual Health Library (VHL), and the World Health Organization Library Information System (WHOLIS). Initial searches were conducted in May 2011, updated in March 2012 and February 2013. Authors contacted organizations and individuals involved in ITN distribution programs or research to identify current initiatives, studies or unpublished data, and searched reference lists of relevant reviews and studies. SELECTION CRITERIA: Randomized controlled trials, non-randomized controlled trials, controlled before-after studies, and interrupted time series evaluating interventions focused on increasing ITN ownership and use were considered. The populations of interest were individuals in malaria-endemic areas. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies to be included. They extracted data from the selected studies and assessed the risk of bias. When consensus was not reached, any disagreements were discussed with a third author. The magnitude of effect and quality of evidence for each outcome was assessed. MAIN RESULTS: Of the 3032 records identified, 10 studies were included in this review. Effect of ITN cost on ownership:Four studies including 4566 households and another study comprising 424 participants evaluated the effect of ITN price on ownership. These studies suggest that providing free ITNs probably increases ITN ownership when compared to subsidized ITNs or ITNs offered at full market price. Effect of ITN Cost on appropriate use of ITNs:Three studies including 9968 households and another study comprising 259 individuals found that there is probably little or no difference in the use of ITNs when they are provided free, compared to providing subsidized ITNs or ITNs offered at full market price. Education:Five studies, including 12,637 households, assessed educational interventions regarding ITN use and concluded that education may increase the number of adults and children using ITNs (sleeping under ITNs) compared to no education.One study, including 519 households, assessed the effects of providing an incentive (an undisclosed prize) to promote ITN ownership and use, and found that incentives probably lead to little or no difference in ownership or use of ITNs, compared to not receiving an incentive.None of the included studies reported on adverse effects. AUTHORS' CONCLUSIONS: Five studies examined the effect of price on ITN ownership and found moderate-certainty evidence that ownership was highest among the groups who received the ITN free versus those who purchased the ITN at any cost. In economic terms, this means that demand for ITNs is elastic with regard to price. However, once the ITN is supplied, the price paid for the ITN probably has little to no effect on its use; the four studies addressing this outcome failed to confirm the hypothesis that people who purchase nets will use them more than those who receive them at no cost. Educational interventions for promoting ITN use have an additional positive effect. However, the impact of different types or intensities of education is unknown.

PROTOCOL: Effects of social prescribing for older adults: An evidence and gap map.

Objectives This is the protocol for an evidence and gap map. The objectives are as follows: The aim of this evidence and gap map is to map the available evidence on the effectiveness of social prescribing interventions addressing a non-medical, health-related social need for older adults in any setting. Specific objectives are as follows: 1.To identify existing evidence from primary studies and systematic reviews on the effects of community-based interventions that address non-medical, health-related social needs of older adults to improve their health and wellbeing.2.To identify research evidence gaps for new high-quality primary studies and systematic reviews.3.To highlight evidence of health equity considerations from included primary studies and systematic reviews.

Effects of guaranteed basic income interventions on poverty-related outcomes in high-income countries: A systematic review and meta-analysis.

Background: High-income countries offer social assistance (welfare) programs to help alleviate poverty for people with little or no income. These programs have become increasingly conditional and stringent in recent decades based on the premise that transitioning people from government support to paid work will improve their circumstances. However, many people end up with low-paying and precarious jobs that may cause more poverty because they lose benefits such as housing subsidies and health and dental insurance, while incurring job-related expenses. Conditional assistance programs are also expensive to administer and cause stigma. A guaranteed basic income (GBI) has been proposed as a more effective approach for alleviating poverty, and several experiments have been conducted in high-income countries to investigate whether GBI leads to improved outcomes compared to existing social programs. Objectives: The aim of this review was to conduct a synthesis of quantitative evidence on GBI interventions in high-income countries, to compare the effectiveness of various types of GBI versus "usual care" (including existing social assistance programs) in improving poverty-related outcomes. Search Methods: Searches of 16 academic databases were conducted in May 2022, using both keywords and database-specific controlled vocabulary, without limits or restrictions on language or date. Sources of gray literature (conference, governmental, and institutional websites) were searched in September 2022. We also searched reference lists of review articles, citations of included articles, and tables of contents of relevant journals in September 2022. Hand searching for recent publications was conducted until December 2022. Selection Criteria: We included all quantitative study designs except cross-sectional (at one timepoint), with or without control groups. We included studies in high income countries with any population and with interventions meeting our criteria for GBI: unconditional, with regular payments in cash (not in-kind) that were fixed or predictable in amount. Although two primary outcomes of interest were selected a priori (food insecurity, and poverty level assessed using official, national, or international measures), we did not screen studies on the basis of reported outcomes because it was not possible to define all potentially relevant poverty-related outcomes in advance. Data Collection and Analysis: We followed the Campbell Collaboration conduct and reporting guidelines to ensure a rigorous methodology. The risk of bias was assessed across seven domains: confounding, selection, attrition, motivation, implementation, measurement, and analysis/reporting. We conducted meta-analyses where results could be combined; otherwise, we presented the results in tables. We reported effect estimates as standard mean differences (SMDs) if the included studies reported them or provided sufficient data for us to calculate them. To compare the effects of different types of interventions, we developed a GBI typology based on the characteristics of experimental interventions as well as theoretical conceptualizations of GBI. Eligible poverty-related outcomes were classified into categories and sub-categories, to facilitate the synthesis of the individual findings. Because most of the included studies analyzed experiments conducted by other researchers, it was necessary to divide our analysis according to the "experiment" stage (i.e., design, recruitment, intervention, data collection) and the "study" stage (data analysis and reporting of results). Main Results: Our searches yielded 24,476 records from databases and 80 from other sources. After screening by title and abstract, the full texts of 294 potentially eligible articles were retrieved and screened, resulting in 27 included studies on 10 experiments. Eight of the experiments were RCTs, one included both an RCT site and a "saturation" site, and one used a repeated cross-sectional design. The duration ranged from one to 5 years. The control groups in all 10 experiments received "usual care" (i.e., no GBI intervention). The total number of participants was unknown because some of the studies did not report exact sample sizes. Of the studies that did, the smallest had 138 participants and the largest had 8019. The risk of bias assessments found "some concerns" for at least one domain in all 27 studies and "high risk" for at least one domain in 25 studies. The risk of bias was assessed as high in 21 studies due to attrition and in 22 studies due to analysis and reporting bias. To compare the interventions, we developed a classification framework of five GBI types, four of which were implemented in the experiments, and one that is used in new experiments now underway. The included studies reported 176 poverty-related outcomes, including one pre-defined primary outcome: food insecurity. The second primary outcome (poverty level assessed using official, national, or international measures) was not reported in any of the included studies. We classified the reported outcomes into seven categories: food insecurity (as a category), economic/material, physical health, psychological/mental health, social, educational, and individual choice/agency. Food insecurity was reported in two studies, both showing improvements (SMD = -0.57, 95% CI: -0.65 to -0.49, and SMD = -0.41, 95% CI: -0.57 to -0.26) which were not pooled because of different study designs. We conducted meta-analyses on four secondary outcomes that were reported in more than one study: subjective financial well-being, self-rated overall physical health, self-rated life satisfaction, and self-rated mental distress. Improvements were reported, except for overall physical health or if the intervention was similar to existing social assistance. The results for the remaining 170 outcomes, each reported in only one study, were summarized in tables by category and subcategory. Adverse effects were reported in some studies, but only for specific subgroups of participants, and not consistently, so these results may have been due to chance. Authors' Conclusions: The results of the included studies were difficult to synthesize because of the heterogeneity in the reported outcomes. This was due in part to poverty being multidimensional, so outcomes covered various aspects of life (economic, social, psychological, educational, agency, mental and physical health). Evidence from future studies would be easier to assess if outcomes were measured using more common, validated instruments. Based on our analysis of the included studies, a supplemental type of GBI (provided along with existing programs) may be effective in alleviating poverty-related outcomes. This approach may also be safer than a wholesale reform of existing social assistance approaches, which could have unintended consequences.

Motivations for investigating health inequities in observational epidemiology: a content analysis of 320 studies.

OBJECTIVES: To enhance equity in clinical and epidemiological research, it is crucial to understand researcher motivations for conducting equity-relevant studies. Therefore, we evaluated author motivations in a randomly selected sample of equity-relevant observational studies published during the COVID-19 pandemic. STUDY DESIGN AND SETTING: We searched MEDLINE for studies from 2020 to 2022, resulting in 16,828 references. We randomly selected 320 studies purposefully sampled across income setting (high vs low-middle-income), COVID-19 topic (vs non-COVID-19), and focus on populations experiencing inequities. Of those, 206 explicitly mentioned motivations which we analyzed thematically. We used discourse analysis to investigate the reasons behind emerging motivations. RESULTS: We identified the following motivations: (1) examining health disparities, (2) tackling social determinants to improve access, and (3) addressing knowledge gaps in health equity. Discourse analysis showed motivations stem from commitments to social justice and recognizing the importance of highlighting it in research. Other discourses included aspiring to improve health-care efficiency, wanting to understand cause-effect relationships, and seeking to contribute to an equitable evidence base. CONCLUSION: Understanding researchers' motivations for assessing health equity can aid in developing guidance that tailors to their needs. We will consider these motivations in developing and sharing equity guidance to better meet researchers' needs.

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.

BACKGROUND: Methotrexate (MTX) is a disease modifying antirheumatic drug (DMARD) used as a first line agent for treating rheumatoid arthritis (RA). Pharmacologically, it is classified as an antimetabolite due to its antagonistic effect on folic acid metabolism. Many patients treated with MTX experience mucosal, gastrointestinal, hepatic or haematologic side effects. Supplementation with folic or folinic acid during treatment with MTX may ameliorate these side effects. OBJECTIVES: To identify trials of supplementation with folic acid or folinic acid during MTX therapy for rheumatoid arthritis and to assess the benefits and harms of folic acid and folinic acid (a) in reducing the mucosal, gastrointestinal (GI), hepatic and haematologic side effects of MTX, and (b) whether or not folic or folinic acid supplementation has any effect on MTX benefit. SEARCH METHODS: We originally performed MEDLINE searches, from January 1966 to June 1999. During the update of this review, we searched additional databases and used a sensitive search strategy designed to retrieve all trials on folic acid or folinic acid for rheumatoid arthritis from 1999 up to 2 March 2012. SELECTION CRITERIA: We selected all double-blind, randomised, placebo-controlled clinical trials (RCTs) in which adult patients with rheumatoid arthritis were treated with MTX (at a dose equal to or less than 25 mg/week) concurrently with folate supplementation. In this update of the review we only included trials using 'low dose' folic or folinic acid (a starting dose of ≤ 7 mg weekly). DATA COLLECTION AND ANALYSIS: Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria. MAIN RESULTS: Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as 'moderate' for each outcome as assessed by GRADE, with the exception of haematologic side effects which were rated as 'low'. There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled.For patients supplemented with any form of exogenous folate (either folic or folinic acid) whilst on MTX therapy for rheumatoid arthritis, a 26% relative (9% absolute) risk reduction was seen for the incidence of GI side effects such as nausea, vomiting or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; P = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; P < 0.00001), as well as reducing patient withdrawal from MTX for any reason (60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; P < 0.00001).We analysed the effect of folic or folinic acid on the incidence of stomatitis / mouth sores, and whilst showing a trend towards reduction in risk, the results were not statistically significant (RR 0.72, 95% CI 0.49 to 1.06)It was not possible to draw meaningful conclusions on the effect of folic or folinic acid on haematologic side effects of methotrexate due to small numbers of events and poor reporting of this outcome in included trials.It does not appear that supplementation with either folic or folinic acid has a statistically significant effect on the efficacy of MTX in treating RA (as measured by RA disease activity parameters such as tender and swollen joint counts, or physician's global assessment scores). AUTHORS' CONCLUSIONS: The results support a protective effect of supplementation with either folic or folinic acid for patients with rheumatoid arthritis during treatment with MTX.There was a significant reduction shown in the incidence of GI side effects, hepatic dysfunction (asmeasured by elevated serum transaminase levels) as well as a significant reduction in discontinuation of MTX treatment for any reason. A trend towards a reduction in stomatitis was demonstrated however this did not reach statistical significance.This updated review with its focus on lower doses of folic acid and folinic acid and updated assessment of risk of bias aimed to give a more precise and more clinically relevant estimate of the benefit of folate supplementation for patients with rheumatoid arthritis receiving methotrexate.

Stretching, Bracing, and Devices for the Treatment of Osteoarthritis-Associated Joint Contractures in Nonoperated Joints: A Systematic Review and Meta-Analysis.

CONTEXT: Many patients with osteoarthritis (OA) develop range of motion (ROM) restrictions in their affected joints (contractures), associated with worse outcomes and rising healthcare costs. Effective treatment guidance for lost ROM in OA-affected joints is lacking. OBJECTIVE: A systematic review and meta-analysis evaluating the effectiveness of stretching and/or bracing protocols on native (nonoperated) joint ROM in the setting of radiographically diagnosed OA. DATA SOURCES: Seven databases, English-language. STUDY SELECTION: Studies including participants with radiographically diagnosed OA in any native joint evaluating the effect of stretching or bracing on ROM. STUDY DESIGN: Systematic review and meta-analysis. LEVEL OF EVIDENCE: Level 2. DATA EXTRACTION: Two reviewers independently screened articles for inclusion and assessed risk of bias in included trials. Primary outcomes were ROM, pain, and adverse events (AEs). RESULTS: We identified 6284 articles. A total of 9 randomized controlled trials, all evaluating the knee, met eligibility criteria. For stretching, 3 pooled studies reported total ROM, which improved by mean difference (MD) of 9.3° (95% CI 5.0°,13.5°) versus controls. Two pooled studies showed improved knee flexion ROM (MD 10.8° [7.3°,14.2°]) versus controls. Five studies were pooled for knee extension with mean improvement 9.1° [3.4°,14.8°] versus controls. Seven pooled studies showed reduced pain (standardized MD 1.9 [1.2,2.6]). One study reported improved knee extension of 3.7° [2.9°,4.5°] with use of a device. No studies used orthoses. One study reported on AEs, with none noted. Performance bias was present in all included studies, and only 3 studies clearly reported blinding of outcome assessors. Strength of evidence for primary outcomes was considered moderate. CONCLUSION: There was moderate-quality evidence that stretching is an effective strategy for improving knee total, flexion and extension ROM, and pain. Our findings suggest that stretching to regain joint ROM in OA is not futile and that stretching appears to be an appropriate conservative intervention to improve patient outcomes as part of a comprehensive knee OA treatment plan before arthroplasty.

Realist review of community coalitions and outreach interventions to increase access to primary care for vulnerable populations: a realist review.

BACKGROUND: There are meaningful gaps in equitable access to Primary Health Care (PHC), especially for vulnerable populations after widespread reforms in Western countries. The Innovative Models Promoting Access-to-Care Transformation (IMPACT) research program is a Canadian-Australian collaboration that aims to improve access to PHC for vulnerable populations. Relationships were developed with stakeholders in six regions across Canada and Australia where access-related needs could be identified. The most promising interventions would be implemented and tested to address the needs identified. This realist review was conducted to understand how community coalition and outreach (e.g., mobile or pop-up) services improve access for underserved vulnerable residents. OBJECTIVE: To inform the development and delivery of an innovative intervention to increase access to PHC for vulnerable populations. METHODS: A realist review was conducted in collaboration with the Local Innovative Partnership (LIP) research team and the IMPACT research members who conducted the review. We performed an initial comprehensive systematic search using MEDLINE, EMBASE, PsycINFO, and the Cochrane Library up to October 19, 2015, and updated it on August 8, 2020. Studies were included if they focused on interventions to improve access to PHC using community coalition, outreach services or mobile delivery methods. We included Randomized Controlled Trials (RCTs), and systematic reviews. Studies were screened by two independent reviewers and the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework was used for data extraction and framework analysis to obtain themes. The LIP research team was also allowed to suggest additional papers not included at screening. RESULTS: We included 43 records, comprising 31 RCTs, 11 systematic reviews, and 1 case control study that was added by the LIP research team. We identified three main themes of PHC interventions to promote access for vulnerable residents, including: 1) tailoring of materials and services decreases barriers to primary health care, 2) services offered where vulnerable populations gather increases the "reach" of the interventions, 3) partnerships and collaborations lead to positive health outcomes. In addition, implementation designs and reporting elements should be considered. CONCLUSION: Realist reviews can help guide the development of locally adapted primary health care interventions.

Equity Considerations in COVID-19 Vaccination Studies of Individuals With Autoimmune Inflammatory Rheumatic Diseases.

OBJECTIVE: We sought to examine the extent to which populations experiencing inequities were considered in studies of COVID-19 vaccination in individuals with autoimmune inflammatory rheumatic diseases (AIRDs). METHODS: We included all studies (n = 19) from an ongoing Cochrane living systematic review on COVID-19 vaccination in patients with AIRDs. We used the PROGRESS-Plus framework (place of residence, race/ethnicity, occupation, gender/sex, religion, education, socioeconomic status, and social capital, plus: age, multimorbidity, and health literacy) to identify factors that stratify health outcomes. We assessed equity considerations in relation to differences in COVID-19 baseline risk, eligibility criteria, and description of participant characteristics and attrition, controlling for confounding factors, subgroup analyses, and applicability of findings. RESULTS: All 19 studies were cohort studies that followed individuals with AIRDs after vaccination. Three studies (16%) described differences in baseline risk for COVID-19 across age. Two studies (11%) defined eligibility criteria based on occupation and age. All 19 studies described participant age and sex. Twelve studies (67%) controlled for age and/or sex as confounders. Eight studies (47%) conducted subgroup analyses across at least 1 PROGRESS-Plus factor, most commonly age. Ten studies (53%) interpreted applicability in relation to at least 1 PROGRESS-Plus factor, most commonly age (47%), then ethnicity (16%), sex (16%), and multimorbidity (11%). CONCLUSION: Sex and age were the most frequently considered PROGRESS-Plus factors in studies of COVID-19 vaccination in individuals with AIRDs. The generalizability of evidence to populations experiencing inequities is uncertain. Future COVID-19 vaccine studies should report participant characteristics in more detail to inform guideline recommendations.