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.

Interventions for promoting reintegration and reducing harmful behaviour and lifestyles in street-connected children and young people.

BACKGROUND: Numbers of street-connected children and young people run into many millions worldwide and include children and young people who live or work in street environments. Whether or not they remain connected to their families of origin, and despite many strengths and resiliencies, they are vulnerable to a range of risks and are excluded from mainstream social structures and opportunities. OBJECTIVES: To summarise the effectiveness of interventions for street-connected children and young people that promote inclusion and reintegration and reduce harms. To explore the processes of successful intervention and models of change in this area, and to understand how intervention effectiveness may vary in different contexts. SEARCH METHODS: We searched the following bibliographic databases, from inception to 2012, and various relevant non-governmental and organisational websites: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE and PreMEDLINE; EMBASE and EMBASE Classic; CINAHL; PsycINFO; ERIC; Sociological Abstracts; Social Services Abstracts; Social Work Abstracts; Healthstar; LILACS; System for Grey literature in Europe (OpenGrey); ProQuest Dissertations and Theses; EconLit; IDEAS Economics and Finance Research; JOLIS Library Catalog of the holdings of the World Bank Group and IMF Libraries; BLDS (British Library for Development Studies); Google, Google Scholar. SELECTION CRITERIA: The review included data from harm reduction or reintegration promotion intervention studies that used a comparison group study design and were all randomised or quasi-randomised studies. Studies were included if they evaluated interventions aimed to benefit street-connected children and young people, aged 0 to 24 years, in all contexts. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias of included studies. Data were extracted on intervention delivery, context, process factors, equity and outcomes. Outcome measures were grouped according to whether they measured psychosocial outcomes, risky sexual behaviours or substance use. A meta-analysis was conducted for some outcomes though it was not possible for all due to differences in measurements between studies. Other outcomes were evaluated narratively. MAIN RESULTS: We included 11 studies evaluating 12 interventions from high income countries. We did not find any sufficiently robust evaluations conducted in low and middle income countries (LMICs) despite the existence of many relevant programmes. Study quality overall was low to moderate and there was great variation in the measurement used by studies, making comparison difficult. Participants were drop-in and shelter based. We found no consistent results on a range of relevant outcomes within domains of psychosocial health, substance misuse and sexual risky behaviours despite the many measurements collected in the studies. The interventions being evaluated consisted of time limited therapeutically based programmes which did not prove more effective than standard shelter or drop-in services for most outcomes and in most studies. There were favourable changes from baseline in outcomes for most particpants in therapy interventions and also in standard services. There was considerable heterogeneity between studies and equity data were inconsistently reported. No study measured the primary outcome of reintegration or reported on adverse effects. The review discussion section included consideration of the relevance of the findings for LMIC settings. AUTHORS' CONCLUSIONS: Analysis across the included studies found no consistently significant benefit for the 'new' interventions compared to standard services for street-connected children and young people. These latter interventions, however, have not been rigorously evaluated, especially in the context of LMICs. Robustly evaluating the interventions would enable better recommendations to be made for service delivery. There is a need for future research in LMICs that includes children who are on the streets due to urbanisation, war or migration and who may be vulnerable to risks such as trafficking.

Methotrexate for ankylosing spondylitis.

BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown cause, characterized by sacroiliitis and spondylitis. Methotrexate (MTX), a widely used disease-modifying antirheumatic drug (DMARD), is effective for rheumatoid arthritis (RA), and so might work for AS. This is an update of a Cochrane review first published in 2004, and previously updated in 2006. OBJECTIVES: To evaluate the benefits and harms of MTX for treating AS. SEARCH METHODS: We searched CENTRAL (The Cochrane Library Issue 6, 2012), MEDLINE (2005 to June 25, 2012), EMBASE (2005 to June 25, 2012), Ovid MEDLINE Scopus, World Health Organization International Clinical Trials Registry Platform and the reference sections of retrieved articles. Trials published in any language were acceptable. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-randomized controlled trials (qRCTs) examining the benefits and harms of MTX versus placebo, other medication, or no medication for treatment of AS. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. We resolved any disagreements through discussions with a third review author. In the absence of significant heterogeneity, we combined results for continuous data using mean difference or standardized mean difference values. We calculated the risk ratio for dichotomous data. MAIN RESULTS: We identified three RCTs (no additional new studies), which included 116 participants. Of these three trials, one was a 12-month trial that compared naproxen plus MTX with naproxen alone. Also, there were two 24-week trials that compared different doses of MTX with placebo. We included the outcomes of response, physical function, pain, spinal mobility, peripheral joints/entheses pain, swelling and tenderness, changes in spine radiographs, and patient and physician global assessment. We judged only one trial to be at low risk of bias. Across these three trials, we did not identify any statistically significant differences favoring MTX treatment over no MTX treatment apart from one exception. The response rate in one trial showed a statistically significant absolute benefit of 36% and a number to treat for benefit (NNT) of three in the MTX group compared to the placebo group (RR 3.18, 95% CI 1.03 to 9.79). This response rate was based on a composite index that included assessments of morning stiffness, physical well-being, Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), health assessment questionnaire for spondyloarthropathies (HAQ-S), and physician and patient global assessment. We did not identify any outcome that showed a statistically significant difference between the MTX treated and no MTX treatment groups when endpoint results were compared. Furthermore, no serious side effects were reported in any of the included trials. AUTHORS' CONCLUSIONS: There is not enough evidence to support any benefit of MTX in the treatment of AS. High-quality RCTs of larger sample sizes are needed to clarify the effect(s) of MTX on AS.

Interventions for promoting reintegration and reducing harmful behaviour and lifestyles in street-connected children and young people.

BACKGROUND: Numbers of street-connected children and young people run into many millions worldwide and include children and young people who live or work in street environments. Whether or not they remain connected to their families of origin, and despite many strengths and resiliencies, they are vulnerable to a range of risks and are excluded from mainstream social structures and opportunities. OBJECTIVES: To summarise the effectiveness of interventions for street-connected children and young people that promote inclusion and reintegration and reduce harms. To explore the processes of successful intervention and models of change in this area, and to understand how intervention effectiveness may vary in different contexts.. SEARCH METHODS: We searched the following bibliographic databases, from inception to 2012, and various relevant non-governmental and organisational websites: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE and PreMEDLINE; EMBASE and EMBASE Classic; CINAHL; PsycINFO; ERIC; Sociological Abstracts; Social Services Abstracts; Social Work Abstracts; Healthstar; LILACS; System for Grey literature in Europe (OpenGrey); ProQuest Dissertations and Theses; EconLit; IDEAS Economics and Finance Research; JOLIS Library Catalog of the holdings of the World Bank Group and IMF Libraries; BLDS (British Library for Development Studies); Google, Google Scholar. SELECTION CRITERIA: The review included data from harm reduction or reintegration promotion intervention studies that used a comparison group study design and were all randomised or quasi-randomised studies. Studies were included if they evaluated interventions aimed to benefit street-connected children and young people, aged 0 to 24 years, in all contexts. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias of included studies. Data were extracted on intervention delivery, context, process factors, equity and outcomes. Outcome measures were grouped according to whether they measured psychosocial outcomes, risky sexual behaviours or substance use. A meta-analysis was conducted for some outcomes though it was not possible for all due to differences in measurements between studies. Other outcomes were evaluated narratively. MAIN RESULTS: We included 11 studies evaluating 12 interventions from high income countries. We did not find any sufficiently robust evaluations conducted in low and middle income countries (LMICs) despite the existence of many relevant programmes. Study quality overall was low to moderate and there was great variation in the measurement used by studies, making comparison difficult. Participants were drop-in and shelter based. We found no consistent results on a range of relevant outcomes within domains of psychosocial health, substance misuse and sexual risky behaviours despite the many measurements collected in the studies. The interventions being evaluated consisted of time limited therapeutically based programmes which did not prove more effective than standard shelter or drop-in services for most outcomes and in most studies. There were favourable changes from baseline in outcomes for most particpants in therapy interventions and also in standard services. There was considerable heterogeneity between studies and equity data were inconsistently reported. No study measured the primary outcome of reintegration or reported on adverse effects. The review discussion section included consideration of the relevance of the findings for LMIC settings. AUTHORS' CONCLUSIONS: Analysis across the included studies found no consistently significant benefit for the 'new' interventions compared to standard services for street-connected children and young people. These latter interventions, however, have not been rigorously evaluated, especially in the context of LMICs. Robustly evaluating the interventions would enable better recommendations to be made for service delivery. There is a need for future research in LMICs that includes children who are on the streets due to urbanisation, war or migration and who may be vulnerable to risks such as trafficking.