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 We searched the bibliographies of retrieved articles and contacted key experts in the field for additional and unpublished data.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.

Tramadol for osteoarthritis.

BACKGROUND: Tramadol is often prescribed to treat pain and is associated physical disability in osteoarthritis (OA). Due to the pharmacologic mechanism of tramadol, it may lead to fewer associated adverse effects (i.e. gastrointestinal bleeding or renal problems) compared to non-steroidal anti-inflammatory drugs (NSAIDs). This is an update of a Cochrane Review originally published in 2006. OBJECTIVES: To determine the benefits and harms of oral tramadol or tramadol combined with acetaminophen or NSAIDs in people with osteoarthritis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase databases, as well as the US National Institutes of Health and World Health Organization trial registries up to February 2018. We searched the LILACS database up to August 2015. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated the effect of tramadol, or tramadol in combination with acetaminophen (paracetamol) or NSAIDs versus placebo or any comparator in people with osteoarthritis. DATA COLLECTION AND ANALYSIS: We used standard methodologic procedures expected by Cochrane. MAIN RESULTS: We included 22 RCTs (11 more than the previous review) of which 21 RCTs were included in meta-analyses for 3871 participants randomized to tramadol alone or tramadol in combination with another analgesic and 2625 participants randomized to placebo or active control. Seventeen studies evaluated tramadol alone and five evaluated tramadol plus acetaminophen. Thirteen studies used placebo controls and eleven studies used active controls (two trials had both placebo and active arms). The dose of tramadol ranged from 37.5 mg to 400 mg daily; all doses were pooled. Most trials were multicenter with a mean duration of two months. Participants were predominantly women with hip or knee osteoarthritis, with a mean age of 63 years and moderate to severe pain. There was a high risk of selection bias as only four trials reported both adequate sequence generation and allocation concealment. There was a low risk for performance bias as most studies blinded participants. There was a high risk of attrition bias as 10/22 trials showed incomplete outcome data. Most of the trials were funded by the pharmaceutical industry.Moderate quality evidence (downgraded due to risk of bias) indicated that tramadol alone and in combination with acetaminophen had no important benefit on pain reduction compared to placebo control (tramadol alone: 4% absolute improvement, 95% confidence interval (CI) 3% to 5%; 8 studies, 3972 participants; tramadol in combination with acetaminophen: 4% absolute improvement, 95% CI 2% to 6%; 2 studies, 614 participants).Fifteen out of 100 people in the tramadol group improved by 20% (which corresponded to a clinically important difference in pain) compared to 10/100 in the placebo group (5% absolute improvement). Twelve out of 100 people improved by 20% in the tramadol in combination with acetaminophen group compared to 7/100 in the placebo group (5% absolute improvement).Moderate quality evidence (downgraded due to risk of bias) indicated that tramadol alone and in combination with acetaminophen led to no important benefit in physical function compared to placebo (tramadol alone: 4% absolute improvement, 95% CI 2% to 6%; 5 studies, 2550 participants; tramadol in combination with acetaminophen: 4% absolute improvement, 95% CI 2% to 7%; 2 studies, 614 participants).Twenty-one out of 100 people in the tramadol group improved by 20% (which corresponded to a clinically important difference in physical function) compared to 16/100 in the placebo group (5% absolute improvement). Fifteen out of 100 people improved by 20% in the tramadol in combination with acetaminophen group compared to 10/100 in the placebo group (5% absolute improvement).Moderate quality evidence (downgraded due to risk of bias) indicated that, compared to placebo, there was a greater risk of developing adverse events with tramadol alone (risk ratio (RR) 1.34, 95% CI 1.24 to 1.46; 4 studies, 2039 participants) and tramadol in combination with acetaminophen compared to placebo (RR 1.91, 95% CI 1.32 to 2.76; 1 study, 308 participants). This corresponded to a 17% increase (95% CI 12% to 23%) with tramadol alone and 22% increase (95% CI 8% to 41%) with tramadol in combination with acetaminophen.The three most frequent adverse events were nausea, dizziness and tiredness. Moderate quality evidence (downgraded due to risk of bias) indicated that there was a greater risk of withdrawing from the study because of adverse events with tramadol alone compared to placebo (RR 2.64, 95% CI 2.17 to 3.20; 9 studies, 4533 participants), which corresponded to a 12% increase (95% CI 9% to 16%).Low quality evidence (downgraded due to risk of bias and inconsistency) indicated that there was a greater risk of withdrawing from the study because of adverse events with tramadol in combination with acetaminophen compared to placebo (RR 2.78, 95% CI 1.50 to 5.16; 2 studies, 614 participants), which corresponded to a 8% absolute improvement (95% CI 2% to 19%).Low quality evidence (downgraded due to risk of bias and imprecision) indicated that there was a greater risk of developing serious adverse events with tramadol alone compared to placebo (110/2459 participants with tramadol compared to 22/1153 participants with placebo; RR 1.78, 95% CI 1.11 to 2.84; 7 studies, 3612 participants), which corresponded to a 1% increase (95% CI 0% to 4%). There were no serious adverse events reported in one small study (15 participants) of tramadol with acetaminophen compared to placebo. AUTHORS' CONCLUSIONS: Moderate quality evidence indicates that compared to placebo, tramadol alone or in combination with acetaminophen probably has no important benefit on mean pain or function in people with osteoarthritis, although slightly more people in the tramadol group report an important improvement (defined as 20% or more). Moderate quality evidence shows that adverse events probably cause substantially more participants to stop taking tramadol. The increase in serious adverse events with tramadol is less certain, due to the small number of events.

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.

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.

Chondroitin for osteoarthritis.

BACKGROUND: Osteoarthritis, a common joint disorder, is one of the leading causes of disability. Chondroitin has emerged as a new treatment. Previous meta-analyses have shown contradictory results on the efficacy of chondroitin. This, in addition to the publication of more trials, necessitates a systematic review. OBJECTIVES: To evaluate the benefit and harm of oral chondroitin for treating osteoarthritis compared with placebo or a comparator oral medication including, but not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, opioids, and glucosamine or other "herbal" medications. SEARCH METHODS: We searched seven databases up to November 2013, including the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, CINAHL, EMBASE, Science Citation Index (Web of Science) and Current Controlled Trials. We searched the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) websites for adverse effects. Trial registers were not searched. SELECTION CRITERIA: All randomized or quasi-randomized clinical trials lasting longer than two weeks, studying adults with osteoarthritis in any joint, and comparing chondroitin with placebo, an active control such as NSAIDs, or other "herbal" supplements such as glucosamine. DATA COLLECTION AND ANALYSIS: Two review authors independently performed all title assessments, data extractions, and risk of bias assessments. MAIN RESULTS: Forty-three randomized controlled trials including 4,962 participants treated with chondroitin and 4,148 participants given placebo or another control were included. The majority of trials were in knee OA, with few in hip and hand OA. Trial duration varied from 1 month to 3 years. Participants treated with chondroitin achieved statistically significantly and clinically meaningful better pain scores (0-100) in studies less than 6 months than those given placebo with an absolute risk difference of 10% lower (95% confidence interval (CI), 15% to 6% lower; number needed to treat (NNT) = 5 (95% CI, 3 to 8; n = 8 trials) (level of evidence, low; risk of bias, high); but there was high heterogeneity between the trials (T(2) = 0.07; I(2) = 70%, which was not easily explained by differences in risk of bias or study sample size). In studies longer than 6 months, the absolute risk difference for pain was 9% lower (95% CI 18% lower to 0%); n = 6 trials; T(2) = 0.18; I(2) = 83% ), again with low level of evidence.For the Western Ontario and McMaster Universities Osteoarthritis Index Minimal Clinically Important Improvement (WOMAC MCII Pain subscale) outcome, a reduction in knee pain by 20% was achieved by 53/100 in the chondroitin group versus 47/100 in the placebo group, an absolute risk difference of 6% (95% CI 1% to 11%), (RR 1.12, 95% CI 1.01 to 1.24; T(2) = 0.00; I(2) = 0%) (n = 2 trials, 1253 participants; level of evidence, high; risk of bias, low).Differences in Lequesne's index (composite of pain,function and disability) statistically significantly favoured chondroitin as compared with placebo in studies under six months, with an absolute risk difference of 8% lower (95% CI 12% to 5% lower; T(2)= 0.78; n = 7 trials) (level of evidence, moderate; risk of bias, unclear), also clinically meaningful. Loss of minimum joint space width in the chondroitin group was statistically significantly less than in the placebo group, with a relative risk difference of 4.7% less (95% CI 1.6% to 7.8% less; n = 2 trials) (level of evidence, high; risk of bias, low). Chondroitin was associated with statistically significantly lower odds of serious adverse events compared with placebo with Peto odds ratio of 0.40 (95% CI 0.19 to 0.82; n = 6 trials) (level of evidence, moderate). Chondroitin did not result in statistically significant numbers of adverse events or withdrawals due to adverse events compared with placebo or another drug. Adverse events were reported in a limited fashion, with some studies providing data and others not.Comparisons of chondroitin taken alone or in combination with glucosamine or another supplement showed a statistically significant reduction in pain (0-100) when compared with placebo or an active control, with an absolute risk difference of 10% lower (95% CI 14% to 5% lower); NNT = 4 (95% CI 3 to 6); T(2) = 0.33; I(2) = 91%; n = 17 trials) (level of evidence, low). For physical function, chondroitin in combination with glucosamine or another supplement showed no statistically significant difference from placebo or an active control, with an absolute risk difference of 1% lower (95% CI 6% lower to 3% higher with T(2) = 0.04; n = 5 trials) (level of evidence, moderate). Differences in Lequesne's index statistically significantly favoured chondroitin as compared with placebo, with an absolute risk difference of 8% lower (95% CI, 12% to 4% lower; T(2) = 0.12; n = 10 trials) (level of evidence, moderate). Chondroitin in combination with glucosamine did not result in statistically significant differences in the numbers of adverse events, withdrawals due to adverse events, or in the numbers of serious adverse events compared with placebo or with an active control.The beneficial effects of chondroitin in pain and Lequesne's index persisted when evidence was limited to studies with adequate blinding or studies that used appropriate intention to treat (ITT) analyses. These beneficial effects were uncertain when we limited data to studies with appropriate allocation concealment or a large study sample (> 200) or to studies without pharmaceutical funding. AUTHORS' CONCLUSIONS: A review of randomized trials of mostly low quality reveals that chondroitin (alone or in combination with glucosamine) was better than placebo in improving pain in participants with osteoarthritis in short-term studies. The benefit was small to moderate with an 8 point greater improvement in pain (range 0 to 100) and a 2 point greater improvement in Lequesne's index (range 0 to 24), both seeming clinically meaningful. These differences persisted in some sensitivity analyses and not others. Chondroitin had a lower risk of serious adverse events compared with control. More high-quality studies are needed to explore the role of chondroitin in the treatment of osteoarthritis. The combination of some efficacy and low risk associated with chondroitin may explain its popularity among patients as an over-the-counter supplement.

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.

Diacerein for osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases. There is currently no consensus on what is the best treatment to improve OA symptoms and slow disease progression. Diacerein is an anthraquinone synthesised in 1980 that interferes with interleukin-1, an inflammatory mediator. It has been proposed that diacerein acts as a slow-acting, symptom-modifying and perhaps disease-structure-modifying drug for OA. This is an update of a Cochrane review first published in 2006. OBJECTIVES: To assess the benefits and harms of diacerein for the treatment of adults with OA when compared with placebo and other pharmacologically active interventions (nonsteroidal anti-inflammatory drugs (NSAIDs) and other symptom-modifying, slow-acting drugs) for OA. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) - The Cochrane Library, Issue 10, 2013, MEDLINE (1966 to 2013), EMBASE (1980 to 2013), LILACS (1982 to 2013), and ACP Journal Club, and we handsearched reference lists of published articles. We also searched the World Health Organization International Clinical Trials Platform ( http://www.who.int/trialsearch/Default.aspx) to identify ongoing trials and screened reference lists of retrieved review articles and trials to identify potentially relevant studies. All searches were up to date as of March 2013. Pharmaceutical companies and authors of published articles were contacted. We searched the websites of the regulatory agencies using the keyword 'diacerein' in November 2013. No language restrictions were applied. SELECTION CRITERIA: Studies were included if they were randomised or quasi-randomised controlled trials that compared diacerein with placebo or another active pharmacological intervention in participants with OA. DATA COLLECTION AND ANALYSIS: Data abstraction and quality assessment were performed by two independent investigators, and their results were compared. The Cochrane risk of bias tool was used. The quality of evidence obtained was assessed using the GRADE approach. MAIN RESULTS: We identified three new trials (141 participants), and this updated review now includes 10 trials, totalling 2,210 participants. The most frequent risk of bias was incomplete outcome data, identified in approximately 80% of the studies. Allocation concealment and random sequence generation were unclear in 90% and 40% of the studies, respectively, because of poor reporting.Low-quality evidence from six trials (1,283 participants) indicates that diacerein has a small beneficial effect on overall pain (measured on a 100 mm visual analogue scale) at three to 36 months (mean difference (MD) -8.65, 95% confidence interval (CI) -15.62 to -1.68), which is equivalent to a 9% pain reduction in the diacerein group (95% CI -16% to -2%) compared with the placebo group. This benefit may not be clinically significant.No statistically significant differences in physical function (4 studies, 1006 participants) were noted between the diacerein and placebo groups (Lequesne impairment index, 0 to 24 points) (MD -0.29, 95% CI -0.87 to 0.28).Low-quality evidence from two trials (616 participants) on slowing of joint space narrowing (a decrease greater than 0.50 mm) in the knee or hip favoured diacerein over placebo (risk ratio (RR) 0.85, 95% CI 0.72 to 0.99), with an absolute risk difference of -6% (95% CI -15% to 2%) and a number needed to treat for an additional beneficial outcome (NNTB) of 14 (95% CI 8 to 203). Analysis of the knee joint alone (1 study, 170 participants) did not reach statistical significance (RR 0.94, 95% CI 0.51 to 1.74).None of the trials of diacerein versus placebo measured quality of life. According to one trial (161 participants), which compared diacerein versus non-steroidal anti-inflammatory drugs (NSAIDs), the quality of life of participants in the two groups (as assessed by the Short Form (SF)-36 health survey questionnaire (0 to 800 sum score)) did not differ significantly (MD -40.70, 95% CI -85.20 to 3.80).Low-quality evidence from seven trials showed significantly more adverse events in the diacerein group compared with the placebo group after two to 36 months, mainly diarrhoea (RR 3.52, 95% CI 2.42 to 5.11), with an absolute risk increase of 24% (95% CI 12% to 35%), and a number needed to treat for an additional harmful outcome (NNTH) of 4 (95% CI 3 to 7).No statistically significant differences in participant withdrawal due to adverse events were seen at two to 36 months for diacerein compared with placebo (RR 1.29, 95% CI 0.83 to 2.01).A search of regulatory websites found a recommendation from the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) that the marketing authorization of diacerein should be suspended across Europe because of harms (particularly the risk of severe diarrhoea and potentially harmful effects on the liver) outweighing benefits. However, this guidance is not final as the PRAC recommendation will be re-examined. AUTHORS' CONCLUSIONS: In this update, the strength of evidence for effectiveness outcomes was low to moderate. We confirmed that symptomatic benefit provided by diacerein in terms of pain reduction is minimal. The small benefit derived in terms of joint space narrowing is of questionable clinical relevance and was observed only for OA of the hip. With respect to adverse effects of diacerein, diarrhoea was most frequent. Given the recent guidance issued by the EMA recommending suspension of diacerein in Europe, the EMA website should be consulted for further recommendations regarding the use of diacerein.

Defining patient perception of overall well-being and disease activity in the OMERACT Juvenile Idiopathic Arthritis (JIA) core domain set: A report from the JIA working group.

OBJECTIVE: The OMERACT Juvenile Idiopathic Arthritis (JIA) Working Group (WG) aimed to reach agreement on a consensus-based definition and description of the core domain related to patient perception of overall well-being and disease activity. METHODS: A committee of patient research partners, clinicians, methodologists, and researchers drafted working definitions and descriptions. The WG conducted two iterative electronic stakeholder surveys to obtain consensus on domain description, definition, and the distinction between patient perception of overall well-being and disease activity. These definitions were then presented at the OMERACT 2023 Special Interest Group (SIG) session for agreement. RESULTS: Forty-five participants, from 7 countries and 4 continents, were comprised of six patients, 18 caregivers, and 21 healthcare providers. The consensus threshold (70%) was exceeded on all survey questions from both stakeholder groups (patients/caregivers, all others). Agreement was obtained on the new definition, description, and domain title, along with agreement on separate assessments of two target domains, patient perception of overall well-being as it relates to disease and patient perception of disease activity. CONCLUSION: Through an iterative consensus process and achieving agreement from the OMERACT SIG session attendees, the JIA WG has created a detailed definition and description for the two target domains in the patient perception of overall well-being related to disease core domain of the JIA mandatory core domain set. The next phase of this work will be instrument selection using the OMERACT filter 2.2.

Exploring the complexities of pain phenotypes: OMERACT 2023 chronic pain working group workshop.

OBJECTIVE: To educate and discuss pain mechanisms (nociceptive, neuropathic, nociplastic) illuminating its possible impact when measuring different outcomes, which may modify, confound and potentially bias the outcome measures applied across various aspects of Rheumatic Musculoskeletal Diseases (RMDs) clinical trials. METHODS: In the plenary presentations, PM lectured on different pain mechanisms and impact on disease activity assessment. Data from two data sets of RMDs patients, which assessed the prevalence and impact of nociplastic pain were presented and reviewed. Audience breakout group sessions and polling were conducted. RESULTS: Mixed pain etiologies may differentially influence disease activity assessment and therapeutic decision-making. Polling demonstrated a consensus on the need to assess different types of pain as a phenotype, as it constitutes an important contextual factor (a variable that is not an outcome of the trial, but needs to be recognized [and measured] to understand the study results), and to standardize across RMDs. CONCLUSION: There is need for a standardized pain measure that can differentiate underlying pain mechanisms.

Consensus of the definitions of the OMERACT glucocorticoid impact core domain set for people with rheumatic and musculoskeletal diseases.

BACKGROUND: The Outcome Measures in Rheumatology (OMERACT) Glucocorticoid (GC) Impact Working Group has been working to develop a core domain set to measure the impact of GCs on patients living with rheumatic and musculoskeletal diseases. The mandatory domains previously identified for inclusion in all clinical trials measuring the GC effects include infection, bone fragility, mood disturbance, hypertension, diabetes, weight, fatigue, and mortality. Before progressing to instrument selection, the Working Group sought to establish precise definitions of all mandatory domains within the core domain set. METHODS: OMERACT methodology was applied with the use of evidence and consensus-based decision making of all stakeholder groups (patient research partners, health care professionals, clinician researchers, industry members and methodologists) to develop detailed definitions for the broad domain, target domain and domain components, taking into consideration sources of variability that could affect measurement of the domain.  The working group synthesized prior qualitative studies, quantitative work, and results from Delphi rounds, to develop a rich definition of 'what' is to be measured. RESULTS: Between 2021 and 2023, the OMERACT Working Group on GC Impact conducted virtual meetings to establish domain definitions. First, we mapped each domain onto an OMERACT Core Area. All domains were primarily represented within the Pathophysiological Manifestations Core Area, except from Fatigue which was primarily Life Impact and Weight which spanned both Core Areas. Sources of variability included cultural factors, age, gender, education level, socioeconomic status, personal experiences, emotional state, and language barriers. The domain definitions will form the foundation for instrument selection and the initial step of domain / concept match and content validity in the OMERACT pillar of 'truth' before moving on to feasibility and discrimination. CONCLUSION: The OMERACT GC Impact Working Group has developed and agreed upon detailed domain definitions for core domains. Future steps of the working group are to select instruments and develop the core outcome measurement set for clinical trials measuring the impact of GC on patients with rheumatic and musculoskeletal diseases.

Embracing unity at OMERACT: Valuing equity, promoting diversity, fostering inclusivity.

OBJECTIVE: To increase awareness and understanding of the principles of Equity, Diversity, and Inclusivity (EDI) within Outcome Measures in Rheumatology's (OMERACT) members. For this, we aimed to obtain ideas on how to promote and foster these principles within the organization and determine the diversity of the current membership in order to focus future efforts. METHODS: We held a plenary workshop session at OMERACT 2023 with roundtable discussions on barriers and solutions to increased diversity within OMERACT. We conducted an anonymous, web-based survey of members to record characteristics including population group, gender identity, education level, age, and ability. RESULTS: The workshop generated ideas to increase diversity of participants across the themes of building relationships [12 topics], materials and methods [5 topics], and conference-specific [6 topics]. Four hundred and seven people responded to the survey (25 % response rate). The majority of respondents were White (75 %), female (61 %), university-educated (94 %), Christian (42 %), spoke English at home (60 %), aged 35 to 55 years (50 %), and did not report a disability (64 %). CONCLUSION: OMERACT is committed to improving its diversity. Next steps include strategic recruitment of members to the EDI working group, drafting an EDI mission statement centering equity and inclusivity in the organization, and developing guidance for the OMERACT Handbook to help all working groups create actionable plans for promoting EDI principles.

Defining domains: developing consensus-based definitions for foundational domains in OMERACT core outcome sets.

OBJECTIVE: To develop a set of detailed definitions for foundational domains commonly used in OMERACT (Outcome Measures in Rheumatology) core domain sets. METHODS: We identified candidate domain definitions from prior OMERACT publications and websites and publications of major organizations involved in outcomes research for six domains commonly used in OMERACT Core Domain Sets: pain intensity, pain interference, physical function, fatigue, patient global assessment, and health-related quality of life. We conducted a two-round survey of OMERACT working groups, patient research partners, and then the OMERACT Technical Advisory Group to establish their preferred domain definitions. Results were presented at the OMERACT 2023 Methodology Workshop, where participants discussed their relevant lived experience and identified potential sources of variability giving the needed detail in our domain definitions. RESULTS: One-hundred four people responded to both rounds of the survey, and a preferred definition was established for each of the domains except for patient global assessment for which no agreement was reached. Seventy-five participants at the OMERACT 2023 Methodology Workshop provided lived experience examples, which were used to contextualise domain definition reports for each of the five domains. CONCLUSION: Using a consensus-based approach, we have created a detailed definition for five of the foundational domains in OMERACT core domain sets; patient global assessment requires further research. These definitions, although not mandatory for working groups to use, may facilitate the initial domain-match assessment step of instrument selection, and reduce the time and resources required by future OMERACT groups when developing core outcome sets.

Consensus on the definitions and descriptions of the domains of the OMERACT Core Outcome Set for shared decision making interventions in rheumatology trials.

OBJECTIVE: To gain consensus on the definitions and descriptions of the domains of the Outcome Measures in Rheumatology (OMERACT) core domain set for rheumatology trials evaluating shared decision making (SDM) interventions. METHODS: Following the OMERACT Handbook methods, our Working Group (WG), comprised of 90 members, including 17 patient research partners (PRPs) and 73 clinicians and researchers, had six virtual meetings in addition to email exchanges to develop draft definitions and descriptions. The WG then conducted an international survey of its members to gain consensus on the definitions and descriptions. Finally, the WG members had virtual meetings and e-mail exchanges to review survey results and finalize names, definitions and descriptions of the domains. RESULTS: WG members contributed to developing the definitions. Fifty-two members representing four continents and 13 countries completed the survey, including 15 PRPs, 33 clinicians and 37 researchers. PRPs and clinicians/researchers agreed with all definitions and descriptions with agreements ranging from 87% to 100%. Respondents suggested wording changes to the names, definitions and descriptions to better reflect the domains. Discussions led to further simplification and clarification to address common questions/concerns about the domains. CONCLUSION: Our WG reached consensus on the definitions and descriptions of the domains of the core domain set for rheumatology trials of SDM interventions. This step is crucial to understand each domain and provides the foundation to identify instruments to measure each domain for inclusion in the Core Outcome Measurement Set. CLINICAL SIGNIFICANCE: The current study provides consensus-based definitions and descriptions for the domains of the OMERACT core domain set for shared decision making interventions from patients/caregivers, clinicians and researchers. This is a crucial step to understand each domain and provides the foundation to identify instruments to measure each domain for inclusion in the Core Outcome Measurement Set for trials of SDM interventions.

Developing an Outcome Measures in Rheumatology (OMERACT) Core set of Outcome Measures for FOot and ankle disorders in RheumaTic and musculoskeletal diseases (COMFORT): core domain set study protocol.

BACKGROUND: Foot and ankle involvement is common in rheumatic and musculoskeletal diseases (RMDs). High-quality evidence is lacking to determine the effectiveness of treatments for these disorders. Heterogeneity in the outcomes used across clinical trials and observational studies hinders the ability to compare findings, and some outcomes are not always meaningful to patients and end-users. The Core set of Outcome Measures for FOot and ankle disorders in RheumaTic and musculoskeletal diseases (COMFORT) study aims to develop a core outcome set (COS) for use in all trials of interventions for foot and ankle disorders in RMDs. This protocol addresses core outcome domains (what to measure) only. Future work will focus on core outcome measurement instruments (how to measure). METHODS: COMFORT: Core Domain Set is a mixed-methods study involving the following: (i) identification of important outcome domains through literature reviews, qualitative interviews and focus groups with patients and (ii) prioritisation of domains through an online, modified Delphi consensus study and subsequent consensus meeting with representation from all stakeholder groups. Findings will be disseminated widely to enhance uptake. CONCLUSIONS: This protocol details the development process and methodology to identify and prioritise domains for a COS in the novel area of foot and ankle disorders in RMDs. Future use of this standardised set of outcome domains, developed with all key stakeholders, will help address issues with outcome variability. This will facilitate comparing and combining study findings, thus improving the evidence base for treatments of these conditions. Future work will identify suitable outcome measurement instruments for each of the core domains. TRIAL REGISTRATION: This study is registered with the Core Outcome Measures in Effectiveness Trials (COMET) database, as of June 2022: https://www.comet-initiative.org/Studies/Details/2081.

Developing a core outcome set for foot and ankle disorders in rheumatic and musculoskeletal diseases: A scoping review and report from the OMERACT 2022 foot and ankle special interest group session.

OBJECTIVES: Foot and ankle involvement is common in rheumatic and musculoskeletal diseases, yet high-quality evidence assessing the effectiveness of treatments for these disorders is lacking. The Outcome Measures in Rheumatology (OMERACT) Foot and Ankle Working Group is developing a core outcome set for use in clinical trials and longitudinal observational studies in this area. METHODS: A scoping review was performed to identify outcome domains in the existing literature. Clinical trials and observational studies comparing pharmacological, conservative or surgical interventions involving adult participants with any foot or ankle disorder in the following rheumatic and musculoskeletal diseases (RMDs) were eligible for inclusion: rheumatoid arthritis (RA), osteoarthritis (OA), spondyloarthropathies, crystal arthropathies and connective tissue diseases. Outcome domains were categorised according to the OMERACT Filter 2.1. RESULTS: Outcome domains were extracted from 150 eligible studies. Most studies included participants with foot/ankle OA (63% of studies) or foot/ankle involvement in RA (29% of studies). Foot/ankle pain was the outcome domain most commonly measured (78% of studies), being the most frequently specified outcome domain across all RMDs. There was considerable heterogeneity in the other outcome domains measured, across core areas of manifestations (signs, symptoms, biomarkers), life impact, and societal/resource use. The group's progress to date, including findings from the scoping review, was presented and discussed during a virtual OMERACT Special Interest Group (SIG) in October 2022. During this meeting, feedback was sought amongst delegates regarding the scope of the core outcome set, and feedback was received on the next steps of the project, including focus group and Delphi methods. CONCLUSION: Findings from the scoping review and feedback from the SIG will contribute to the development of a core outcome set for foot and ankle disorders in RMDs. The next steps are to determine which outcome domains are important to patients, followed by a Delphi exercise with key stakeholders to prioritise outcome domains.

Protocol for the development of guidance for collaborator and partner engagement in health care evidence syntheses.

BACKGROUND: Involving collaborators and partners in research may increase relevance and uptake, while reducing health and social inequities. Collaborators and partners include people and groups interested in health research: health care providers, patients and caregivers, payers of health research, payers of health services, publishers, policymakers, researchers, product makers, program managers, and the public. Evidence syntheses inform decisions about health care services, treatments, and practice, which ultimately affect health outcomes. Our objectives are to: A. Identify, map, and synthesize qualitative and quantitative findings related to engagement in evidence syntheses B. Explore how engagement in evidence synthesis promotes health equity C. Develop equity-oriented guidance on methods for conducting, evaluating, and reporting engagement in evidence syntheses METHODS: Our diverse, international team will develop guidance for engagement with collaborators and partners throughout multiple sequential steps using an integrated knowledge translation approach: 1. Reviews. We will co-produce 1 scoping review, 3 systematic reviews and 1 evidence map focusing on (a) methods, (b) barriers and facilitators, (c) conflict of interest considerations, (d) impacts, and (e) equity considerations of engagement in evidence synthesis. 2. Methods study, interviews, and survey. We will contextualise the findings of step 1 by assessing a sample of evidence syntheses reporting on engagement with collaborators and partners and through conducting interviews with collaborators and partners who have been involved in producing evidence syntheses. We will use these findings to develop draft guidance checklists and will assess agreement with each item through an international survey. 3. CONSENSUS: The guidance checklists will be co-produced and finalised at a consensus meeting with collaborators and partners. 4. DISSEMINATION: We will develop a dissemination plan with our collaborators and partners and work collaboratively to improve adoption of our guidance by key organizations. CONCLUSION: Our international team will develop guidance for collaborator and partner engagement in health care evidence syntheses. Incorporating partnership values and expectations may result in better uptake, potentially reducing health inequities.

Physicians' vs patients' global assessments of disease activity in rheumatology and musculoskeletal trials: A meta-research project with focus on reasons for discrepancies.

BACKGROUND: In most rheumatic and musculoskeletal diseases (RMDs), global assessments of disease activity by physicians and patients are 'anchor outcomes' in therapeutic trials evaluating whether a treatment is effective. OBJECTIVES: To compare physicians' vs patients' global assessments of disease activity in RMD trials and explore reasons for discrepancies between them. METHODS: Eligible trials were sampled from systematic reviews of treatments for RMDs by using the Cochrane database of systematic reviews (i.e., reviews from the Cochrane Musculoskeletal Group, [CMSG]). Randomized controlled trials (RCTs) of interventions for RMDs were eligible if they reported quantitative analyses of both physicians´ and patients´ global assessments at the same time point for the comparison of the same experimental intervention against the same comparator (i.e., placebo, no treatment, or other treatment). We accepted data from trial comparisons for each type of outcome, regardless of the type of intervention and type of RMD within the CMSG. Using mixed-effects meta-regression models, we assigned the dependent variable as the ratio of odds ratios (ROR) of global change with the experimental intervention, versus the control comparator. An ROR>1 would indicate that physicians rated the experimental intervention more favorable than their patients did. RESULTS: We were able to estimate the ROR (data from both physicians' and patients' global assessments) across 70 trials (116 randomized comparisons) in 7 diseases (ankylosing spondylitis, fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, systemic lupus erythematosus, and gout). The combined ROR across all effectiveness comparisons were rated significantly in favor of the intervention by physicians: ROR=1.15 CI 95% (1.07 to 1.23). This combined ROR was based on a substantial heterogeneity across comparisons (I2=89.1%). Across all the stratified analyses, the type of the RMD was an informative reason for discrepancies, with a statistically significant ROR in rheumatoid arthritis ROR=1.33, CI 95% (1.13 to 1.56), unlike the ROR in all other conditions (ROR=1.04, CI 95% (0.95-1.14). CONCLUSION: In comparative effectiveness research on rheumatology, physicians' global assessments of disease activity, surprisingly, are more in favor of the experimental interventions than are those of the patients.

Composite outcomes at OMERACT: Multi-outcome domains and composite outcome domains.

The OMERACT Technical Advisory Group recognises that working groups during the process of creating a core outcome set may identify an outcome domain that would be best represented as a composite that encapsulates these component outcome domains by bringing them together into a single outcome. A multi-outcome domain (MOD) is a within-patient combination of component outcomes, and an individual patient's evaluation depends on the observation of all of the components in that patient with a single overall rating determined according to a specified rule; which is often applicable when we consider a disease activity score. A composite outcome domain (COD) consists of a number of component outcomes and is defined as the occurrence in a patient of one, some or all of these specified components; which is often applicable when we consider the risk of adverse events or remission criteria. We review the general benefits, challenges, reporting and interpretation of using MODs and CODs. The development of the MOD or COD instrument for an OMERACT core outcome measurement set is considered through four distinct steps: choosing relevant outcome domains; finding high quality instruments for each of these outcome domains; weighting the outcome domain instruments in the MOD/COD instrument; and putting MOD/COD instrument through the OMERACT Filter. Guidance and training are in preparation for working groups who will be completing the OMERACT Instrument Selection Algorithm (OFISA). As for other initiatives in OMERACT, we will seek feedback from OMERACT working groups who complete the development of their MOD/COD, which will then be incorporated into the refinement of the guidance and training.