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.

INTRODUCTION:

Biologic therapies have improved the clinical management of ankylosing spondylitis (AS). Few head-to-head studies have directly compared the efficacy of these agents. This study was conducted to indirectly compare the efficacy of biologic agents for treatment of active AS.

METHODS:

A targeted literature review was conducted to identify randomized clinical trials for adalimumab, infliximab, golimumab, certolizumab pegol, etanercept, and secukinumab for the treatment of active AS. The clinical efficacy was evaluated using ASAS20 and ASAS40 and synthesized via a Bayesian network meta-analysis. Number needed to treat (NNT) was calculated as the reciprocal of incremental response rate of each biologic versus placebo. Comparisons were also made in terms of cost per incremental ASAS20 or ASAS40 responder.

RESULTS:

Fifteen studies were identified, which included ASAS20 and/or ASAS40 response rates at Week 12 to Week 16. Patients with AS treated with infliximab had the lowest NNT for ASAS20 of 2.3, followed by those treated with adalimumab (2.8) and etanercept (2.9). Adalimumab had the lowest 12-week cost per additional ASAS20 responder at $26,888, followed by infliximab at $28,175 and golimumab at $28,199. Patients treated with infliximab also had the lowest NNT for ASAS40 (2.6), followed by those treated with adalimumab (2.8) and secukinumab (3.5). Adalimumab had the lowest cost per additional ASAS40 responder at $26,898, followed by infliximab at $32,508 and etanercept at $34,406.

CONCLUSION:

Infliximab had the lowest NNT to achieve an additional ASAS20/40 response, and adalimumab had the lowest cost per ASAS20/40 responder among biologic agents for the treatment of active AS.

FUNDING:

AbbVie.

AIM:

The present paper aims to review the recent advances in diagnosis and management of ankylosing spondylitis (AS).

METHOD:

Medline and abstracts submitted to the recent European League Against Rheumatism (EULAR) congress were searched to obtain quality-controlled information on the management of AS.

RESULTS:

The use of magnetic resonance imaging (MRI) allows the diagnosis of AS to be made in the pre-radiographic stage. The Assessment in Spondylarthritis International Society recommendations for the management of AS have been modified so that patients with non-radiographic spondyloarthritis (SpA) can now be considered for biological therapy. The 'older' anti-tumour necrosis factor (TNF) continued to be effective in longer-term studies. Studies with longer duration of follow-up have shown that some patients with pre-radiographic SpA entered into prolonged drug-free remission. It is likely that in the foreseeable future, more AS patients will be treated with biological therapies at an earlier stage of the disease. New biologic therapies, golimumab and secukinumab, are looking promising in improving the signs and symptoms of AS, at least in the short-term.

CONCLUSION:

Longer-term studies of AS patients treated with infliximab, etanercept and adalimumab continued to show a good clinical response. There is a need for more long-term studies to examine the longitudinal efficacy of golimumab and secukinumab in AS.

BACKGROUND AND OBJECTIVES:

Five-tumour necrosis factor (TNF)-blockers (infliximab, etanercept, adalimumab, certolizumab pegol and golimumab) are available for treatment of rheumatoid arthritis. Only few clinical trials compare one TNF-blocker to another. Hence, a systematic review is required to indirectly compare the substances. The aim of our study is to estimate the efficacy and the safety of TNF-blockers in the treatment of rheumatoid arthritis (RA) and indirectly compare all five currently available blockers by combining the results from included randomized clinical trials (RCT).

METHODS:

A systematic literature review was conducted using databases including: MEDLINE, SCOPUS (including EMBASE), Cochrane library and electronic search alerts. Only articles reporting double-blind RCTs of TNF-blockers vs. placebo, with or without concomitant methotrexate (MTX), in treatment of RA were selected. Data collected were information of patients, interventions, controls, outcomes, study methods and eventual sources of bias.

RESULTS:

Forty-one articles reporting on 26 RCTs were included in the systematic review and meta-analysis. Five RCTs studied infliximab, seven etanercept, eight adalimumab, three golimumab and three certolizumab. TNF-blockers were more efficacious than placebo at all time points but were comparable to MTX. TNF-blocker and MTX combination was superior to either MTX or TNF-blocker alone. Increasing doses did not improve the efficacy. TNF-blockers were relatively safe compared to either MTX or placebo.

CONCLUSIONS:

No single substance clearly rose above others in efficacy, but the results of the safety analyses suggest that etanercept might be the safest alternative. Interestingly, MTX performs nearly identically considering both efficacy and safety aspects with a margin of costs.

Biological agents directed against tumor necrosis factor (TNF) represent therapeutic options for patients with ankylosing spondylitis with high disease activity despite use of non-steroidal anti-inflammatory drugs. To evaluate the efficacy and safety of the anti-TNF agents infliximab, etanercept, adalimumab, golimumab, and certolizumab for the treatment of ankylosing spondylitis, we performed a systematic review of randomized clinical trials on adult patients with ankylosing spondylitis using articles culled from the EMBASE, MEDLINE, Cochrane Controlled Trials Register and LILACS databases (September/2012), manual literature search, and the gray literature. Study selections and data collection were performed by two independent reviewers, with disagreements solved by a third reviewer. The following outcomes were evaluated: ASAS 20 response, disease activity, physical function, vertebral mobility, adverse events, and withdraws. The meta-analysis was performed using the Review Manager(®) 5.1 software by applying the random effects model. Eighteen studies were included in this review. No study of certolizumab was included. Patients treated with anti-TNF agents were more likely to display an ASAS 20 response after 12/14 weeks (RR 2.21; 95 % CI 1.91; 2.56) and 24 weeks (RR 2.68; 95 % CI 2.06; 3.48) compared with controls, which was also true for several other efficacy outcomes. Meta-analysis of safety outcomes and withdraws did not indicate statistically significant differences between treatment and control groups after 12 or 30 weeks. Adalimumab, infliximab, etanercept, and golimumab can effectively reduce the signs and symptoms of the axial component of ankylosing spondylitis. Safety outcomes deserve further study, especially with respect to long-term follow-ups.

BACKGROUND:

The short-term efficacy of biological disease modifying anti-rheumatic drugs (bDMARDs) for the treatment of established moderate to severe rheumatoid arthritis (RA) has been demonstrated by various randomized placebo or active treatment controlled trials. However, there is a lack of direct comparison of these agents.

SCOPE:

To compare the short-term efficacy of nine bDMARDs - abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab and tocilizumab - in patients with established RA.

FINDINGS:

A systematic review was conducted to obtain all available efficacy data for each included bDMARD. Medline, EMBASE, and Cochrane clinical trials were searched for trials in patients with RA. Twenty-seven trials were retrieved from a systematic literature search and included in the meta-analysis. Mixed treatment comparison (MTC) techniques were used to perform indirect comparisons. Analyses were conducted to estimate the odds ratio of an ACR20, ACR50, and ACR70 response at approximately six months if treated with a bDMARD compared with placebo or methotrexate. Between-drug comparisons were also made. The analyses were performed including recommended doses only (as per the product information). All drugs except anakinra and golimumab demonstrated a statistically significant advantage compared to control treatment for ACR20 responses. The between-drug comparisons revealed a statistically significant advantage for certolizumab compared to most bDMARDs for ACR20, ACR50 and ACR70 response and for etanercept versus adalimumab and anakinra for ACR20 and ACR50 response, as well as a statistically significant advantage for tocilizumab versus anakinra for ACR50 response.

CONCLUSION:

The analyses, using MTC of efficacy of nine bDMARDs suggest that treatment with anakinra is inferior to other bDMARDs and that etanercept and certolizumab may be more effective than other bDMARDs. There are some limitations of our analyses due to MTC assumptions, variations in trial design and the fact that only ACR outcomes at six months were included.

What is known and Objective: A number of biological treatments are available for rheumatoid arthritis. They are effective some patients but their comparative efficacy is inadequately evaluated. Our aim was to compare the efficacy of adalimumab, etanercept, infliximab, abatacept, tocilizumab, golimumab and certolizumab pegol in rheumatoid arthritis, refractory to disease-modifying antirheumatic drugs (DMARDs), through a systematic review of published trials. Methods: As there were no direct comparisons, we searched for studies with similar characteristics to identify trials with results suitable for indirect comparison. Randomized, placebo-controlled pivotal clinical trials, with reported American College of Rheumatology ACR50 data at 24/30 weeks as efficacy endpoint, approved clinical doses and patients resistant to DMARDs who had not previously received other biological treatments were included. ACR50 was defined as the primary endpoint for the indirect comparison, with ACR20 and ACR70 as secondary endpoints. When two or more trials on one same drug were available, and a combined analysis was performed when appropriate. In the indirect comparison, the Bucher adjusted method was used with etanercept as reference drug. In the equivalence study, the equivalence window was a response efficacy difference of 15% between the alternatives. Results and Discussion: Ten trials were found suitable for detailed analysis. In the clinical trials, all the biological drugs were seen to be more effective than placebo. Indirect comparison based on the ACR50 efficacy criterion all biological treatments showed similar results within the defined equivalence Δ value. The absolute efficacy difference (reduction of absolute risk, RAR) versus etanercept being 2·6% with adalimumab, 14% with infliximab, 11·6% with abatacept, 3% with tocilizumab, 12·4% with golimumab and 6·5% with certolizumab pegol. What is new and Conclusion: The biological drugs used in rheumatoid arthritis are no different in efficacy. Their therapeutic positioning depends on their relative safety and convenience profiles.