CRD summary

This review found that anti-tumour necrosis factor agents demonstrated a higher probability of achieving an improvement in rheumatoid arthritis symptoms than other biological agents in patients with inadequate response to methotrexate. These conclusions are supported by the data, but should be interpreted with some caution due to the lack of a formal quality assessment and possibility of missing studies.

Authors' objectives

To compare the efficacy of biological antirheumatic agents in patients with active rheumatoid arthritis and an inadequate response to methotrexate and anti-tumour necrosis factor (TNF)-agents.

Searching

MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for studies published up to October 2009. Search terms were reported. No language restrictions were applied. Abstracts from two relevant conferences were screened. Where necessary, drug companies were contacted.

Study selection

Double blind randomised controlled trials (RCTs) that compared a biological agent to placebo in adult patients with established rheumatoid arthritis who had an inadequate response to methotrexate or to anti-TNF treatment were eligible for inclusion. Treatment duration had to be at least 24 weeks. Trials were required to administer methotrexate or another disease-modifying anti-rheumatic agent (DMARD) in addition to the biological agent or placebo. The review focused on intervention dosages used in clinical practice; full details were reported in the paper. The primary outcome was ACR50 criteria (defined as at least 50% improvement according to American College of Rheumatology criteria) in the number of swollen and tender joints and in three of the following five parameters: physician global assessment of disease, patient global assessment of disease, patient assessment of pain, C reactive protein or erythrocyte sedimentation rate and the Health Assessment Questionnaire at 24 to 30 weeks.

Biological agents assessed in the review included rituximab, abatacept, tocilizumab, newer anti-TNFs (golimumab, certolizumab) and older anti-TNF agents (infliximab, etanercept, adalimumab). All included studies except one used concomitant methotrexate treatment; one study treated patients with concomitant DMARD therapy. Definitions of active disease varied from at least four to nine swollen and tender joints and presence of an acute phase response or morning stiffness. Most of the participants were women (70% to 90%). Mean age ranged from 49 to 56 years. Mean duration of disease ranged from six to 13 years. The proportion of patients with positive rheumatoid factor ranged from 73% to 100%.

The authors did not state how many reviewers performed the study selection.

Assessment of study quality

The authors did not formally assess study quality, but the review was restricted to double blind RCTs and use of an intention-to-treat analysis was assessed.

Data extraction

Two reviewers independently extracted data on the proportion of patients in each treatment arm who achieved ACR 50 and used these data to calculate odds ratios (ORs) together with 95% confidence intervals (CIs).

Methods of synthesis

Where more than one study assessed a particular agent, data were pooled using a random-effects model. Heterogeneity was assessed using the I² statistic. Indirect comparisons were used to evaluate the relative efficacy of the various biological agents compared to a common comparator (the placebo group). Initially comparisons were made between older anti-TNFs; where these were found to be similar they were treated as a single group for subsequent analyses. Comparisons were made between all anti-TNF agents and all other biological agents and compared to specific biological agents. Each non anti-TNF agent was compared in paired comparisons. Sensitivity analysis was conducted to investigate the effect of trial design (trials with a rescue design) and patient characteristics.

Results of the review

Eighteen studies were included in the review (n=6,138 participants). All trials performed an ITT analysis.

Efficacy of biological agents in patients with an inadequate response to methotrexate (15 RCTs, n=4,627):

There was no significant difference in response rates at six months between older anti-TNFs and newer ones (p=0.08 compared to certolizumab and p=0.33 compared to golimumab) and so all anti-TNFs were considered as a single group.

All agents showed a significant improvement in ACR50 compared to methotrexate treatment alone (abatacept OR 3.3, 95% CI 2.4 to 4.4; three RCTs, rituximab OR 3.1, 95% CI 2.1 to 4.7; three RCTs and anti-TNF OR 6.0, 95% CI 4.7 to 7.6; 10 RCTs). There was no heterogeneity for either abatacept or rituximab (I²=0%). Heterogeneity was substantial for anti-TNF agents (I²=57%). Anti-TNF agents were associated with a significantly greater likelihood of achieving an ACR50 response at six months compared to all non anti-TNF agents combined (OR 1.55, 95% CI 1.12 to 2.16) and for abatacept (OR 1.81, 95% CI 1.23 to 2.65). There was no significant difference compared to rituximab. Tocilizumab was significantly more effective than abatacept (OR 1.97, 95% CI 1.08 to 3.59). There was no significant between tocilizumab and rituximab and abatacept and rituximab.

Efficacy of biological agents in patients with an inadequate response to anti-TNFs (five RCTs, n=1,511):

There was no significant difference between tocilizumab, rituximab, abatacept and golimumab in the likelihood of response to ACR50.

Authors' conclusions

In patients with inadequate response to methotrexate, anti-TNFs demonstrated a higher probability of achieving an ACR50 response than abatacept. In patients with inadequate response to anti-TNF, there was no difference between tocilizumab, rituximab, abatacept and golimumab.

CRD commentary

The review addressed a focused question and inclusion criteria were defined. The literature search was adequate for published studies. No language restrictions were applied. Restriction of the review to published studies risked publication bias. Appropriate steps were taken to minimise bias and errors when extracting data; it was unclear whether such steps were taken when selecting studies for inclusion. Study quality was not formally assessed and this made it difficult to determine the reliability of the included studies, although the review was restricted to double blind RCTs and all trials used an ITT analysis. Methods used to pool data appeared appropriate and results were clearly presented.

The authors' conclusions are supported by the data, but should be interpreted with some caution due to the lack of a formal quality assessment and the possibility of missing studies.

Implications of the review for practice and research

Practice: The authors stated that for patients with rheumatoid arthritis with an inadequate response to methotrexate, anti-TNFs may be more likely than certain non anti-TNF biologicals to achieve an ACR50 response. The choice of biological agent on a patient level also involves other factors that doctors and patients need to consider when choosing a new biological agent.

Research: The authors stated that head-to-head trials of the different biological agents were needed to confirm these results.

Funding

Not stated.

Bibliographic details

Salliot C, Finckh A, Katchamart W, Lu Y, Sun Y, Bombardier C, Keystone E. Indirect comparisons of the efficacy of biological antirheumatic agents in rheumatoid arthritis in patients with an inadequate response to conventional disease-modifying antirheumatic drugs or to an anti-tumour necrosis factor agent: a meta-analysis. Annals of the Rheumatic Diseases 2011; 70(2): 266-271. [PubMed: 21097801]

Original Paper URL

http://ard.bmj.com/content/70/9/1575.abstract

Other publications of related interest

Erratum: Indirect comparisons of the efficacy of biological antirheumatic agents in rheumatoid arthritis in patients with an inadequate response to conventional disease-modifying antirheumatic drugs or to an anti-tumour necrosis factor agent: a meta-analysis. Annals of the Rheumatic Diseases 2011; 70(3):560.

Indexing Status

Subject indexing assigned by NLM

MeSH

Antibodies, Monoclonal, Murine-Derived /therapeutic use; Antirheumatic Agents /therapeutic use; Arthritis, Rheumatoid /drug therapy; Drug Therapy, Combination; Humans; Methotrexate /therapeutic use; Treatment Outcome; Tumor Necrosis Factor-alpha /antagonists & inhibitors

AccessionNumber

12011001287

Database entry date

26/10/2011

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.