A Cochrane review [Abstract] 1 included 21 short-term (24 weeks or less) studies with a total of 3 308 subjects; 18 contributed data to the mixed treatment comparison analysis: adalimumab (4 studies), etanercept (8 studies), golimumab (2 studies), infliximab (3 studies), and one head-to-head study (etanercept versus infliximab). 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, patients on an anti-TNF agent were more likely to achieve an ASAS40 response (40% improvement in pain, function, and inflammation as measured by morning stiffness, and patient overall well-being) and ASAS partial remission by 6 months (table T1). There was improvement in physical function on a 0 to 10 scale (BASFI; table T2) with TNF-alpha inhibitors compared with placebo. There was 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.
| Outcome/Intervention | Participants (studies) | Relative effect (95% CrI) | Assumed risk - placebo | Corresponding risk - intervention (95% CrI) | NNT (95% CI) |
|---|---|---|---|---|---|
| CrI = credible interval; CI = confidence interval; NNT = number needed to treat | |||||
| ASAS40 | |||||
| Adalimumab vs. placebo | 659 (2 studies) | RR 3.53(2.49 to 4.91) | 13 per 100 | 46 per 100(32 to 64) | 4 (2 to 6) |
| Etanercept (25 mg twice weekly or 50 mg once weekly) vs. placebo | 584 (3 studies) | RR 3.31(2.38 to 4.53) | 13 per 100 | 43 per 100(31 to 59) | 4 (3 to 6) |
| Golimumab vs. placebo | 429 (2 studies) | RR 2.90 (1.90 to 4.23) | 13 per 100 | 38 per 100(25 to 55) | 5 (3 to 9) |
| Infliximab vs. placebo | 355 (2 studies) | RR 4.07(2.80 to 5.74) | 13 per 100 | 53 per 100(36 to 75) | 3 (2 to 5) |
| ASAS partial remission | |||||
| Adalimumab vs. placebo | 659 (2 studies) | RR 6.28(3.13 to 12.78) | 3 per 100 | 19 per 100(9 to 38) | 7 (3 to 16) |
| Etanercept (25 mg twice weekly or 50 mg once weekly) vs. placebo | 785(3 studies) | RR 4.24(2.31 to 8.09) | 3 per 100 | 13 per 100(7 to 24) | 11 (5 to 26) |
| Golimumab vs. placebo | 216(1 study) | RR 5.18 (1.90 to 14.79) | 3 per 100 | 16 per 100(6 to 44) | 8 (3 to 38) |
| Infliximab vs. placebo | 348(2 studies) | RR 15.41(5.09 to 47.98) | 3 per 100 | 47 per 100(16 to 90) | 3 (2 to 8) |
| Intervention | Participants (studies) | The mean BASFI in the control groups | The mean BASFI in the intervention groups (95% CrI) | NNT to achieve the MCID of 0.7 points (95% CI) |
|---|---|---|---|---|
| MCID = minimally important difference | ||||
| Adalimumab vs. placebo | 786 (4 studies) | 5 points | 1.6 lower(2.2 to 0.9 lower) | 4 (3 to 5) |
| Etanercept (25 mg twice weekly or 50 mg once weekly) vs. placebo | 553(6 studies) | 5 points | 1.1 lower(1.6 to 0.6 lower) | 4 (4 to 6) |
| Golimumab vs. placebo | 429(2 studies) | 5 points | 1.5 lower(2.3 to 0.7 lower) | 4 (3 to 5) |
| Infliximab vs. placebo | 348(2 studies) | 5 points | 2.1 lower(2.7 to 1.4 lower) | 2 (2 to 3) |
When all the anti-TNF agents were combined against placebo, there was an increased risk of withdrawals due to adverse events in the anti-TNF group though the absolute increase in harm was small (1%, 95% CI 0% to 2%). Results for individual agents are shown in table T3. Due to low event rates, results on serious adverse events were inconclusive (table T3).
| Outcome/Intervention | Participants (studies) | Relative effect (95% CI or CrI) | Assumed risk - placebo | Corresponding risk - intervention (95% CI or CrI) | |
|---|---|---|---|---|---|
| Results for individual anti-TNF agents are based on the mixed treatment comparison analyses, and the 'All anti-TNF agents versus placebo' results are based on standard meta-analyses. | |||||
| Withdrawals due to adverse events | |||||
| Adalimumab vs. placebo | 659(2 studies) | RR 1.69(0.35 to 10.84) | 7 per 1000 | 12 per 1000(3 to 80) | |
| Etanercept (25 mg twice weekly or 50 mg once weekly) vs. placebo | 1 061(8 studies) | RR 3.65(1.27 to 11.79) | 7 per 1000 | 26 per 1000(9 to 83) | |
| Golimumab vs. placebo | 429(2 studies) | RR 1.97 (0.36 to 17.51) | 7 per 1000 | 14 per 1000(3 to 123) | |
| Infliximab vs. placebo | 424(3 studies) | RR 1.77(0.43 to 8.46) | 7 per 1000 | 12 per 1000(3 to 59) | |
| All anti-TNF agents versus placebo | 2 623(16 studies) | Peto OR 2.44 (1.26 to 4.72) | 7 per 1000 | 16 per 1000(8 to 33) | |
| Serious adverse events | |||||
| Adalimumab vs. placebo | 659(2 studies) | RR 0.92(0.26 to 3.93) | 15 per 1000 | 14 per 1000(4 to 59) | |
| Etanercept (25 mg twice weekly or 50 mg once weekly) vs. placebo | 1 061(8 studies) | RR 1.69(0.76 to 3.72) | 15 per 1000 | 25 per 1000(11 to 56) | |
| Golimumab vs. placebo | 216 (1 study) | RR 0.69(0.15 to 3.32) | 15 per 1000 | 10 per 1000(2 to 50) | |
| Infliximab vs. placebo | 422 (3 studies) | RR 2.53(0.76 to 11.09) | 15 per 1000 | 38 per 1000(11 to 166) | |
| All anti-TNF agents versus placebo | 2 408(15 studies) | Peto OR 1.45 (0.85 to 2.48) | 15 per 1000 | 22 per 1000(13 to 36) | |
Differences between individual anti-TNF-agents were examined 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.
No evidence of an increase in serious adverse events was found, though event rates were low and studies had a short duration. Regulatory agencies have published warnings about rare adverse events of serious infections, including tuberculosis, malignancies and lymphoma.
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