This quantitative overview provides convincing evidence that, when combined with methotrexate, most biologics are effective at slowing X-ray progression assessed by mean change or odds of progression. The exceptions to this are golimumab (mean change) and abatacept (odds of progression). The magnitude of benefit from methotrexate was a standardized mean difference of 0.36.1
The estimates from this study are additional to the effect of methotrexate. Therefore, the total effect from the combination of biologics and methotrexate will be greater. For example, for infliximab plus methotrexate, the effect is estimated as a standardized mean difference of 1.04 (0.36 + 0.68), which is a large effect. For most agents, the total benefit is high-moderate to large in magnitude, which is clearly of major clinical significance for sufferers of rheumatoid arthritis. It is worthwhile pointing out that the scores did not decrease, with only two exceptions (one trial of infliximab and one of etanercept), suggesting that these agents slow progression rather than stop it. The results were not statistically different between agents, although infliximab was superior to the bottom four agents in each table. This should be interpreted with caution for two reasons. Firstly, the trials were not head-to-head so this is an indirect comparison. Secondly, the characteristics of patients with rheumatoid arthritis in the trials have changed over time. The patients in the infliximab trials had a very high rate of progression compared with the other trials, creating more potential for a greater benefit. It is also possible that the weight-based dosing of infliximab compared with the other anti-tumor necrosis factor agents may confer an additional benefit. In contrast, the golimumab trials may have been negative due to less strict inclusion criteria and a resultant low rate of progression (noted in and ), making it difficult to show a positive result. Indeed, a further study using magnetic resonance imaging assessment of joint damage did show a beneficial effect of golimumab.25
Golimumab and infliximab are very similar chemically, with the former being fully humanized, so this seems the most likely explanation for the variation in efficacy. With most patients not changing X-ray scores in trials, it may be that the odds of progression may be a more sensitive outcome measures than the mean change, as is seen for golimumab. However, most agents were significant in both outcome measures with the other exception being abatacept, which was not significant for the odds of progression. In total, these results suggest that all currently available biologic DMARDs work well for decreasing disease progression when combined with methotrexate.
There is less evidence for monotherapy when the biologic is used without methotrexate. Only three agents were effective. Tocilizumab seems to have similar or slightly less efficacy than when combined with methotrexate, which would be consistent with the recent ACT RAY study.26
Conversely, adalimumab and etanercept were better than methotrexate but the magnitude of benefit was smaller than when these were used in combination with methotrexate. When combined with the clinical data suggesting they are of similar efficacy to methotrexate as monotherapy,27
this suggests these latter two agents are best given with methotrexate. Golimumab monotherapy was ineffective for both outcomes.
There are some potential limitations. Missing data are present in some categories, but most trials had data included in at least one of the outcome measures, suggesting that this did not have a major effect. The excluded etanercept trial appeared to have broadly similar results to the included trials.22
The two denosumab trials both suggested that denosumab prevented erosions without affecting disease activity, but the clinical significance of this is uncertain.23
In some included trials, there is also a disconnect between radiographic results and disease activity. This is most notable for etanercept and adalimumab monotherapy where the radiographic data are more convincing than the clinical data. Publication bias would seem unlikely because there are few trials overall, and even negative trials are published. Secondly, heterogeneity between trials in terms of variation in disease duration and severity may cause problems with pooling of studies, but this was not present for any of the pooled 52-week results, suggesting broadly similar results over this time frame, even given the differing rates of progression and varying disease duration. This observation is consistent with the previous results in our earlier meta-analysis.1
Lastly, there are limited trials comparing combination therapy with methotrexate or biologic therapy. Cyclosporin also seemed to add to methotrexate for radiographic outcomes in two trials, and the magnitude of benefit appears similar to that of biologic DMARDs.1
Triple therapy is better than monotherapy for long-term radiographic outcomes in early rheumatoid arthritis,29
and a recent trial suggested that etanercept plus methotrexate was superior to triple therapy for radiographic but not clinical outcomes.30
This suggests there is insufficient information on which to base decision-making at this point in time.
Implications for practice
In a patient who can take methotrexate, all biologic DMARDs (with the possible exception of infliximab and golimumab) have similar efficacy, thus can be selected without reference to their effect on radiographic progression. In the not uncommon patient who cannot take methotrexate, the data favor tocilizumab as the treatment of choice at this time. Given the lower severity of disease in more recent trials, more sensitive methods for assessing disease progression are needed for future clinical trials in rheumatoid arthritis.