This study is the largest prospective clinical evaluation of a TNF antagonist for the treatment of RA. The safety profile of adalimumab observed in this study was consistent with that previously reported for adalimumab, etanercept and infliximab.1,3,25,26,27
The range of DMARDs used concomitantly with adalimumab in ReAct reflected standard treatment for patients with long‐standing severe RA.28,29,30
No clinically important differences in the safety profile of adalimumab according to the number or type of concomitant DMARDs were evident. Notably, the rate of AEs did not increase as the number and variety of concomitant DMARDs increased in ReAct, a finding that is consistent with use of multiple DMARDs in other studies.31,32
The combinations of adalimumab and LEF or SSZ were associated with higher rates of SAEs compared with patients receiving adalimumab and MTX or AM.
Rheumatoid arthritis and age are both known risk factors for infection.19,33
The serious infection rate of 5.5/100 PYs is similar to reports of patients with RA receiving either infliximab or etanercept in the German and British biologics registries20,34
; these rates were somewhat higher than those seen in patients treated with conventional DMARDs in these registries. The identified predictors for a serious infection in this study were increased age, male sex, comorbid pulmonary and cardiovascular conditions, and a higher baseline HAQ DI score.
All patients were carefully screened for latent TB before enrolment. In total, 835 patients (12.6%) received treatment for latent TB in accordance with national guidelines. Overall, published literature indicates that the rate of active TB has decreased since the initiation of routine screening for latent TB in patients receiving TNF antagonists.27,35
In the present study, the rate of TB (0.5/100 PYs) remains higher than expected in the general population. However, the underlying risk of TB in patients with RA seems to exceed that of the background population.35,36
The SIRs of 0.71 for malignancies and 1.09 for lymphoma in this study are consistent with rates observed in patients with RA (SIR of 0.98−1.1 for malignancies overall and SIR of 1.0−11.5 for lymphoma).13,37,38,39
A meta‐analysis of pooled AE data from randomised, controlled trials suggested an OR of 3.3 (95% CI 1.2 to 9.1) for malignancies.40
Calculation of SIRs based on population‐based incidence data and determination of ORs based on meta‐analytical methodology both have limitations. Analysis of a clinical trial safety database of 10
050 adalimumab‐treated patients with RA reported an SIR of 1.06 for malignancies overall and an SIR of 3.19 for lymphoma.27
Notably, there is a strong association between inflammatory activity and lymphoma in patients with RA.41
The standardised mortality ratio of 1.07 (95% CI 0.75 to 1.49) was slightly lower than the expected range for patients with RA.42
Adalimumab provided substantial improvement in multiple measures of effectiveness in patients with long‐standing active RA despite extensive standard treatment. Randomised, controlled trials have shown that significantly more patients experience a reduction of disease activity when treated with MTX and a TNF antagonist versus a TNF antagonist alone.1,2,3
After adjustment for differences in baseline characteristics in this study, patients receiving adalimumab and an AM had a similar therapeutic response to the patients receiving adalimumab and MTX. Concomitant treatment with adalimumab and LEF was found to be slightly less effective than concomitant treatment with adalimumab and MTX, AM or SSZ but more effective than adalimumab alone after adjustment for differences in baseline characteristics between subgroups.
Although a placebo‐controlled trial is necessary to prove the efficacy of a drug, an open‐label study conducted in a large cohort of patients in multiple countries and a variety of clinical practice sites should provide reassurance about the safety and effectiveness of adalimumab in typical practice. The ACR20 response rates in ReAct were within the range reported in randomised, double‐blind studies of adalimumab.1,25,43,44
The duration of RA and baseline disease activity of participants reflect the RA population typically treated with TNF antagonists and are consistent with most national guidelines for this treatment. By comparison with national biologic registers, which observe treatment outcomes associated with a variety of biologics for several years, this was an industry‐sponsored clinical study conducted in 12 countries with careful site monitoring for a limited treatment period.