This trial demonstrated that certolizumab pegol plus MTX significantly improved the signs and symptoms of RA, inhibited progression of joint damage and increased physical function and quality of life versus placebo plus MTX in patients with active RA despite MTX. Statistically significant and clinically meaningful differences between placebo and both certolizumab pegol doses were observed with respect to the primary end point (ACR20 response) and all secondary end points (including ACR50, ACR70, ACR core set variables such as swollen and tender joint counts, changes in DAS28 and DAS28 remission). These clinical benefits were achieved rapidly, as early as 1 week of treatment, in this population of patients with severe disease (91% with DAS28 >5.1 at baseline). Although the weekly dosage of MTX used in this trial was low by US standards, post hoc analyses showed that ACR20/50/70 response rates at week 24 were similar in patients who received baseline MTX doses of 10 mg/week, >10–15 mg/week and >15 mg/week. There were no statistically significant differences in clinical efficacy on any study primary or secondary end points between the two certolizumab pegol dose groups, suggesting that a 200 mg dose every 2 weeks is optimal for treatment.
Both doses of certolizumab pegol plus MTX significantly inhibited the progression of structural joint damage compared with placebo plus MTX, as demonstrated by significantly lower mean changes from baseline in mTSS, ES and JSN scores. Comparable inhibition of progression was seen with both certolizumab pegol doses and there was some suggestion of repair of joint damage in the 400 mg dose group (negative 95% CI of the change in mTSS).28
An additional analysis of the radiographic data from patients who withdrew at week 16 owing to ACR20 non-response (per protocol) found that certolizumab pegol had slowed the progression of joint damage in these patients even though they had not achieved an ACR20 response, confirming that certolizumab pegol rapidly inhibits joint damage. These data are also in line with previous findings on a dissociation of inflammation and destruction in the course of anti-TNF plus MTX treatment.29
Certolizumab pegol provided rapid, significant and clinically meaningful improvements in physical function and quality of life, with significant changes in HAQ-DI at week 1 and in SF-36 PCS, MCS and PF domains at week 12, which continued to improve through to week 24. As functional outcomes are associated with structural damage in progressive RA,30–32
treatments that can both improve physical function and inhibit joint damage may help prevent long-term disability. The robustness of all clinical, radiographic and physical function findings were confirmed by sensitivity analyses (data not shown).
Certolizumab pegol plus MTX had an acceptable safety profile with a low incidence of discontinuations due to adverse events. An isolated increase in aPTT was seen for patients treated with certolizumab pegol and placebo in this study. However, no association was seen between increased coagulation assay time and bleeding events. Additional laboratory analyses have shown that this observation was an in vitro phenomenon and that there is no effect on in vivo coagulation function (data not shown). Serious infections, including tuberculosis, were reported more frequently with certolizumab pegol than placebo, consistent with rates associated with other anti-TNF treatments.33
Tuberculosis was reported in a total of five patients (all treated with certolizumab pegol) and was partly attributable to insufficient stringency in screening results by local investigators combined with high background rates of tuberculosis.34
If current criteria were used to screen for tuberculosis, two of these patients would have been classified as having positive PPD reactions and would have been excluded from the study. The incidence of malignancy was low (one patient in each treatment group), with no reported lymphomas.
One limitation of this study was its relatively short duration. Longer-term experience, especially related to safety, will need to be obtained from long-term extension trials and registries. Nevertheless, the study demonstrates that the efficacy and safety of certolizumab pegol is consistent with previously published results for other anti-TNF therapies.5–7
The three licensed anti-TNF agents are either monoclonal antibodies (adalimumab, infliximab) or receptor constructs (etanercept) and all contain an immunoglobulin G Fc portion. Interestingly, the data shown here show that the Fc portion, which is lacking in certolizumab pegol, is not necessary for TNF inhibitors to be clinically effective in RA. Thus, the primary mode of action of TNF inhibitors in RA does not appear to involve Fc-mediated effects but rather the binding and inactivation of TNF and, probably, reverse signalling,35 36
which can also be mediated by an Fc-free Fab′ molecule such as certolizumab pegol.
In summary, this study demonstrated that certolizumab pegol rapidly and significantly ameliorates clinical signs and symptoms of RA, inhibits progression of structural damage and improves physical function and quality of life in patients with active RA despite MTX. These clinical benefits are associated with a low rate of injection-site reactions and a safety profile consistent with other anti-TNF therapies. Therefore, certolizumab pegol expands the treatment armamentarium for patients with RA.