In the present study, we prospectively evaluated the 4-year continuation rates and efficacy of infliximab in a large cohort of patients with long-standing refractory RA. Relatively few patients were lost to follow-up, which is important when estimating continuation rates and efficacy of therapy. After a 4-year study period, 61.6% of patients enrolled in the study were still receiving infliximab therapy. Over the same time period, 13.6% of patients discontinued infliximab therapy due to lack of efficacy, 16.9% due to safety issues, and 7.9% due to elective reasons. This is the first study that describes 4-year infliximab continuation rates in a large cohort of patients. Long-term continuation rates have also been reported for etanercept (25 mg) and adalimumab (40 mg) in open-label extensions of double-blind controlled trials [19
]. In early RA and MTX-naïve patients who received etanercept, 63% of the 468 patients who entered the 3-year open-label extension were still receiving etanercept at the 5-year follow-up [19
]. Similarly, 4 years after the initiation of the ARMADA (Anti-TNF Research Study Program of the Monoclonal Antibody D2E7 in Patients with RA) trial, 64% of the 271 enrolled patients were still receiving adalimumab therapy (mean duration of treatment = 3.4 years) [20
Results of some smaller studies showed similar or lower infliximab continuation rates after 3 years (Voulgari et al
= 84, 59%), after 2 years (Geborek et al
= 135 75%; Wendling et al
= 41, 67%), and at 1 year (Flendrie et al
= 120, 58%; Zink et al
= 343, 65%; Chevillotte et al
= 60, 64%). Differences between results may be explained by differences in study populations and different availability of treatment alternatives.
Another manner of accessing long-term data is through national registry databases, which are primarily maintained to evaluate effectiveness and safety issues [27
]. Evaluation of the efficacy of long-term therapy shows that, after 4 years of infliximab therapy, the majority of patients had a low level of disease activity and that approximately half of the patients met the criteria for minimal disease activity [18
]. Moreover, we demonstrated that, after the initial rapid response to infliximab therapy between baseline and week 22, a further decrease in disease activity was observed over the remaining 3.5 years. This decrease in disease activity was observed in both the patients who continued with infliximab therapy and those who discontinued treatment later on due to safety or elective reasons. It is also important to mention that low levels of disease activity could be achieved and maintained with a standard infliximab dosage of 3 mg/kg and that dosage increases were transient in a majority of patients. The higher percentage of patients who need a dosage increase in some American studies might be explained by greater flexibility in the U.S. label or by a lower concomitant use of MTX in U.S. practice as compared with our study, in which 90% of the patients continue on infliximab + MTX combination therapy.
Also, transiently increasing the infliximab dose at week 22 in a subgroup of patients with a persistently high level of disease activity did not appear to affect the continuation rate.
We also assessed whether long-term response to infliximab therapy could be predicted early in the treatment protocol. Our findings suggest that persistently high levels of disease activity after an induction regimen of infliximab, as measured by the DAS28 score at week 14 or 22, was predictive of subsequent treatment discontinuation due to lack of efficacy. This observation corroborates the notion that a change in treatment strategy should be considered for patients with high levels of disease activity after 6 months of infliximab therapy. Switching to alternative therapies after 3 to 6 months if no therapeutic effect is observed is common in daily clinical practice and has been used in different studies to explore treatment options [29
]. The optimal time point (that is, week 14 or 22) for determining whether a patient should continue therapy remains to be established and should take into account that predictive values may be highly influenced by the a priori
chance to withdraw from treatment due to inefficacy, which was 13.6% in the present population. This a priori
chance was modified to an a posteriori
chance of 50% when the DAS28 at week 14 or 22 was higher than 6.
However, the data presented here clearly show that this decision is best made using the DAS28 score and not employing single measurements of swollen or tender joint count or response scores such as DAS28 response or ACR response score.