This study describes the seven-year continuation rates, safety and efficacy of infliximab in a large cohort of patients with severe long-standing refractory RA. Of the initial 507 patients who started therapy, 49 patients were lost to follow up after seven years. This is less than 10% of patients, which is acceptable for interpreting the evaluation of continuation rates, safety and efficacy of therapy. Of the remaining 441 patients, 160 (36%) were still receiving infliximab therapy after seven years.
Due to the chronic nature of RA, requiring therapy for many years, long-term data to evaluate the efficacy and safety of the compounds are very important. This information can be obtained by cohorts or extensions of controlled trials, mostly focusing on one compound [10
], or by registries [12
]. This study could possibly bridge the gap between extensions of clinical trials and nationwide registries: the inclusion criteria of the program were based on inclusion criteria similar to the daily clinical practice reimbursement criteria, and less stringent compared with clinical trials. Due to limited time span of inclusion, this study can be considered as an inception cohort, which has specific advantages for the analysis of trends over time, which is more difficult in registries.
Differences in baseline characteristics may be a reason for heterogeneity between studies. The heterogeneity between the different studies results in large differences in retention rates and Kaplan-Meier curves of anti-TNF therapy survival. The patients presented in this cohort suffered from severe long-standing disease, which may differ from that in patients in more recent studies and registries, in whom disease duration and activity tend to be less severe [15
Interestingly, in this study, we were able to evaluate the different reasons for discontinuation over time. Discontinuation due to ineffectiveness seemed to be quite constant over time, resulting in a linear Kaplan-Meier curve (Figure ), whereas discontinuation due to safety issues was most frequent during the first two years of therapy. This resulted in a decline of the slope of the curve over time (Figure ). Finally, discontinuation due to elective reasons not directly related to product safety or ineffectiveness was most frequent around year four (Figure ), when a new subcutaneous TNF blocker (adalimumab) became available in Belgium.
Regarding discontinuation, several factors should be taken into account. First, the acceptance of remaining disease activity may differ between physicians and patients and change over time. When patients have failed several therapies and few alternatives are available, one can assume that more remaining disease activity will be tolerated. In contrast, when more alternatives become available, one can assume that less remaining disease activity will be tolerated, resulting in an earlier start of a new biologic therapy [13
] and earlier switching of therapies. In this study, mean DAS28 at the time of treatment discontinuation due to ineffectiveness showed a trend to decrease over time from 5.6 in 2001 to 4.8 in 2008. Second, discontinuation due to safety issues may differ between populations and eras. For example, a large proportion of patients in this cohort started infliximab therapy before general TB screening was recommended. With mandatory screening, it is possible that some TB cases in this cohort could have been avoided.
Finally, discontinuation due to elective reasons may be highly dependent on local situations (eg, reimbursement rules, national guidelines, access to infusion clinics) and the availability of new therapeutic options.
Long-term infliximab therapy seems to be efficacious and safe. More than 60% of patients still on infliximab at the seven-year follow up had low disease activity, and more than 45% of patients who continued infliximab treatment were in remission at year seven. Similarly low disease activity was observed in patients who discontinued therapy due to elective reasons. Higher levels of disease activity were observed at the time patients discontinued therapy due to safety issues or ineffectiveness.
Most safety issues resulting in therapy discontinuation occurred during the first two years of therapy. This was especially true for infusion reactions and infections. The trend toward a decrease in infection rates in the long term might be caused by the elimination of subgroups of patients determined to be at higher risk for infections on anti-TNF therapy. No unexpected cases of atypical infections were observed in this cohort.
Unfortunately, a majority of patients had to withdraw from infliximab therapy. Extrapolating the data from other registries and compounds (biologics and DMARDs) [16
] over 5 to 10 years demonstrated that, irrespective of the compound, more than half of RA patients will drop out of therapy. This suggests that further research is needed on the optimisation of treatment strategies in this era, when an increasing number of compounds became available for the treatment of patients with this chronic disease.