- Top of page
The introduction of tumour necrosis factor (TNF)-blockade with infliximab, adalimumab, or certolizumab has offered significant advances in the treatment of inflammatory bowel disease and its complications. Indeed, infliximab has been demonstrated in multiple randomized controlled clinical trials to be efficacious for the treatment of both luminal and fistulizing Crohn’s disease and in decreasing the rate of hospitalizations and surgical interventions.1–5 Two recent single centre cohort studies, one from Canada and another from Belgium, demonstrated the efficacy of infliximab in ‘real-life’ clinical practice with induction of clinical improvement rates of 88% and 89%, and maintenance of clinical benefit rates of 83% and 84% at 1 year respectively.6,7
Despite this efficacy, issues relating to cost and long-term safety, in relation to infection and neoplasia, lead to the inevitable question: can the infliximab treatment be discontinued after induction of clinical remission, and/or mucosal healing, and will the patient remain in extended remission on maintenance immunosuppressant therapy? Existing clinical trial data are limited to answer the question whether infliximab can be discontinued and how long the patients will remain in remission thereafter. Infliximab was combined with methotrexate in 120 Dutch rheumatoid arthritis patients with severe disease activity. Seventy seven of the 120 patients discontinued infliximab after reaching a state of clinical remission; of these, 66 (86%) had a sustained remission off infliximab for at least 1 year.8 Similarly, nine patients with rheumatoid arthritis were able to discontinue infliximab after maintenance of remission and sustain their remission on methotrexate alone for a mean of 14 months.9 In patients with Crohn’s disease, the Leuven centre in Belgium followed up a group of 82 patients who had discontinued infliximab therapy for reasons other than loss of response, and found a median sustained remission period of 47 months.6 In a prospective study from France currently underway, but reported as an abstract, patients with luminal Crohn’s disease treated for at least 1 year with combined infliximab and an immunosuppressant were recruited to discontinue infliximab and continue the immunosuppressant. After a median follow-up of 1 year, 45/115 (40%) of patients relapsed.10
The objective of this study was to assess, in patients who had obtained a stable infliximab-induced corticosteroid-free remission, the proportion who relapsed after infliximab discontinuation and to examine factors associated with this relapse.
- Top of page
While the advent of anti-TNF-agents to manage Crohn’s disease has revolutionized treatment paradigms in the last decade, the duration anti-TNF therapy should be continued in patients in remission and when, and if, anti-TNF agents can ever be stopped remain unknown. This is a particularly relevant clinical question given the cost and safety profile of these agents in conjunction with the lifelong affliction of the disease.12, 13
In this longitudinal cohort study, we followed up, for up to nearly 7 years, patients with Crohn’s disease who had an infliximab-induced corticosteroid-free clinical benefit and then discontinued infliximab for reasons other than loss of response. The patients with Crohn’s disease received infliximab through a protocol-based ‘step-up’ approach whereby, to receive an induction dose of infliximab, patients must have demonstrated remission failure or adverse events to both corticosteroids and immunosuppressive drugs.14
In this current study, Kaplan–Meier analysis of both patients maintaining remission and those with a clinical relapse demonstrated that approximately 50% of patients will have relapsed within 477 days after the discontinuation of infliximab therapy. Interestingly, there is a plateau beginning ∼750 days after the final infliximab infusion and becoming flat at ∼1300 days that demonstrate an extended and stable long-term remission for approximately 35% of the patients.
Similar results were found in a Belgian study where patients with Crohn’s disease received a median of 4 infliximab injections over a median of 6 months and then had the infliximab stopped while in remission. These patients remained in clinical remission for a median period of 47 months (∼1400 days) ranging between 21 and 66 months (∼630 to ∼2000 days).6 In another European prospective study, infliximab was discontinued in steroid-dependent patients with Crohn’s. After 12 months, 40% of the patients with Crohn’s disease had relapsed.10 Moreover, an additional study found that 23% of patients receiving placebo medication after their original loading doses of infliximab at weeks 0, 2, and 6 maintained clinical remission when assessed at 54 weeks.13 While these studies examined clinical remission after infliximab discontinuance, the duration of their assessment was short relative to the lifelong nature of Crohn’s disease. Our study not only reaffirms the short-term duration of clinical remission found in these previous studies but also demonstrates, for the first time, that a significant subset of patients can sustain clinical benefit for long intervals after infliximab was discontinued.
Factors affecting the duration of a clinical benefit after discontinuing infliximab remain speculative. Multivariate analysis of concomitant drug therapy, number of infliximab doses, age, gender and disease location did not statistically impact the survivor curve (data not shown). Instead, it is very likely that a patient’s initial response to infliximab, and in conjunction the sustained response, or not, after discontinuance of infliximab, is based on a patient-unique genetic type of Crohn’s disease.15–18 Indeed, recent studies using microarray data sets to assess gene arrays have identified predictive panels of genes for response and/or nonresponse to infliximab in patients with ulcerative colitis and rheumatoid arthritis.19, 20 Future studies are needed to analyse genetically patients with Crohn’s disease who have discontinued infliximab therapy in attempt to correlate their duration of remission with their disease genotype.
Anti-TNF-induced mucosal healing has been demonstrated to prolong remission and reduce hospitalizations and surgery.21 Furthermore, complete mucosal healing has been found to occur in approximately one quarter of patients, a value similar to the number of patients in our study who had extended long-term clinical benefit after the infliximab was discontinued. It is possible that this same group of patients with complete mucosal healing are also those who have the sustained clinical benefit following infliximab discontinuation. Unfortunately, the current study patients did not have prospective sequential endoscopies to assess mucosal healing and thus future studies will need to address this question.
In summary, this longitudinal cohort study identified that nearly two-thirds of patients with Crohn’s disease who are in an infliximab-induced clinical remission will ultimately relapse after their anti-TNF therapy is discontinued and that in 50% of patients, this relapse will occur within 500 days. It should be noted, however, that one-third of our cohort achieved long-term remission after the discontinuance of infliximab therapy. Extrinsic factors affecting the duration of Crohn’s remission could not be identified making a genetic link plausible.