Discussion
inflammation, Crohn's disease
INFLAMMATION, DISEASE, SECONDARY, REMISSION, HOLIDAY, CROHN'S DISEASE, INFUSION REACTION, EVENTS
The SPARE trial showed an increased risk of relapse over 2 years in patients with Crohn's disease in clinical remission on combination therapy when discontinuing infliximab as compared with patients continuing infliximab either as monotherapy or in combination with an immunosuppressant therapy. Conversely, discontinuing the immunosuppressant therapy did not affect the relapse rate. Retreatment with infliximab allowed rapid recapture and maintenance of remission in patients who relapsed, and treatment failure rates were similar across treatment groups. Despite this result, the non-inferiority hypothesis for the time spent in remission over 2 years after infliximab withdrawal was rejected. Alongside infliximab withdrawal, other predictors of relapse were young age at onset, and evidence of ongoing inflammation at baseline assessment.A higher relapse rate after stopping infliximab in patients on combination therapy was expected in light of published data.Our working hypothesis upon study design was that, despite this increased risk of relapse, the time spent in remission over 2 years would not be inferior in patients discontinuing infliximab, anticipating a rapid recapture of remission when retreating them and no greater numbers of treatment failure. In patients discontinuing infliximab, retreatment was well tolerated and successful in almost all patients. The treatment failure rate over 2 years was similar and low (around 10%) in the three groups and the difference in the time spent in remission was only around 14 days over 2 years between patients stopping or continuing infliximab. However, the 95% CIs of the differences between study groups in time spent in remission included the non-inferiority threshold, and the non-inferiority hypothesis was thus rejected.A series of other factors were also associated with relapse in multivariable analysis and should be mentioned: higher hsCRP, faecal calprotectin greater than 300 μg/g, and young age at onset (<17 years). Predictors such as higher CDEIS and SES-CD scores and elevated hsCRP and faecal calprotein levels have been reported in previous studies,Sustained clinical remission without steroids over 2 years was not significantly different between the three groups. The main reasons for not achieving sustained clinical remission without steroids were early withdrawal and fluctuating CDAI of 150 or higher, which were not systematically associated with a confirmed relapse.There was no significant difference in change in endoscopic scores of activity, hsCRP, or faecal calprotectin between baseline and end of study visit across groups, suggesting no signal for any subclinical disease escape during these 2 years of treatment de-escalation. Infliximab trough levels at the end of the trial in the retreated patients were very similar to those observed at baseline. The relative stability of infliximab trough levels and low levels of anti-infliximab antibodies in this group might look surprising considering previous concerns regarding the risk of anti-infliximab antibody development and pharmacokinetic loss of response after episodic monotherapy therapy with infliximab.The lack of a difference in relapse rate (and in changes between baseline and end of study in endoscopic scores, markers of inflammation, infliximab trough levels, and anti-infliximab antibodies) between patients continuing and those stopping immunosuppressant therapy when being on infliximab confirms the lack of clinical benefit of continuing immunosuppressant therapy in patients treated with infliximab for a median of more than 2 years. The clinical outcome is in agreement with a previous controlled study,Our study was not powered to identify differences in safety profiles accurately across the treatment groups, but no new safety signals were observed in any group. Interestingly, no acute infusion reaction was observed in the group of patients discontinuing infliximab and being retreated after a drug holiday period. This observation is consistent with the absence of development of anti-infliximab antibodies in that group and also with previous findings.We acknowledge that our trial was limited by the absence of blinding. This limitation might have impacted the assessment of the primary endpoint based on CDAI variations. Indeed, subjective measures are included in CDAI, which could have been influenced by the knowledge of the administered treatment. Subjectivity of the endpoint was limited by the mandatory confirmation of relapse with one objective marker of inflammation (hsCRP or faecal calprotectin). Another limitation is the relatively low number of events, reducing accuracy in determining risk factors associated with either relapse or treatment failure. We also acknowledge some missing data for biomarkers, particularly faecal calprotectin at baseline and end of study, and endoscopy at end of study. Finally, although infliximab trough levels and anti-infliximab antibodies were measured for secondary endpoints in the trial, they were not used for treatment optimisation.In conclusion, the results of the SPARE trial show that discontinuation of infliximab in patients on combination therapy is associated with an increase in the risk of relapse compared with patients continuing combination therapy and also with those switching to infliximab monotherapy. We were able to identify clinical characteristics of patients with high risk of relapse and failure. In the group of patients experiencing relapse, the large majority responded promptly to infliximab retreatment, so that the loss of time spent in remission was only 2–3 weeks over 2 years. These results provide information to help guide treatment decisions for clinicians and for patients on sustained remission under combination therapy with infliximab and immunosuppressant therapy. An informed decision on treatment de-escalation by withdrawing either infliximab or immunosuppressant therapy might be agreed, taking into account these findings together with patient preferences, clinical characteristics, and other factors including national health policy guidelines and economic considerations.
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