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Editorial: withdrawal of anti‐TNFalpha—are we ready for biological therapy cycling? Authors' reply

Dr Pugliese and Dr Armuzzi raise three pertinent questions that every clinician considers when faced with the decision of whether or not to discontinue antiTNF therapy.1 First, what is the right moment? After achieving remission? Several studies have shown that if the antiTNF is stopped when the patient is in clinical and endoscopic remission, the relapse rates are lower than if they are not.2 However, in our study, the relapse rate was similar in those patients who discontinued the antiTNF therapy in deep remission (clinical plus endoscopic or radiologic) compared with those who discontinued the therapy being only in clinical remission.3 In fact, other retrospective studies were not able to demonstrate the association between relapse rate and mucosal healing.46 It is possible that the predictive factors of relapse are confounded by differences in study design (most of them retrospective) and insufficient data to allow the assessment of all potential contributor factors.7 Second, what are the best candidates and how much does the overall disease burden impact on the decision? We found that Crohn's disease patients with colonic location and stricturing phenotype had a higher risk of relapse after antiTNF discontinuation. Nevertheless, perianal disease or history of abdominal surgeries were not associated with higher relapse rates.3 Undoubtedly, again, the identification of predictive factors of relapse is influenced by the different study designs, and the different sample sizes. Also, these predictive factors still need to be validated and their usefulness in clinical practice must be established. Finally, what is the real advantage in terms of efficacy and safety of continuing with/starting thiopurines after antiTNF discontinuation? According to our results, continuing therapy with immunomodulators (thiopurines/methotrexate) after antiTNF discontinuation was associated with a lower risk of relapse.3,5 In some studies, lack of maintenance therapy with thiopurines after antiTNF withdrawal was associated with a higher rate of relapse.4 On the contrary, other studies could not confirm this beneficial effect of immunomodulators.8 After all this, are we ready for biological therapy cycling? We believe that the answer is “not yet.” Although it is probable that this strategy will be adopted in the future, we still need to obtain clear answers to these three posed questions, and robust evidence about the effect of antiTNF discontinuation on the natural history of IBD is needed. In this respect, our group is coordinating the EXIT trial (EudraCT 201500141010, NCT02994836), a quadruple blind, randomised, controlled study conducted at 47 Spanish IBD hospitals.7 This trial is aimed to evaluate the risk of relapse in patients with IBD who discontinue antiTNF therapy after achieving remission in comparison with those who continue receiving antiTNFs. In addition, it is aimed to identify predictors of relapse in this group of patients.7 EXIT trial was designed to address the existing knowledge gap about the clinical impact of withdrawing antiTNF agents in patients in sustained remission. Data obtained from this trial will contribute to help solve some uncertainties remaining in this controversial aspect of IBD management and will provide valuable information for clinical practice.