Reply.

Abstract

We thank Orlando et al1Orlando A. et al.Clin Gastroenterol Hepatol. 2016; Google Scholar for describing their successful experience using the strategy of adding a concomitant immunomodulator to patients who are primary or secondary anti–tumor necrosis factor (TNF) nonresponders. However, we offer a warning to be careful to not overinterpret these results. Four reasons drive this warning. First, this was an uncontrolled observation in a small sample of patients and, thus, the study should be viewed as hypothesis-generating. Second, their study lacked data on the reasons for primary or secondary anti-TNF failure, the status of drug and antibody concentrations, and objective markers of disease activity or remission (eg, inflammatory markers, mucosal inflammation). Without this accompanying information, it is difficult to interpret their results and a change in clinical practice on the use of anti-TNF agents should not be recommended. Third, antibodies to anti-TNFs can develop early, and once formed are difficult to overcome.2Yanai H. et al.Clin Gastroenterol Hepatol. 2015; 13: 522-530Abstract Full Text Full Text PDF Scopus (238) Google Scholar The fourth reason for this warning relates to the reference by Orlando et al1Orlando A. et al.Clin Gastroenterol Hepatol. 2016; Google Scholar to our recently published meta-analysis.3Jones J.L. et al.Clin Gastroenterol Hepatol. 2015; 13: 2233-2240Abstract Full Text Full Text PDF Scopus (86) Google Scholar The patients in our meta-analysis who were on combination therapy included only patients who previously failed immunomodulator treatment at the time of trial enrollment. Although our overall analysis showed that there was no difference when continuing immunomodulators when starting anti-TNFs, there was a statistically significant difference in monotherapy vs combination therapy with induction response, 6-month remission rates, and prevention of infusion reactions when stratified by all infliximab users compared with the other anti-TNF agents. Caution must be exercised with these results as well, but it does show that we need to carefully make decisions based on the specific treatment scenario as opposed to a one-size-fits-all approach. In fact, in one of our previous publications offering guidance on the use of combination as opposed to monotherapy, we reviewed 134 unique patient scenarios.4Melmed G.Y. et al.Clin Gastroenterol Hepatol. 2010; 8: 655-659Google Scholar Tailoring the therapy plan to individual patients is the most sophisticated approach to treating inflammatory bowel disease. This is not always possible owing to incomplete data for guidance, but there is little disagreement that a patient’s first shot at anti-TNF therapy is their best.5Gisbert J.P. et al.Aliment Pharmacol Ther. 2015; 41: 613-623Google Scholar Therefore, we need to do as much as possible to optimize therapy early. With what is known about immunogenicity against anti-TNFs, most likely we need either combination therapy at the outset or carefully managed anti-TNF drug concentrations6Vaughn B.P. et al.Inflamm Bowel Dis. 2014; 20: 1996-2003Google Scholar to provide the highest chance for long-term remission. Consequently, the “delayed immunomodulator” option presented by Orlando et al1Orlando A. et al.Clin Gastroenterol Hepatol. 2016; Google Scholar may work for some patients, but may bring risk to others. Our warning is to recognize the limitations of the data presented, the risk of early antibody formation, and to consider the many different types of patients encountered in clinical practice who each require a carefully planned treatment regimen. Selective Use of Combination Therapy in Patients With Infliximab-resistant Inflammatory Bowel Disease: Data From a Tertiary Referral CenterClinical Gastroenterology and HepatologyVol. 14Issue 6PreviewInfliximab is an effective treatment for induction and maintenance of clinical remission in patients with moderate to severe inflammatory bowel disease.1–3 However, the immunogenicity of infliximab is an important cause of treatment failure. Combination therapy with immunosuppressants is considered the best treatment choice in this setting of patients.3,4 However, the effectiveness and security of concomitant use of immunosuppressants is still questionable. A recent meta-analysis showed that the concomitant use of immunosuppressants and anti–tumor necrosis factor-α is no more effective than anti–tumor necrosis factor-α monotherapy in inducing and maintaining remission in patients with Crohn disease (CD). Full-Text PDF