A User’s Guide to De-Escalating Immunomodulator and Biologic Therapy in Inflammatory Bowel Disease

We found the review written by Hirten et al1Hirten R.P. et al.Clin Gastroenterol Hepatol. 2020; 18: 1336-1345Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar timely, published at the height of the COVID-19 pandemic, when pervasive concerns about immunomodulators or biologic drugs prevailed. In the review, the authors present a practical guide to de-escalating patients with evidence to support who to de-escalate and what happens after de-escalation. We would like to caution against a monodimensional approach to de-escalation. First, only the detrimental aspect of outcomes was considered (ie, the risk of relapse). Through no fault of the authors, the practical task of counseling patients about de-escalation is stymied by the lack of data for the benefits of withdrawal. For de-escalation to succeed in the clinical setting, data on parallel risk reduction of infections, lymphoproliferative disorders, and nonmelanoma skin cancers (NMSCs) should be presented. The risk of lymphoproliferative disorders was shown to decrease on thiopurine withdrawal whereas the risks of NMSCs persists even after drug discontinuation—past exposure to thiopurine caries a 4-fold risk of NMSCs.2Peyrin-Biroulet L. et al.Gastroenterology. 2011; 141: 1621-1628.e1–5Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar,3Beaugerie L. et al.Lancet. 2009; 374: 1617-1625Abstract Full Text Full Text PDF PubMed Scopus (771) Google Scholar Until studies designed to show harm (relapse) and benefits (no treatment related drug effects) are presented, clinicians facing risk-benefit discussions will struggle present information coherently and comprehensively to support patients in their decisions. A second issue that stems from adopting a restricted perspective to risk is exemplified in the Figure 1, and implies that ulcerative colitis patients who are young and male should continue therapy because of the high risk of relapse. Yet, we know that this group is often targeted for withdrawal therapy due to the risk of hepatosplenic T cell lymphoma. Even though the estimated risk in men <35 years of age is small (1 in 7404), the consequences of such a diagnosis are life changing.4Kotlyar D.S. et al.Clin Gastroenterol Hepatol. 2011; 9: 36-41.e1Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar Recognition that a relapse is more easily treatable than a lymphoma might sway the decision toward withdrawal despite a high relapse rate. The algorithm may misguide clinicians on 2 counts—it refers to risk of relapse for withdrawal without balancing against benefits and risks of withdrawal without risks of continued therapy. Last, awareness and consideration of the nature of the risk or adverse event is closely linked to patients’ risk preferences, which are not fixed. Most patients may be willing to accept risks of drug adverse effects with maintenance therapy, as a trade-off to symptom resolution when experiencing a relapse. A survey of 640 patients with inflammatory bowel disease showed that 41% of ulcerative colitis patients valued efficacy as a key decision-making factor when considering treatment with an immunomodulator or biologic compared with 38% who valued safety.5Almario C.V. et al.Am J Gastroenterol. 2018; 113: 58-71Crossref PubMed Scopus (18) Google Scholar Such priorities may alter depending on disease state: depending on the severity of active symptoms at initiation of treatment, risk acceptance differs to disease remission for treatment discontinuation.6Johnson F.R. et al.Gastroenterology. 2007; 133: 769-779Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar Such risk preferences should be weighted to reflect the impact of uncommon but life-changing adverse events on decisions as well as baseline clinical state. In the absence of a complete picture of risk reduction associated with treatment withdrawal and the inclusion of risk preferences, the optimal approach might be to check suitability of withdrawal, as presented by Hirten et al,1Hirten R.P. et al.Clin Gastroenterol Hepatol. 2020; 18: 1336-1345Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar followed by a shared decision-making process using data about benefits vs harms of treatment in parallel with the harms of stopping therapy (ie, risk of relapse), and an assumption that benefits are reversal of drug-related risks. We are still a long way away from an evidence-based algorithm for de-escalation. The current trials with on biologic therapy de-escalation will provide much needed data to support actions. In the meantime, clinicians should familiarize themselves with their patients’ preferences and risk presentation. A User’s Guide to De-escalating Immunomodulator and Biologic Therapy in Inflammatory Bowel DiseaseClinical Gastroenterology and HepatologyVol. 18Issue 6PreviewDe-escalation of immunomodulators and biologic agents in inflammatory bowel disease is frequently discussed with patients and must weigh the risk of continued medical therapy with the risk of disease recurrence. Risk factors for disease flare after withdrawal of inflammatory bowel disease medications such as disease activity at de-escalation, disease prognostic features, and prior course of disease have been identified predominately in retrospective studies, allowing for risk stratification of patients. Full-Text PDF ReplyClinical Gastroenterology and HepatologyVol. 19Issue 6PreviewWe appreciate the letter by Arebi and colleagues regarding our review article on the de-escalation of immunomodulators and biologic therapy in inflammatory bowel disease and agree that this review is timely during the COVID-19 pandemic. We, however, disagree with their comments that our approach was “monodimensional” and only took into account the detrimental aspects of de-escalation (ie, the risk of relapse), which may “misguide” clinicians. We are indeed well aware of the benefit provided by stopping medications, such as reducing the risk of lymphomas when stopping thiopurines, even though there is limited evidence beyond this observation regarding improved safety with stopping other medications. Full-Text PDF