From the Division of Gastroenterology University of Washington, Seattle, WA (Dr. Tiderington), and the Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center and The Ohio State University Inflammatory Bowel Disease Center, Columbus, OH (Dr. Afzali).
Abstract
- Objective: To provide a practical approach to the management of patients with inflammatory bowel disease (IBD) following tumor necrosis factor (TNF) alpha antagonist failure.
- Methods: Review of the literature.
- Results: TNF alpha antagonists play a central role in the treatment of IBD. Unfortunately, some patients will not respond to therapy with TNF antagonists, and others will lose response during treatment. When patients present with persistent or recurrent symptoms suggesting active IBD while on anti-TNF therapy it can present a dilemma for the clinician. In this paper we review the mechanisms of drug failure, the use of reactive therapeutic drug monitoring to guide clinical decision making, and propose an evidence-based method for managing this common clinical scenario.
- Conclusion: Despite the improved clinical outcomes seen since the introduction of TNF antagonists for the management of IBD, there remains a significant need for additional medical therapies. Fortunately, the armamentarium is expected to expand dramatically over the next decade.
Key words: TNF antagonists; therapeutic drug monitoring; biologic failure; Crohn’s disease treatment; ulcerative colitis treatment.
Ulcerative colitis and Crohn’s disease are the two types of inflammatory bowel disease (IBD), and they are characterized by chronic, immunologically mediated inflammation involving the gastrointestinal tract [1]. Guided by an understanding of the role of tumor necrosis factor (TNF) alpha in the pathogenesis of IBD, TNF antagonists have played a central role in modern treatment algorithms [2]. Unfortunately, roughly one third of patients will not have a clinical response when given induction dosing of the currently available anti-TNF agents, and of those who do respond to treatment, up to one half will lose response to treatment within the first year [3]. When patients present with persistent or recurrent symptoms suggesting active IBD while on anti-TNF therapy it can present a dilemma for the clinician. Once the clinician has confirmed that active IBD is present based on endoscopic, cross-sectional imaging and/or biochemical markers of inflammation, the next step is to identify the cause of the treatment failure, as this guides management. Here we review the body of literature that guides our understanding of treatment failure as well as therapeutic drug monitoring and propose an evidence-based algorithm for managing this common clinical scenario.
Defining Treatment Failure
Patients who receive anti-TNF therapy but demonstrate active IBD should be classified as having either primary nonresponse or secondary loss of response. Primary nonresponse is defined as having either no response, or only partial response, to induction with anti-TNF therapy [4]. Data from pivotal trials and meta-analyses suggest that about one third of patients will not show any clinical response to induction with anti-TNF therapies, with response typically being defined using composite endpoints favoring clinical symptoms and only sometimes incorporating endoscopic findings [5]. An additional one third of patients will have only a partial response, without remission. Patients with ulcerative colitis are at a slightly increased risk of primary nonresponse compared to patients with Crohn’s disease. Though the time frame for defining primary nonresponse is different for each agent because each agent has a slightly different induction schedule, in general the maximal response to therapy is typically seen by week 12, and it is reasonable to use this as a time cutoff [6].
Secondary loss of response is likewise defined as recrudescence of clinically active disease after an initial response. In general, the presence of secondary loss of response should not be invoked until week 12 of therapy. In most pivotal trials, secondary loss of response was seen in roughly half of patients at 1 year. In clinical practice, however, particularly as therapeutic drug monitoring has become more common, the observed rates of secondary loss of response have been lower [6].
Applying these definitions appropriately is important because it dictates the next steps in management. When a patient presents with symptoms suggesting active IBD while on anti-TNF therapy, either during induction when primary nonresponse is possible, or in maintenance when secondary loss of response would be invoked, the first step is to determine if active IBD is the etiology for the presenting symptoms. The initial evaluation should rule out common infectious causes of symptoms mimicking IBD. In particular, Clostridium difficile infection should be ruled out with stool testing. In certain circumstances, ruling out cytomegalovirus (CMV) colitis is important, so an endoscopic evaluation with colonic biopsies should be considered. In the absence of infectious colitis, the presence of active inflammation can often be identified endoscopically, or can be inferred from noninvasive markers with a fair degree of certainty. Fecal calprotectin is an ideal choice for this purpose. In ulcerative colitis it is estimated to have a sensitivity of 0.88 and a specificity of 0.79 for the prediction of endoscopically active disease. The estimated sensitivity for detecting endoscopically active Crohn’s disease is essentially the same (0.87), and the specificity is only slightly lower (0.67). C-reactive protein demonstrates a better specificity (0.92), but has a marginal sensitivity (0.49) [7]. Other etiologies for the patient’s symptoms should also be considered, including medication side effects including use of nonsteroidal anti-inflammatory medications, bile acid malabsorption, small intestinal bacterial overgrowth (SIBO), irritable bowel syndrome (IBS), diverticular disease, ischemic colitis, fibrostenotic strictures, and cancer, depending on comorbidities and the history of present illness.
Once it has been determined that active IBD is the etiology for the patient’s symptoms, the patient should be classified as having either primary nonresponse or secondary loss of response as described above. For the clinician, the next question is how to alter or optimize therapy.
The decision of how to optimize therapy will largely depend on which anti-TNF therapy the patient is currently receiving, and whether they are receiving it as monotherapy or as combination therapy with an immunomodulator. Optimizing therapy will involve either increasing the dose or frequency of administration of the anti-TNF therapy, increasing the dose of azathioprine if indicated, adding an immunomodulator if the patient is on anti-TNF monotherapy, changing to a different anti-TNF agent, or changing to a different class of medication with a different mechanism of action. The recently released American Gastroenterological Association (AGA) guidelines on therapeutic drug monitoring in IBD provide a framework for making these decisions [8]. In general, the clinical choice will be dictated by the etiology of the drug failure.