Medical treatment options for patients with inflammatory bowel diseases (IBD) — Crohn’s disease and ulcerative colitis (UC) — have rapidly expanded with several different classes of medications now available. Traditionally, conventional therapy has consisted of mesalamine, steroids and immunomodulators, but in the era of biologic therapy, new options are available. However, variability remains in approaches to optimizing treatment in patients who don’t respond to initial conventional therapies. The purpose of this review is to give a perspective on how to best approach such situations.
First, prior to making changes in medical therapy in patients who appear to not be responding to conventional treatment, it is important to assess for nonadherence with therapy and to consider possible superimposed etiologies that can mimic symptoms of IBD. The prevalence of nonadherence to medical regimens for IBD is important to recognize as it can be as high as 30 to 45 percent and have an impact on disease course.1 Superimposed conditions that can mimic symptoms of active IBD include infections — especially Clostridium difficile (C. difficile) and cytomegalovirus (CMV) infection, small bowel bacterial overgrowth, and irritable bowel syndrome. C. difficile infection can lead to symptoms that mimic those of IBD, and its prevalence among IBD patients with flares may be as high as 20 to 30 percent. CMV is a well-recognized cause of infection in immunosuppressed patients and can be a cause for relapse, a more severe disease course or non-response to medical therapy in IBD patients. CMV tends to localize to the colon in patients with IBD, but disseminated disease has been reported. Patients with Crohn’s are at increased risk of developing small bowel bacterial overgrowth due to structural abnormalities, such as strictures, fistulas and ileocecal resection. In addition, in patients with Crohn’s who have obstructive symptoms, it is important to consider the possibility of predominant fibrostenotic disease, which may require surgery instead of further medical therapy.
Once it has been established that symptoms are truly caused by refractory IBD, escalation of medical therapy can be pursued. The main options consist of optimizing doses of agents that patients are already on (see below for discussion of therapeutic drug monitoring), escalation to biologic therapy, or switching of biologic agents in patients already on such treatment. There are now three FDA-approved categories of biologic agents for the treatment of IBD: anti-tumor necrosis factor (TNF) antibodies, anti-integrin antibodies and, most recently, an anti-interleukin 12/23 antibody. The anti-TNF and anti-integrin agents are approved for treatment of both Crohn’s and UC, while the anti-interleukin 12/23 agent is approved for Crohn’s. Choosing among these agents depends in part on factors such as patient preference for injection versus intravenous therapy and insurance coverage issues. In addition, because of its gut-selective mechanism of action, the anti-integrin antibody vedolizumab appears to have an advantageous safety profile. In a recently published safety analysis of six clinical trials involving more than 2,800 patients treated with vedolizumab, no increased infectious risk was found.
After choosing a biologic, the next decision relates to the use of concomitant therapy with an immunomodulator. Data from studies such as SONIC and SUCCESS have shown that use of concomitant immunodulators is associated with increased therapeutic efficacy, less immunogenicity and higher biologic drug levels. There has been concern regarding possible risks of combination therapy, but these appear to be minimal. In particular, the risk of hepatosplenic T-cell lymphoma, a rare but aggressive lymphoma, has been brought up. It is important to note that this lymphoma has also been reported in patients taking long-term thiopurine monotherapy. Given that this malignancy may be more common in young men, an alternative option is to use methotrexate as the concomitant immunomodulator in this demographic group. In contrast, in young women, thiopurines can be used because of the teratogenic potential of methotrexate with pregnancy. Many patients are concerned about the use of long-term approach in those who are responding to treatment is to re-evaluate the objective status of inflammation and disease activity 6 to 12 months after initiation of combination therapy. In patients who have achieved normalization of symptoms and inflammatory markers along with mucosal healing, one can try to stop the immunomodulator while continuing biologic monotherapy and closely monitoring symptoms and objective evidence of subclinical inflammation.
What if patients have ongoing objective inflammation despite biologic therapy? This is when therapeutic drug monitoring can be of particular benefit. There are currently clinically available drug-level assays for thiopurine metabolites and drug and antibody level testing for some of the biologic agents. In terms of thiopurines, dosing should be maximized to achieve therapeutic 6-thioguanine nucleotide metabolite levels while monitoring for shunting to alternate metabolism of 6-methyl mercaptopurine.2 Among patients on anti-TNF therapy, measurement of drug and antibody levels can help classify further management options into three categories (figure 1).3
In summary, among IBD patients failing conventional treatment, biologic agents provide several alternative options, and more aggressive approaches, such as ‘top-down therapy’ and ‘treat to target,’ have entered the lexicon of the IBD-treatment arena. After excluding nonadherence and superimposed conditions, choosing a biologic agent, using a concomitant immunomodulator and pursuing therapeuticdrug monitoring (at least in non-responders) can help maximize therapy.
Dr. Achkar has no conflicts to disclose.
1. Jackson, C.A., Clatworthy, J., Robinson, A., Horne, R. Factors associated with non-adherence to oral medication for inflammatory bowel disease: a systematic review. Am J Gastroenterol. 2010; 105(3): 525-39.
2. Achkar, J.P., Stevens, T., Easley, K., et al. Indicators of clinical response to treatment with six-mercaptopurine or azathioprine in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2004; 10(4): 339-45.
3. Yanai, H., Lichtenstein, L., Assa, A., et al. Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015; 13: 522-530.