Assessing response and loss of response to biological therapies in IBD

The advent of biological therapies for inflammatory bowel disease (IBD) began in 1998 with the approval of infliximab for the treatment of refractory (to conventional agents) Crohn's disease (CD). Since then, the indications for anti-tumor necrosis factor-α (anti-TNFα) therapy have increased to include induction and maintenance of clinical responses and remissions for luminal and fistulizing CD, the treatment of children with CD, and the treatment of adults with ulcerative colitis. Additional utilities of biological therapies have included demonstrable mucosal healing, improvement in quality of life, reduction in surgeries and hospitalizations, and the treatment of extraintestinal manifestations of IBD including central and peripheral arthritis and pyoderma gangrenosum. Natalizumab has also been approved for the treatment of refractory Crohn's in patients who have failed conventional agents and anti-TNFα therapies. Unfortunately, despite the overall effectiveness of biological agents in a spectrum of indications for IBD, a significant proportion of patients do not respond or lose response over time. In this review, we intend to appraise the latest evolution in treatment strategies in IBD and to suggest an evidence-based approach and risk stratification while coping with cases of non-responders or loss of response to biological therapies.

We conducted a literature search of English publications listed in the electronic databases of MEDLINE (source PUBMED) and constructed an analytical review based on definitions of response and loss of response, considering potential responsible mechanisms, clinical assessment tools, and finally recommending a practical approach for its prevention and management.

Favorable clinical outcome appears to be the consequence of sustained therapeutic drug levels, and the current literature supports a practice of dose adjustments. When immunogenicity develops to a single biological agent, response can be regained by introduction of an alternative biological agent of the same or different class. Efficacy is reduced with second-line agents either within or across classes compared with naive patients. In the absence of direct measurement of drug levels and anti-drug antibodies, clinical judgment is necessary to assess the mechanisms of loss of response, and more empiric decision making may be necessary to determine the choice of second-line biological agents. Optimal treatment strategies are still controversial.

It is essential to recognize the spectrum of mechanisms affecting response and loss of response to form a logical and efficient management algorithm, and, perhaps, it is time to incorporate the measurement of trough levels and anti-drug antibodies in the strategy of such an assessment. Prospective controlled trials are direly needed to investigate the optimal tailored management in individual patients who lose response.