Personalizing Therapy for Inflammatory Bowel Diseases

Ashwin N Ananthakrishnan


Expert Rev Gastroenterol Hepatol. 2013;7(6):549-558. 

In This Article

Personalizing Loss of Response

Our recent ability to measure drug levels has proven useful in the management of loss of response to both anti-TNF biologics and thiopurines.[97–99] For thiopurines, a large prospective Spanish study found no association between 6-thioguanine (6-TGN) or thiopurine methyl transferase activity (TPMT) and response to AZA or 6-mercaptopurine. However, an earlier review by Osterman et al. that included 12 articles suggested that patients who were able to maintain remission with thiopurines had a 6-TGN level that was 66 pmol/108 RBCs higher than in non-responders.[97] Patients with thiopurines levels above 230–260 pmol/108 RBCs were thrice as likely to remain in remission (OR: 3.3; 95% CI: 1.7–6.3).

An important mechanism for loss of response to anti-TNF biologics is through the formation of anti-drug antibodies that impair the ability to maintain adequate drug trough levels. A recent meta-analysis by Nanda et al. summarized 13 studies and included 1378 patients.[100] The presence of antibodies to infliximab was associated with a threefold increase in loss of response (OR: 3.2; 95% CI: 2.0–4.9). Furthermore, Afif et al. demonstrated that patients who developed antibodies to infliximab had a superior response when switched to another anti-TNF drug (92%) compared with those who were maintained on the same drug with an escalation of their dose (17%).[101] On the other hand, patients who had subtherapeutic trough levels responded well with just dose escalation and were able to remain on infliximab. However, immunogenicity may not be a persistent phenomenon and there have been no prospective studies randomizing patients to different management strategies (dose escalation, switching to a second anti-TNF agent, class switching) based on trough and antibody levels. In a study by Vande Casteele et al. from the Leuven IBD group which included 1232 serum samples from 90 patients, 53 patients (59%) were found to have detectable antibodies to infliximab.[102] However, in nearly a third of the patients (28%), the antibodies disappeared over time. Patients who had sustained antibodies were five-times more likely to require cessation of drug due to loss of response or hypersensitivity compared with those with transient antibodies (relative risk [RR]: 5.1; 95% CI: 1.4–19.0). In a small case series by Ben-Horin et al., five patients who had positive antibodies to infliximab could regain response to the drug despite the presence of antibodies by addition of a thiopurine or methotrexate.[103] In all patients, follow-up testing revealed reduction in the levels of antibodies to infliximab and an increase in drug trough levels. An understanding of the role of trough levels and antidrug antibodies for other biologics as they become commercially available may allow for informed and tailored dose modification that allows for optimization of current therapy in the setting of persistent disease, or indicate the need for a different therapeutic class.