Addressing Primary Nonresponse to Infliximab in Inflammatory Bowel Disease

With infliximab used in the treatment of inflammatory bowel disease (IBD), primary nonresponse, or lack of improvement in clinical signs and symptoms, is a serious problem because of the implications it can have for a patient’s health. If a patient has a severe case of IBD and experiences primary nonresponse, it can lead to fecal loss of infliximab as well as lower levels of infliximab. Furthermore, if systemic inflammation continues, it can lead to the formation of immune complexes which experience phagocytosis and proteolytic degradation of the reticuloendothelial system.

In an editorial that was recently published in Alimentary Pharmacology and Therapeutics, authors D. Sawbridge, MD, and S. Subramanian, MD, discussed how to mitigate primary nonresponse to infliximab. In the article, the authors wrote of the need for an improved definition of the clinical and pharmacokinetic features of primary nonresponders so as to potentially allow for targeted dose increases, or to highlight those who require alternative therapy early on.

The editorial was written in response to a clinical trial, also published in Alimentary Pharmacology and Therapeutics, that addressed the prediction of primary nonresponse to infliximab therapy based on early drug and anti-infliximab antibody levels. The authors agreed that while anti—tumor necrosis factor (anti-TNF) drugs have transformed IBD therapy, 20% to 30% of patients fail to respond to the induction regimen (primary nonresponse), while of the population that does respond initially, about 10% will lose response to the therapy annually (secondary loss of response).

The study was also able to identify week 2 infliximab levels and anti-drug antibodies that were “significantly predictive” of primary nonresponse. The editorial’s authors note that the early development of anti-drug antibodies to infliximab has also been found in other studies, and more than 75% of patients who develop anti-drug antibodies will do so within the first 6 months of treatment. The authors believe that this finding shows that low infliximab levels may provoke immunogenicity, though other host genetic factors may also be involved.

Before putting these findings into clinical practice, Sawbridge and Subramanian argue that there are still significant barriers that remain, such as the need to establish a consensus standard for the wide range of assays used to determine infliximab and anti-drug antibody levels.

The authors say that there is a need for a large-scale study that promotes the development of a “pharmacokinetic dashboard.” This dashboard would incorporate patient information such as genetics, body mass index, and smoking status with disease characteristics, including disease activity and history of surgeries, to assist in predicting induction trough levels using standardized assays and permitting individual treatment strategies.