Aug. 16, 2019
Approved in 1998 for use in treating Crohn's disease and subsequently in 2005 for treating ulcerative colitis, anti-tumor necrosis factor (TNF) agents have provided a potent tool for managing inflammatory bowel disease (IBD) symptoms. Unfortunately, about a third of individuals diagnosed with IBD do not respond to anti-TNF agents, and half of the patients who initially have a positive response during induction treatment subsequently experience a loss of response to these drugs.
Researchers have identified multiple clinical factors that appear to be associated with a better response from anti-TNF agents. These factors include: age at diagnosis, shorter duration of disease, lack of previous IBD-related surgery or stricturing phenotype, higher C-reactive protein level, no evidence of previous corticosteroid or immunomodulator failures, no history of smoking, and optimized trough level of anti-TNF agent.
Anti-TNF therapy is costly and has several associated adverse effects. Therefore, the ability to identify patients whose IBD is refractory to this treatment can help clinicians prevent unnecessary anti-TNF therapy and associated potential adverse effects, and accelerate the process of providing effective, individualized treatment strategies for each patient.
Mayo Clinic researchers and colleagues from Washington University School of Medicine in St. Louis, and Massachusetts General Hospital and Harvard Medical School in Boston conducted a hypothesis-free genetic association study designed to develop and validate a model predicting the influence of both disease-specific and genetic factors on an individual's responsiveness to anti-TNF therapy. The results of the study were published in the Journal of Crohn's and Colitis in 2019.
"With the recent advances in microarray-based genomic sequencing, a long-awaited new era of precision medicine to redefine subtypes of complex disease like IBD is getting closer than ever. Through the multi-institutional collaboration, for the first time we are able to discover and further validate the association between the novel genetic variants and anti-TNF treatment response in patients with IBD," says Ming-Hsi Wang, M.D., Ph.D., the first and lead author on the Journal of Crohn's and Colitis article and a gastroenterologist at Mayo Clinic Health System in Mankato, Minnesota.
"By developing an exploratory predictive risk model and risk score integrating both clinical and genetic predictors, this research could facilitate an efficient way for clinicians to identify patients who may not respond to anti-TNF agents," explains William A. Faubion, M.D., a senior lead author on the Journal of Crohn's and Colitis article, the Mayo Clinic IBD cohort primary investigator, and a gastroenterologist at Mayo Clinic's campus in Rochester, Minnesota.
Study methods
The researchers used Mayo Clinic and Washington University IBD genetic association study cohorts as discovery and replicate data sets, respectively. They focused on a variety of clinical factors, including sex, age at diagnosis, disease duration and phenotype, disease location, history of bowel resection, tobacco use, family history of IBD, extraintestinal manifestations, and response to anti-TNF therapy.
Results
Clinical factors associated with anti-TNF response
- Among the 474 individuals with IBD who were treated with anti-TNF therapy, 41 (8.7%) were refractory to therapy and 433 (91.3%) responded to treatment.
- Multivariate analysis showed that a history of immunomodulator use (odds ratio, 10.2, p = 8.73E-4) and bowel resection (odds ratio, 3.24, p = 4.38E-4) were associated with refractory response to anti-TNF agents.
"We also identified several disease-specific factors that did not appear to impact response to anti-TNF agents," explains study co-investigator Shabana F. Pasha, M.D., a gastroenterologist at Mayo Clinic's campus in Arizona. "Age at diagnosis, disease duration, family history and phenotypes of IBD, advanced disease behavior, perianal disease involvement, and extraintestinal manifestations of IBD were not associated with anti-TNF response."
Genetic factors associated with anti-TNF response
- Two genetic loci (rs116724455 in TNFSF4/18, rs2228416 in PLIN2) were successfully replicated and another four (rs762787, rs9572250, rs144256942, rs523781) with suggestive evidence were found.
- An exploratory risk model predictability (area under the curve) increased from 0.72 (clinical predictors) to 0.89 after adding genetic predictors.
- Through identified clinical and genetic predictors, investigators constructed a preliminary anti-TNF refractory score to differentiate anti-TNF nonresponders: mean (standard deviation) score, 5.49 (0.99) from responders: 2.65 (0.39); p = 4.33E-23.
According to co-investigator Michael F. Picco, M.D., Ph.D., a gastroenterologist at Mayo Clinic's campus in Jacksonville, Florida, these findings should clarify why the response to anti-TNF agents varies. "We identified novel genome-wide significant signals in TNFSF4/18 loci and several other suggestive loci linked to TNF-α, all of which may predict anti-TNF response in patients with IBD," says Dr. Picco.
The investigators acknowledge that additional research is needed to help determine which patients experience primary nonresponse versus secondary nonresponse to anti-TNF agents in the study cohorts, and to further validate this model in an independent prospective cohort.
Co-investigator Laura E. Raffals, M.D., a gastroenterologist at Mayo Clinic's campus in Rochester, Minnesota, notes that these results could lead to a welcome advance in the tools available for the management of IBD. "In time, this type of research may accelerate the development of an individualized medicine tool that can help clinicians make safe and effective choices when considering different treatment options and strategies," says Dr. Raffals.
For more information
Wang MH, et al. Novel genetic risk variants can predict anti-TNF agent response in patients with inflammatory bowel disease. Journal of Crohn's and Colitis. In press.