Response to Letter to the Editor: “Failure Rate of Antitumor Necrosis Factor Alpha Biologics in Very Early Onset Inflammatory Bowel Disease”

To the Editors,

In their letter, Watson et al report on antitumor necrosis factor (anti-TNF) failure in the Texas Children’s Hospital very early onset inflammatory bowel disease (VEOIBD) cohort who have undergone whole exome sequencing (WES; n = 56), highlighting greater racial and ethnic diversity compared with our recently published Boston Children’s Hospital cohort (n = 216). Despite differences in baseline characteristics—in particular in reported percentages of Hispanic and Black patients—rates of anti-TNF failure were similar in both cohorts, at 50% to 60%.

The diverse cohort that Watson et al contribute is important to understanding the various patient factors that underlie treatment responses. As nicely stated in work by Borrell et al, while race in clinical research has inherent limitations, it is directly associated with genetic ancestry and therefore indirectly related to genetic variants that may affect disease and health outcomes.¹ This concept is underscored in recent post hoc analyses of phase 2 and phase 3 randomized clinical trials of golimumab in adults with moderate to severe ulcerative colitis. Despite the uniform, protocolized treatment approach, after controlling for confounders, racial minority groups were less likely to achieve clinical response, clinical remission, and endoscopic remission with golimumab compared with white patients.² Other studies have honed in on inflammatory bowel disease (IBD) risk loci unique to specific ancestral populations.^3,4 Collectively, this and other data highlight the importance of diverse study populations to the creation of generalizable IBD research. This diversity is at least as important in VEOIBD patient populations, who likely have greater genetic risk burden for disease.^5,6

Interestingly, our cohorts also varied in other baseline characteristics, with the Texas Children’s Hospital cohort having higher rates of infantile-onset disease, more extraintestinal manifestations, and younger age at anti-TNF initiation. This is likely a reflection of a sicker patient population selected for WES compared with the Boston Children’s Hospital cohort in which WES was universally available. Such factors are also important to consider in generalizability of measured outcomes.

Our collective findings underscore the need for large, multicenter, prospective studies of VEOIBD patients, as raised by Watson et al. These studies might focus on 2 areas of unmet need for VEOIBD patients: (1) expanded access to WES and (2) expanded access to advanced IBD therapies. While WES is increasingly becoming a standard-of-care diagnostic tool in VEOIBD (and in particular in infantile-onset IBD),^7,8 it remains difficult to access for many. Making WES more widely available for VEOIBD patients is essential to furthering our understanding of the genetic landscape of disease, including the genetic basis of outcome differences tied to ancestry. Secondly, despite differences in baseline characteristics, both cohorts found that at least half of VEOIBD patients fail anti-TNF, reinforcing the critical need for study of next-line therapies in these vulnerable patients.

Funding

L.V.C. is supported by Crohn’s and Colitis Foundation Research Fellows Award (award number 830997). S.B.S. is supported by National Institute of Diabetes and Digestive Kidney Diseases of the National Institutes of Health under (award number RC2DK122532) and (award number P30DK03485), and the Leona M. and Harry B. Helmsley Charitable Trust.

Conflicts of Interest

S.B.S. declares the following interests: scientific advisory board participation for Pfizer, BMS, Lilly, IFM therapeutics, Merck, and Pandion Inc; grant support from Pfizer, Novartis, Takeda; consulting for Hoffman La Roche, Takeda, and Amgen.