Sir,
We read with interest the review article by Johnson and Loftus discussing the impact of obesity on inflammatory bowel disease (IBD) patients.[1] The authors discussed the negative impact obesity has on therapeutic response to monoclonal antibodies in this patient population, including the “TNF Sink,” resulting in lower drug trough levels and suboptimal clinical response. However, the potential beneficial rule of small molecules in these patients warrants highlighting. The first class of these molecules to be used in IBD is the JAK inhibitors tofacitinib, the pharmacokinetics of which is not affected by the patient's body weight.[2] In a post hoc analysis of the OCTAVE clinical program, baseline body mass index (BMI) had no bearing on the proportion of patients achieving efficacy endpoints.[3] In practice, clinicians might be limited to prescribing tofacitinib to bio-naïve patients, as its current approval is for those in whom treatment with conventional therapy and monoclonal antibodies failed.
The situation may change with the introduction of other agents of this class. Filgotinib, a highly selective JAK1 inhibitor, showed good efficacy in ulcerative colitis (UC) patients in whom conventional therapy and/or biologics failed. Data from the phase III SELECTION trial showed a favorable safety profile.[4] Similar to filgotinib, upadacitinib showed promising results in the phase II trials in UC and Crohn's disease (CD), UACHIEVE, and CELEST.[5,6] The impact of body weight on the pharmacokinetics of these agents is expected to be similar to tofacitinib.[7] Other small molecules such as S1P modulators are also thought to be unaffected by body weight. In short, with the expanding therapeutic armamentarium in IBD and the move toward a personalized approach to treatment, clinicians could well consider the use of small molecules in obese IBD patients.
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Conflicts of interest
There are no conflicts of interest.
REFERENCES
- 1.Johnson AM, Loftus EV. Obesity in inflammatory bowel disease: A review of its role in the pathogenesis, natural history, and treatment of IBD. Saudi J Gastroenterol. 2021;27:183–90. doi: 10.4103/sjg.sjg_30_21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Singh S, Picardo S, Seow CH. Management of inflammatory bowel diseases in special populations: Obese, Old, or Obstetric. Clin Gastroenterol Hepatol. 2020;18:1367–80. doi: 10.1016/j.cgh.2019.11.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Farraye FA, Qazi T, Kotze PG, Moore GT, Mundayat R, Lawendy N, et al. The impact of body mass index on efficacy and safety in the tofacitinib OCTAVE ulcerative colitis clinical programme. Aliment Pharmacol Ther. 2021;54:429–40. doi: 10.1111/apt.16439. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Feagan BG, Danese S, Loftus EV, Jr, Vermeire S, Schreiber S, Ritter T, et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): A phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet. 2021;397:2372–84. doi: 10.1016/S0140-6736(21)00666-8. [DOI] [PubMed] [Google Scholar]
- 5.Sandborn WJ, Ghosh S, Panes J, Schreiber S, D'Haens G, Tanida S, et al. Efficacy of upadacitinib in a randomized trial of patients with active ulcerative colitis. Gastroenterology. 2020;158:2139–49.e14. doi: 10.1053/j.gastro.2020.02.030. Erratum in: Gastroenterology 2020;159:1192. [DOI] [PubMed] [Google Scholar]
- 6.Sandborn WJ, Feagan BG, Loftus EV, Jr, Peyrin-Biroulet L, Van Assche G, D'Haens G, et al. Efficacy and safety of upadacitinib in a randomized trial of patients with Crohn's disease. Gastroenterology. 2020;158:2123–38.e8. doi: 10.1053/j.gastro.2020.01.047. [DOI] [PubMed] [Google Scholar]
- 7.D'Amico F, Fiorino G, Furfaro F, Allocca M, Roda G, Loy L, et al. Patient's profiling for therapeutic management of inflammatory bowel disease: A tailored approach. Expert Rev Gastroenterol Hepatol. 2020;14:765–73. doi: 10.1080/17474124.2020.1772057. [DOI] [PubMed] [Google Scholar]