OR WAIT null SECS
Findings from a novel study supports the JAK inhibitor tofacitinib as a potential first-line therapy for ASUC.
Acute severe ulcerative colitis (ASUC) is managed with corticosteroids; however, approximately 30 - 40% of patients are refractory to corticosteroids and require medical or surgical rescue therapy.
Corticosteroid refractoriness may be attributed to genetics as well as expression of pro-inflammatory cytokines. Downstream signaling of interleukin 2 (IL-2) prevents glucocorticoid receptor translocation, but this may be dampened by Janus kinase (JAK) inhibition. Singh et al. conducted a single-center, prospective, double-blind randomized controlled trial in India to determine if the addition of tofacitinib, a JAK1 and JAK3 inhibitor, to corticosteroids was superior to corticosteroids alone in hospitalized patients with ASUC.1
The study randomized patients with ASUC to tofacitinib 10 mg 3 times daily (n = 53) versus placebo (n = 51) plus hydrocortisone 100 mg every 6 hours. An intention-to-treat analysis after 7 days of clinical assessment revealed patients in the tofacitinib group had higher responses to therapy, defined by a decline in Lichtiger index >3 points and an absolute score <10 for 2 days (difference, 24.2%; odds ratio [OR], 3.42; 95% CI 1.37 - 8.48; P = .007), and lower need for rescue therapy (difference, -20.1%; OR, 0.27; 95% CI 0.09 - 0.78; P = .01) compared to placebo.
Following the 7 days, patients and investigators were unblinded. The probability of infliximab or total colectomy up to 90 days was found to be significantly lower in the tofacitinib responders who were continued on tofacitinib and a prednisone taper compared to non-responders who were continued on 5-ASA or azathioprine and a prednisone taper (P = .003).
Despite these positive outcomes, adverse effects were relatively high amongst the tofacitinib (24.5%) and placebo (13.7%) groups. In the tofacitinib group, most of these adverse events were not major (hair loss, acne, upper respiratory tract infections, etc.). However, 1 death and 4 deaths were noted in the tofacitinib and placebo groups, respectively. Deaths were attributed to mostly severe disease phenotype, but also systemic toxicity (n=2) and hemorrhagic venous infarct (n = 1). One venous thromboembolism event, a dural venous thrombus, occurred in a patient in the tofacitinib group.
This novel study suggests that tofacitinib plus corticosteroids may be a first-line therapy that supplements the limited options available for patients with ASUC. Limitations include external validity, objective measures of disease activity, and the non-conventional duration of 7 days of corticosteroids that may hinder clinical applicability in the US.
Future studies to personalize this approach, limit generalizability, optimize dosage and duration of up-front therapy, and further delineate adverse event rates are required to further support the use of JAK inhibition for ASUC.
Reference
Related Content: