Tofacitinib in Acute Severe Ulcerative Colitis (TACOS): A Randomized Controlled Trial
Ellen Axenfeld, MD1 and Elie S. Al Kazzi, MD, MPH2
1Clinical Instructor, Division of Gastroenterology & Hepatology, New York University Langone Health, New York, NY
2Assistant Professor of Medicine, New York University Grossman School of Medicine, New York, NY
This summary reviews Singh A, Goyal MK, Midha V, et al. Tofacitinib in acute severe ulcerative colitis (TACOS): A randomized controlled trial. Am J Gastroenterol 2024; 119 (7), 1365-1372.
Access the article in The American Journal of Gastroenterology.
Correspondence to Elie S. Al Kazzi, MD, MPH, Associate Editor Email: EBGI@gi.org
Keywords: Ulcerative colitis, infliximab, steroids, salvage therapy
STRUCTURED ABSTRACT
Question: Among adult patients with acute severe ulcerative colitis (UC), is the addition of tofacitinib to steroids more effective than steroids alone for treatment responsiveness?
Design: Prospective, double-blind (converted to open-label on day 7), placebo-controlled randomized trial (RCT) followed for 90 days.
Setting: This study was conducted at a single tertiary care center in India.
Patients: Patient included in the study were adult (18-years old and over) patients admitted to the hospital with acute severe ulcerative colitis (ASUC), defined by the Truelove and Witts severity criteria. Excluded patients were those who had received intravenous corticosteroids or tofacitinib within 4 weeks before hospitalization, those with active infection e.g. Clostridioides difficile or cytomegalovirus, those with toxic megacolon, or those that were pregnant.
Interventions: Participants received hydrocortisone 100 mg every 6 hours plus tofactinib 10 mg 3 times daily for 7 days vs hydrocortisone plus placebo.
Outcomes: The primary outcome was the proportion of patients who responded to treatment, defined as a decline in the Lichtiger index by >3 points and an absolute score <10 for 2 consecutive days without the need for rescue therapy) by day 7. Secondary outcome included cumulative probability of patients requiring initiation of infliximab or undergoing colectomy after discharge within 90 days of randomization.
Data Analysis: Analyses were performed based on an intention-to-treat analysis. Descriptive analysis was done on patients’ characteristics and outcomes. The Kaplan-Meier survival analysis was used to evaluate the cumulative probability of need for rescue therapy.
Funding: Funding was provided by the Research and Development Center of Dayanand Medical College and Hospital in Ludhiana, India. The funding source did not have a role in data collection, data analysis, data interpretation, or writing of the report.
Results: Among 150 patients hospitalized for ASUC during the study period, 104 participants were randomized (median age 37.5, 59% male, median disease duration of 2 years) to receive either tofacitinib (n=53) or placebo (n=51) in addition to standard of care steroid.
The primary outcome was met in 44 of 53 (83.01%) patients receiving tofacitinib vs 30 of 51 (58.82%) patients receiving placebo (odds ratio [OR] 3.42, 95% confidence interval [CI] 1.37–8.48, P = 0.007).
Rescue therapy by day 7 was required in 6 of 53 (11.32%) patients in the tofacitinib arm vs 16 of 51 (31.37%) patients receiving placebo (OR 0.27, 95% CI 0.09–0.78, P = 0.01). One patient in the tofacitinib arm and 3 patients in the placebo arm required colectomy between days 7 and 90 (after failure of infliximab rescue therapy). One patient in the tofacitinib arm developed hemorrhagic venous infarct in the left temporal lobe and dural venous sinus thrombosis.
Figure 1. Efficacy outcomes at day 7. Rate of response to treatment by day 7 (primary outcome) and the percentage of patients requiring rescue treatment by day 7. CI, confidence interval; OR, odds ratio.
COMMENTARY
Why Is This Important?
Despite recent advancements in the treatment of UC, ASUC remains a severe complication affecting up to 25% of patients with UC.1 Intravenous steroids continue to be the standard of care for initial treatment of ASUC, however up to 30%-40% of patients require a second line of therapy, or “rescue therapy”.2 Randomized controlled trials (RCTs) of infliximab and cyclosporine have shown equivalent efficacy as medical rescue therapies in ASUC, while non-randomized studies have suggested that infliximab has a better treatment response and reduced risk of colectomy.3 Although the rates of urgent colectomy have decreased in the era of infliximab and cyclosporine, this remains a prominent issue affecting up to 30% of patients with ASUC.4
This data underscores the need for advancements to improve responsiveness to medical therapy in ASUC. Prior to the TACOS trial, retrospective studies were published suggesting the effectiveness of Janus-kinase inhibitors (JAKi) for the treatment of ASUC. Berinstein et al, found that concomitant tofacitinib and intravenous corticosteroids may be an effective induction strategy in biologic-experienced patients hospitalized with ASUC.5 To date, this is the first prospective, placebo-controlled RCT to evaluate the effectivity of a JAKi in the treatment of ASUC.
Key Study Findings
The need for rescue therapy by day 7 was seen in 6 of 53 (11.32%) patients in the tofacitinib arm when compared with 16 of 51 (31.37%) patients receiving placebo (OR 0.27, 95% CI 0.09–0.78, P = 0.01). Five patients in the tofacitinib arm and 11 patients in the placebo arm received infliximab as rescue therapy, while 1 patient in the tofacitinib arm and 5 patients in the placebo arm underwent colectomy. In the open-label phase of the study (after unblinding at day 7 and until day 90), 1 patient in the tofacitinib arm and 3 in the placebo arm required initiation of infliximab. Furthermore, 1 patient in the tofacitinib arm and 3 patients in the placebo arm, who did not respond to the initial medical rescue therapy with infliximab, required colectomy between days 7 and 9. None of the patients received cyclosporine as rescue therapy.
The rates of both medical (infliximab) and surgical rescue therapy (colectomy) were lower in the patients receiving tofacitinib at days 7, 30, and 90. The cumulative probability of need for rescue therapy at day 90 was 0.13 in patients who received tofacitinib vs 0.38 in patients receiving placebo (log-rank P = 0.003).
The median CRP at day 7 was 5.17 (2.97–11.54) mg/L in the tofacitinib arm vs 6.18 (2.15–12.80) mg/L in the placebo arm. The total duration of hospital stay was shorter in the tofacitinib arm (9.69 ± 2.84 days) compared with that in the placebo arm (11.01 ± 5.99 days) though statistical significance could not be demonstrated (P = 0.15).
On subgroup analysis, in the tofacitinib arm, of the 26 patients who were on oral corticosteroids at the time of hospitalization, 5 (19.23%) patients required rescue therapy. On the contrary, 13 (56.52%) of the 23 patients in the placebo arm, who were on oral corticosteroids at the time of hospitalization, required rescue therapy. Similarly, in patients with previous exposure to thiopurines, the use of rescue therapy was lower in the tofacitinib arm (1/8, 12.5%) compared with that in the placebo arm (6/6, 100%).
Caution
This study is inherently limited by being a single-study center in India with a population that may not represent and therefore may not be generalizable to the UC patient demographics in the United States. The study period of 90 days may also be too short to evaluate important outcomes such as rates of colectomy. This study also used tofacitinib as a first line therapy prior to the use of an anti-tumor necrosis factor which is prohibited in the US due to FDA regulations. Outside of legal regulations, the lack of availability of generic formulation as was used in this study make this treatment strategy cost prohibitive in many hospitals worldwide. Finally, recent studies of comparative effectiveness including network meta-analyses have concluded that upadacitinib is more effective than tofacitinib in the treatment of UC.6, 7
My Practice
Our institution’s practice strategy for ASUC begins with a similar approach. Patients are identified as presenting with ASUC and initiated on intravenous steroids (methylprednisolone 60 mg/day) with simultaneous stool infection testing. If patients are not responding adequately after approximately 48–72 hours of intravenous steroids based on clinical assessment or biochemical markers such as CRP, rescue therapy is pursued. Cyclosporine has largely fallen out of favor. In infliximab-naïve patients, infliximab 10 mg/kg is our standard of care for rescue therapy. If there is an inadequate response to infliximab, we would consider the use of upadacitinib as second-line rescue therapy.
For Future Research
The TACOS trial represents a proof-of-concept study showing the effectiveness of JAKi in the treatment of ASUC. Unknowns that remain are (1) the effectiveness of upadacitinib vs placebo as rescue therapy in ASUC and (2) the positioning strategy of JAKi vs anti-TNF as first-line rescue therapy, which would most ideally be evaluated in a head-to-head RCT.
Conflict of Interest
Dr. Ellen Axenfeld and Dr. Elie Al kazzi report no potential conflicts of interest related to this study.
Abbreviations
ASUC, acute severe ulcerative colitis; CI, confidence interval; FDA, Food and Drug Administration; OR, odds ratio; RCT, randomized controlled trial; TNF, tumor necrosis factor; UC, ulcerative colitis; US, United States
REFERENCES
- Dinesen LC, Walsh AJ, Protic MN et al. The pattern and outcome of acute severe colitis. J Crohns Colitis. 2010 Oct;4(4):431-7.
- Turner D, Walsh CM, Steinhart AH, Griffiths AM. Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression. Clin Gastroenterol Hepatol. 2007 Jan;5(1):103-10.
- Narula N, Marshall JK, Colombel JF, et al. Systematic review and meta-analysis: infliximab or cyclosporine as rescue therapy in patients with severe ulcerative colitis refractory to steroids. Am J Gastroenterol. 2016 Apr;111(4):477-91.
- Holvoet T, Lobaton T, Hindryckx P. optimal management of acute severe ulcerative colitis (ASUC): Challenges and solutions. Clin Exp Gastroenterol. 2021 Mar 8;14:71-81.
- Berinstein JA, Sheehan JL, Dias M, et al. Tofacitinib for biologic-experienced hospitalized patients with acute severe ulcerative colitis: A retrospective case-control study. Clin Gastroenterol Hepatol. 2021 Oct;19(10):2112-2120.e1.
- Kochhar GS, Khataniar H, Jairath V, Farraye FA, Desai A. Comparative effectiveness of upadacitinib and tofacitinib in ulcerative colitis: A US propensity-matched cohort study. Am J Gastroenterol. 2024 Dec 1;119(12):2471-2479.
- Boneschansker L, Ananthakrishnan AN; Massachusetts General Hospital Crohn’s and Colitis Center Collaborators. Comparative effectiveness of upadacitinib and tofacitinib in inducing remission in ulcerative colitis: Real-world data. Clin Gastroenterol Hepatol. 2023 Aug;21(9):2427-2429.e1.