Real-world clinical efficacy of tofacitinib in moderate-to-severe ulcerative colitis

Abstract

Tofacitinib is an oral small-molecule Janus kinase (JAK) inhibitor that preferentially inhibits JAK1 and JAK3. Its efficacy in inducing and maintaining remission in ulcerative colitis (UC) as well as its safety profile has been demonstrated in multicenter, randomized, double-blind, placebo-controlled trials. Additionally, real-world studies evaluating the effectiveness and adverse effects of tofacitinib have been conducted, affirming its clinical efficacy in moderate-to-severe UC.

Key Words: Ulcerative colitis; Tofacitinib; Real-world studies; Inflammatory bowel disease; Janus kinase inhibitor

Core Tip: Tofacitinib, an oral small-molecule agent, has proven efficacy in inducing and maintaining remission among patients with moderate-to-severe ulcerative colitis. Real-world studies have showcased its effectiveness and safety profile to treat ulcerative colitis, primarily within Western countries. There have been a limited number of studies conducted on Asian patients.

TO THE EDITOR

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by recurrent, relapsing inflammation of the gastrointestinal tract, with a negative effect on quality of life. Symptoms associated with UC include urgency, increased frequency of bowel movements, bloody diarrhea, and abdominal pain[1].

Tofacitinib is an oral, small-molecule Janus kinase (JAK) inhibitor that inhibits all JAKs, but preferentially inhibits JAK1 and JAK3. Efficacy to induce and maintain remission in UC and the safety profile have been proven in multicenter, randomized, double-blind, placebo-controlled trials: OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain[2,3]. Tofacitinib was approved for the treatment of refractory moderate-to-severe UC in 2018. A few real-world studies assessing effectiveness and adverse effects of tofacitinib have been conducted, mainly in Western countries[4-6].

DISCUSSION

With this in mind, we would like to extend our congratulations to Kojima et al[7] for their article recently published in the World Journal of Gastroenterology. Their results demonstrate the efficacy and safety of tofacitinib for UC in a cohort of Asian patients. In a retrospective unicentric study involving 111 patients with UC, the authors demonstrated that tofacitinib effectively induced and maintained clinical remission. By week 8, 66.3% of UC patients responded to tofacitinib treatment. Although response rates decreased over time, nearly half (47.1%) of the patients still responded in the subsequent weeks. The overall cumulative clinical remission rate at week 48 was 61.7%, and this efficacy was not affected by prior treatment with anti-tumor necrosis factor (TNF)-α agents (P = 0.25). Notably, most patients received prior treatments, with 20.7% (n = 23) using corticosteroids at baseline. These results are consistent with the existing literature. A meta-analysis of 17 studies, including 1162 patients, reported clinical response and remission rates of 62.1% and 34.7% at week 8, respectively[8]. Regarding safety, the authors reported that 34.2% of patients experienced at least one adverse event, leading to treatment discontinuation in 6.3% of cases. The incidence rate of herpes zoster was 7.5 per 100 patient-years, and only one patient developed a thromboembolic complication. The safety profile observed in this study aligns with findings from other real-world studies. The same meta-analysis reported an overall adverse event rate of 26% and an incidence rate of herpes zoster at 6.9 per 100 patient-years[8].

However, the retrospective and unicentric design of the study introduces inherent limitations, including selection bias, potential data inaccuracies, and challenges in controlling confounding variables, along with a limited sample size. Furthermore, there are some unanswered questions that warrant a comment.

Firstly, there is limited data regarding endoscopic healing. Among the 39 patients who underwent endoscopy, the authors reported complete endoscopic remission in 7.7% of patients and an endoscopic remission rate of 23.1% at week 16. Achieving endoscopic remission is a long-term treatment target in UC[9]. While it was not the primary or secondary outcome of this study, it would have been valuable to observe the endoscopic response in more patients and over the extended follow-up period.

Moreover, information about other targets is missing, specifically fecal calprotectin, a recognized intermediate target in UC[9]. As a marker of active disease, it would have been valuable to include this biomarker and observe its trajectory during the follow-up period.

Regarding tapering off treatment after achieving clinical remission, Kojima et al[7] found that 45.7% of patients experienced relapse upon tapering off tofacitinib, with most patients (69%) attaining clinical remission at week 12 after re-increasing the dosage. The median duration from the start of tapering to re-escalation of the dosage was 95 days. Analyzing potential disparities in baseline characteristics between patients who experienced relapse and those who did not, particularly in terms of baseline endoscopic findings or prior exposure to TNF-α agents, could offer further insights to aid in identifying individuals at greater risk of relapse.

With respect to safety, while the authors did observe an adverse event rate comparable to that reported in pivotal trials and other real-world studies, the incidence of serious adverse events should be clarified. Serious adverse events encompass not only those necessitating treatment discontinuation, but also those leading to hospitalization, as per standard definitions. Furthermore, concerning the most common adverse event, dyslipidemia, which occurred in 17% of patients, the authors should provide data concerning the fluctuations in serum lipid levels throughout the entire follow-up period, to determine whether these changes are transient or cumulative.

CONCLUSION

Kojima et al[7] made a significant contribution by addressing the effectiveness and safety profile of tofacitinib in Asian patients with moderate-to-severe UC. Nonetheless, we agree that prospective longer-term studies, some of which are currently ongoing, are needed to assess predictive factors associated with relapse following the tapering of tofacitinib, and to enhance the management of patients with active UC and concomitant cardiovascular risk factors who are treated with tofacitinib.