Tofacitinib safe, effective in UC, but response fades after dose reduction

Treatment with tofacitinib is both safe and effective in a real-world setting, as shown in a Canadian study, in which a third of patients with ulcerative colitis (UC) achieved clinical remission with few serious adverse events. However, nearly half of them have lost response following dose de-escalation, and this is only partially recaptured with re-escalation.

“Those with negative prognostic factors should be counselled about the risks and benefits of continuing high doses of tofacitinib,” the researchers said.

In this multicentre cohort study, data from 334 consecutive adult outpatients with UC treated with tofacitinib were obtained. Predictors of loss of response after tofacitinib dose de-escalation to 5 mg twice daily (BID) were assessed using a multivariable Cox proportional hazards model.

Achievement of clinical and endoscopic remission was the primary outcome. Incidence rates (events per 100 patient-years of exposure) were used to report safety outcomes.

Of the patients, 35.3 percent (106/300) achieved clinical remission at week 12, 36.0 percent (104/289) at week 24, and 35.2 percent (93/264) at week 52. Furthermore, 18.5 percent (15/81), 23.0 percent (28/122), and 25.7 percent (35/136) achieved endoscopic remission at weeks 12, 24, and 52, respectively. [Am J Gastroenterol 2023;118:861-871]

Incidence rates of serious infections, herpes zoster, and venous thromboembolism were 2.1, 0.5, and 1.1 events per 100 patient-years, respectively.

Response loss

Notably, almost half of the UC patients (44.5 percent, 109/245) lost response when the dose was reduced to 5 mg BID, and only 54.9 percent (39/71) were recaptured after re-escalating to 10 mg BID.

In other investigations, 25 percent of patients de-escalating in the OCTAVE Open long-term extension study lost remission, while 77.1 percent of those randomized to 5 mg BID in the RIVETING de-escalation trial remained in remission at 6 months. [J Crohns Colitis 2021;15:1130-1141; Aliment Pharmacol Ther 2020;51:271-280]

“The Canadian product monograph recommends 8 weeks of induction treatment at 10 mg BID, followed by de-escalation to maintenance dosing at 5 mg BID,” the researchers said. “Stepping down to the lowest effective dose during maintenance is recommended, but the appropriate dose depends on the initial treatment response.”

Factors associated with response loss after dose reduction in the current study were a baseline Mayo endoscopic score of 3 (adjusted hazard ratio [aHR], 3.60, 95 percent confidence interval [CI], 1.70‒7.62) and prior biologic failure (aHR, 3.89, 95 percent CI, 1.28‒11.86).

“Higher loss of response rates in our cohort likely reflects shorter time to dose reduction (median time to de-escalation only 8 weeks in our cohort) and the relative depth of remission before de-escalation,” the researchers said.

Of note, the achievement of endoscopic improvement alone failed to prevent loss of response after de-escalation. In addition, substantial risk for hospitalization and colectomy was observed, especially in patients treated with tofacitinib after multiple biologic failures.

“Taken together, these findings will help inform decisions about starting and optimizing Janus kinase inhibitor therapy in patients with UC,” the researchers said.