A significant portion of patients with ulcerative colitis (UC) experience a flareup after dropping their tofacitinib (Xeljanz) dose from 10 mg twice a day to 5 mg twice a day, and only about two thirds are able to recapture clinical response to the JAK inhibitor, a real-world analysis suggests.
Patients most likely to experience UC complications after dropping the dose are those with an induction course lasting fewer than 16 weeks and active endoscopic disease at 6 months after induction, the data show.
Based on the results, it’s “reasonable to perform an objective assessment prior to dose reduction and consider dose reduction only in those who have achieved endoscopic remission,” senior investigator Kendall Beck, MD, with the Division of Gastroenterology and Hepatology, University of California San Francisco, told Medscape Medical News.
This “informative” study suggests that “one needs to be cautious in considering dose de-escalation, particularly if there are limited safety benefits to the lower dose weighed against the risk of disease relapse,” Ashwin Ananthakrishnan, MBBS, MPH, with Massachusetts General Hospital and Harvard Medical School in Boston, who was not involved in the study, told Medscape Medical News.
The study was published online May 13 in Clinical Gastroenterology and Hepatology.
Treatment with tofacitinib is effective and associated with sustained steroid-free remission in patients with UC, with the lowest effective dose recommended for maintenance therapy. However, there are limited real-world data to guide decisions on the optimal maintenance regimen.
Beck and colleagues assessed predictors and outcomes of disease activity after tofacitinib dose de-escalation in a retrospective, real-world study of adults with moderate to severe UC treated at a single academic medical center between June 2012 and January 2022.
Among 162 patients (median age, 35 years; 54% male), 52% continued taking tofacitinib 10 mg twice a day and 48% underwent dose de-escalation to 5 mg twice a day.
Overall, within 12 months of initiating tofacitinib, 92 patients (57%) experienced a UC disease activity-related event, defined as UC-related hospitalization, surgery, new initiation of corticosteroids, change to another UC therapy, or re-escalation to tofacitinib 10 mg twice daily.
Among those who underwent dose de-escalation, over half (56%) experienced a UC event within 12 months. The cumulative 12-month event rate was 58% in those who did not de-escalate therapy.
Patients who continued 10 mg twice a day had higher proportions of UC-related hospitalization (27% vs 14%, P = .04) and therapy switch (39% vs 13%, P < .01), compared with those who de-escalated.
Twenty-seven patients (17%) who de-escalated therapy required re-escalation to 10 mg twice a day, and 17 of the 27 (63%) recaptured a clinical response at the higher dose.
Among the five patients with dose re-escalation who had available endoscopic evaluation at 12 months, all achieved endoscopic response with Mayo 0 or 1 disease.
Among the 10 patients (37%) who were not able to recapture clinical response after dose re-escalation, four (40%) required UC-related surgery, six (60%) required change in therapy, and five (50%) required hospitalization.
Induction Length Matters
As for predictors of UC events after dose de-escalation, a prolonged induction course (more than 16 weeks) with 10 mg twice a day was protective (hazard ratio [HR], 0.37).
Currently, tofacitinib induction with 10 mg twice a day beyond 16 weeks is not recommended, Beck and colleagues note. However, patients with induction period >16 weeks were 63% less apt to experience a UC event following dose de-escalation, “suggesting that there may be a subgroup of patients who may benefit from a longer induction course,” they write.
“Nonetheless, the decision for prolonged induction dosing is an individualized decision between the patient and provider, taking into consideration the patient’s clinical status, endoscopic activity, and risk of dose-dependent adverse advents, particularly [venous thromboembolism],” the authors emphasize.
The study also found that ongoing severe disease (Mayo 3) was associated with UC events (HR, 6.41), which remained significant after adjusting for age, sex, duration of induction course, and corticosteroid use at dose de-escalation (HR, 6.05).
“It is not surprising that those who had ongoing severe Mayo 3 disease would have worsening disease with dose de-escalation,” Jami Kinnucan, MD, a gastroenterologist at Mayo Clinic, Jacksonville, Florida, who wasn’t involved in the study, told Medscape Medical News.
“What this points to is how important clinical and objective remission are prior to dose de-escalation of therapy,” Kinnucan said.
Beck and colleagues note that, while “dose de-escalation is preferable for long-term maintenance therapy to reduce potential lifetime risk of medication-related adverse events, it must be balanced with sustained remission to prevent short- and long-term disease-related complications.”
Dose de-escalation “needs to be done on a personalized basis for each patient, rather than automatic with a low threshold to consider re-escalating back to the 10 mg twice a day dose (rather than abandon treatment) should someone relapse, as this study suggests that over half can be re-captured with the dose escalation,” Ananthakrishnan said.
Further studies are needed to examine the mechanism of disease loss of response with de-escalation and to determine if it is similar with other JAK inhibitors, such as upadacitinib (Rinvoq), which differ in their induction and maintenance dose, he added.
The study had no specific funding. The study authors, Ananthakrishnan, and Kinnucan report no relevant financial relationships.
Clin Gastro Hepatol. Published online May 13, 2023. Abstract
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