Effectiveness and safety of a second JAK inhibitor in ulcerative colitis: The J2J multicentre study

Use of a second Janus kinase inhibitor in multi-refractory patients with ulcerative colitis

Janus kinase (Jak) inhibitors are small molecules that inhibit pro-inflammatory signaling pathways and the production of multiple cytokines by blocking the Jak-STAT signaling pathway intracellularly. Tofacitinib, an unselective Jak inhibitor, as well as filgotinib and upadacitinib, both selective Jak1 inhibitors, are approved for the treatment of ulcerative colitis. The various Jak inhibitors differ in their potency and selectivity. Advantages include oral administration, rapid onset of action, and good efficacy, including effectiveness in managing extraintestinal manifestations. Reported adverse events include an increased risk of infection, cardiovascular events, and a potentially elevated risk of cancer.
Despite the growing number of therapeutic options, many patients fail to respond to treatment. In patients who are refractory to multiple therapeutic agents, one possible strategy is to reintroduce a previously used mechanism of action. In particular, anti-TNF antibodies are often re-administered, sometimes very successfully. However, it remains unclear to what extent retreatment with Jak inhibitors is effective and safe.
This multicenter, retrospective observational study included patients who had previously been treated with one of the three approved Jak inhibitors and had active ulcerative colitis (partial Mayo score ≥ 3). The primary endpoint was steroid-free clinical remission after induction (weeks 8–14, defined as partial Mayo score ≤ 2, no subscore > 1). Data from 169 patients with a median follow-up period of 96 days were analyzed. 38% were female, and the mean age at inclusion was 34.6 years. The mean disease duration was 7.4 years. A total of 93.5% of patients had been pretreated with at least two biologics (in addition to a Jak inhibitor). 67.5% had received tofacitinib, 27.2% filgotinib, and 5.3% upadacitinib as their first Jak inhibitor. Discontinuation of first-line Jak inhibitor therapy occurred in 57% of cases due to secondary loss of response and in 39% due to primary nonresponse. The mean treatment duration with the first Jak inhibitor was 162 days. Approximately 62% received upadacitinib, 32% filgotinib, and 6% tofacitinib in the second line.
Steroid-free clinical remission at weeks 8–14 was achieved in 47.9% of patients (55.2% with upadacitinib, 33.3% with filgotinib, and 50% with tofacitinib). The overall clinical response rate was 69.8%, with 61.5% achieving a steroid-free clinical response. During follow-up, 30.8% of patients discontinued Jak inhibitor therapy due to primary or secondary loss of response. Treatment persistence after six months was 72.8% for upadacitinib, 57.2% for filgotinib, and 66.7% for tofacitinib. Although no head-to-head trials are available, other small observational studies and real-world data analyses have also shown the highest effectiveness for upadacitinib compared with filgotinib or tofacitinib. Interestingly, the effectiveness of upadacitinib appeared to be independent of prior Jak inhibitor exposure.
Baseline steroid use and the presence of an ileorectal anastomosis were associated with poorer outcomes. Adverse events occurred in 24.3% of patients, most commonly infections and skin lesions/acne. Serious adverse events occurred in 5% of patients. No deaths, cancer, or cardiovascular events were observed. However, the cohort mainly included young patients and only a small proportion of active smokers, limiting conclusions regarding higher-risk populations. Two cases of ophthalmic herpes zoster were reported, both occurring in unvaccinated patients.
In summary, this study demonstrates that the use of a second Jak inhibitor in the second line appears to be both effective and safe, at least in individuals without pre-existing risk factors. These results are directly translatable to clinical practice: in particular, treatment with upadacitinib in patients who have previously received multiple advanced therapies, including Jak inhibitors, is promising. However, larger cohorts are needed to further evaluate the efficacy and safety of different Jak inhibitor sequencing strategies, especially outcomes after upadacitinib used as first-line therapy would be of interest. To assess the durability of response/remission and long-term safety, a substantially longer follow-up period and a prospective study design would be desirable.