Letter: Toward Intra-Class Switching With JAK Inhibitors?

Abstract

Akiyama et al. reported the real-world effectiveness of three JAK inhibitors in a Japanese multicentre cohort of 602 patients with ulcerative colitis (UC); 228, 215 and 159 patients, respectively, were treated with upadacitinib, filgotinib and tofacitinib [1]. Among these patients, 106 (46%) in the upadacitinib group, 30 (14%) in the filgotinib group and none in the tofacitinib group had prior exposure to another JAK inhibitor.

Using propensity score matching, they analysed 92 upadacitinib-treated patients previously exposed to other JAK inhibitors, including tofacitinib (n = 31), filgotinib (n = 54) or both (n = 7). Clinical remission was achieved by 57.3% (43/75) of these patients at 10 weeks and 82.9% (34/41) at 58 weeks. For filgotinib, 21 patients were treated after prior JAK inhibitor exposure: tofacitinib (n = 19), upadacitinib (n = 1) or both (n = 1). Clinical remission rates were 28.6% (4/14) at 10 weeks and 62.5% (5/8) at 58 weeks [1].

Other smaller observational studies have reported outcomes of JAK inhibitor use in patients previously exposed to another JAK inhibitor, almost exclusively focusing on upadacitinib in patients refractory to tofacitinib. For example, Levin et al. demonstrated that 36% of 16 tofacitinib-refractory patients achieved both clinical and steroid-free remission with upadacitinib [2]. Similarly, Gilmore et al. provided real-world evidence on upadacitinib in a multicentre Australian study. Of 152 patients, 42 were tofacitinib-experienced. Clinical remission rates were 24% (10/42) at baseline and 72% (30/42) at Week 8 for tofacitinib-experienced patients, compared to 19% (21/110) at baseline and 78% (86/110) at Week 8 for tofacitinib-naïve patients (p = 0.17) [3]. There are no controlled data on the effectiveness of switching from one JAK inhibitor to another.

While indirect and direct comparisons suggest that upadacitinib may be the best-in-class in terms of effectiveness [4, 5], this has yet to be specifically demonstrated in JAK inhibitor-refractory patients.

As the number of patients refractory to multiple treatment lines, including different mechanisms of action, continues to rise—along with the proportion of patients exposed to at least one JAK inhibitor—it is crucial to generate data to refine treatment strategies. Switching within the same class of drugs is an established practice with anti-TNF agents [6, 7]. However, this is relatively new for JAK inhibitors including three FDA- and EMA-approved drugs with distinct JAK selectivity profiles [8].

Notably, it is unknown whether tofacitinib may be beneficial after the use of a JAK1 inhibitor, or what is the best cycling strategy among JAK inhibitors.

Consequently, further studies are needed to evaluate intra-class switching between JAK inhibitors on a larger scale and to guide clinical management. GETAID has coordinated a French and Belgian initiative to collect data on all patients treated with one JAK inhibitor following prior exposure to another. Additionally, the European Crohn's and Colitis Organisation has launched a global initiative to report the effectiveness and safety of these patients. Results are anticipated in 2025.