Three Janus kinase inhibitors in ulcerative colitis: is upadacitinib taking the lead?
Article information
The treatment paradigm for moderate to severe ulcerative colitis (UC) has evolved rapidly over the past two decades, transitioning from anti-tumor necrosis factor (TNF)-focused therapy to a broader range of targeted therapies, including novel biologics such as anti-integrin α4β7 and anti-interleukin-12/23 monoclonal antibodies and small molecules such as Janus kinase (JAK) inhibitors [1-5]. Yet, in clinical practice, optimal positioning of these therapies remains elusive, particularly in patients with prior anti-TNF exposure [6-8].
In this issue of Intestinal Research, Ikenouchi et al. [9] present timely and clinically relevant results that compare the real-world effectiveness of 3 JAK inhibitors—tofacitinib (TFB), filgotinib (FIL), and upadacitinib (UPA)—in patients with UC, stratified by prior anti-TNF exposure. Although this study is retrospective in nature and includes a relatively small number of patients, the use of propensity score (PS) matching to minimize differences in patient background—such as disease activity, serum C-reactive protein (CRP), disease duration, and baseline corticosteroid use, which may affect outcomes—enhances the reliability of the results.
A key finding of the study is that UPA demonstrated a superior steroid-free clinical remission rate compared to TFB and FIL in patients with previous anti-TNF exposure. These results suggest that UPA may be a potentially preferred second-line treatment option among JAK inhibitors in this population. Notably, this superiority did not extend to anti-TNF naive patients, underscoring the need to tailor therapy selection based on treatment history. The FIL group showed significantly lower partial Mayo scores and CRP levels compared to the other 2 groups, indicating a lower disease activity. This appears to reflect a clinical trend in which FIL is preferentially prescribed to patients with milder disease activity. Although the authors did not present partial Mayo scores and CRP levels stratified by prior anti-TNF exposure, it is plausible that patients without prior anti-TNF exposure had lower disease activity than those previously exposed. Therefore, comparisons between the FIL group and the other 2 groups after PS matching among patients without prior anti-TNF exposure likely reflect comparisons between patients with relatively milder activity. This study suggests that the efficacy of FIL is not inferior to the other 2 JAK inhibitors in patients with relatively milder UC. When selecting a JAK inhibitor as a first-line therapy, UPA or TFB may be preferentially considered for patients with severe UC, while FIL may be more appropriate for those with moderate UC.
Beyond efficacy, safety issues should be given significant weight in drug selection. UPA had a slightly higher incidence of adverse effects (particularly infections) compared to other 2 JAK inhibitors. Among the 3 JAK inhibitors, FIL is the most selective JAK1 inhibitor and is therefore considered to have the most favorable safety profile [10]. UPA is theoretically expected to have fewer adverse events compared to TFB owing to its more selective JAK1 inhibition [10]. However, this study shows that UPA is not completely free from the adverse events associated with JAK inhibitors. TFB has been reported to be associated with an increased risk of venous thromboembolism (VTE) and major adverse cardiovascular events (MACE) [1]. In this study, no patient developed VTE or MACE with either TFB or UPA, but the follow-up period of 8 weeks was too short to evaluate these adverse events. It is also noteworthy that pericarditis occurred in 1 of the 47 patients taking UPA.
As JAK inhibitors gain ground in the UC treatment algorithm, real-world data provided by Ikenouchi et al. [9] are valuable in complementing randomized clinical trial results and supporting personalized treatment strategies. In particular, in Asian populations where data on FIL and UPA remain limited, this study may help guide drug selection for patients with UC who have failed anti-TNF therapy. This study suggests that among the 3 JAK inhibitors, UPA may be the preferred option as a second-line treatment for patients with UC after failure of anti-TNF therapy. However, clinicians should remain vigilant in monitoring for adverse events and further long-term comparative studies are needed to determine the durability, safety, and cost-effectiveness of JAK inhibitors across diverse patient populations.
Notes
Funding Source
The author received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
Jung YS is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Data Availability Statement
Not applicable.
Author Contributions
Writing and approval of the final manuscript: Jung YS.