Effectiveness of upadacitinib in ulcerative colitis patients with prior tofacitinib exposure: a systematic review and meta-analysis

Fariha Hasana, Ayesha Liaquatb, Ahmed Razac, Zain Ali Nadeemd, Fatima Farooqib, Hassam Alie, Dushyant Singh Dahiyaf, Zeina Issag, Bhanu Siva Mohan Pinnamf, Saqr Alsakarnehh, Islam Mohamadi, Gursimran S. Koccharj

Cooper University Health Care, Camden, NJ, USA; Dow Medical College, Karachi, Pakistan; Services Institute of Medical Sciences, Pakistan; dAllama Iqbal Medical College, Lahore, Pakistan; ECU Health, Greenville, NC, USA; University of Kansas School of Medicine, Kansas City, KS, USA; Cooper Medical School of Rowan University, Camden, NJ, USA; Mayo Clinic, Rochester, MN, USA; University of Missouri, Columbia, MO, USA; Allegheny Health Network, Pittsburgh, PA, USA

aCooper University Health Care, Camden, NJ, USA (Fariha Hasan); bDow Medical College, Karachi, Pakistan (Ayesha Liaquat, Fatima Farooqi); cServices Institute of Medical Sciences, Pakistan (Ahmed Raza); dAllama Iqbal Medical College, Lahore, Pakistan (Zain Ali Nadeem); eECU Health, Greenville, NC, USA (Hassam Ali); fUniversity of Kansas School of Medicine, Kansas City, KS, USA (Dushyant Singh Dahiya, Bhanu Siva Mohan Pinnam); gCooper Medical School of Rowan University, Camden, NJ, USA (Zeina Issa); hDepartment of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA (Saqr Alsakarneh); iDepartment of Gastroenterology and Hepatology, University of Missouri, Columbia, MO, USA (Islam Mohamad); jDepartment of Gastroenterology and Hepatology, Allegheny Health Network, Pittsburgh, PA, USA (Gursimran S. Kocchar)

Correspondence to: Zeina Issa, Cooper Medical School of Rowan University, Camden, New Jersey, USA, e-mail: issaz2@rowan.edu
Received 28 April 2025; accepted 5 July 2025; published online 14 August 2025
DOI: https://doi.org/10.20524/aog.2025.0991
© 2025 Hellenic Society of Gastroenterology

Abstract

Background Upadacitinib, a selective Janus kinase (JAK) inhibitor, is a recently approved therapy for moderate-to-severe ulcerative colitis (UC). Limited data are available on its efficacy in patients previously exposed to tofacitinib, a non-selective JAK inhibitor. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy of upadacitinib in UC patients with prior tofacitinib treatment.

Methods PubMed, Embase, Web of Science, and Cochrane Library were queried for studies evaluating the effectiveness of upadacitinib in UC patients with prior tofacitinib treatment. Primary outcomes included clinical remission, steroid-free clinical remission (SFCR), and clinical response. Secondary outcomes were the mean decrease in fecal calprotectin, and adverse events. Statistical analyses were performed using R, calculating pooled proportions with 95% confidence intervals (CI) for dichotomous outcomes and mean differences with 95%CI for continuous outcomes using a random-effects model.

Results Five studies, with 127 patients, were included in the final analysis. Upadacitinib increased pooled clinical remission rates by 57% (95%CI 0.32-0.80), SFCR rates by 52% (95%CI 0.26-0.78), and clinical response rates by 75% (95%CI 0.44-0.96). Upadacitinib reduced mean fecal calprotectin levels by 597.59% (95%CI 350.94-844.324). Adverse events, such as headache, acne vulgaris, rash, nasopharyngitis and infections, were reported in 34% of patients (95%CI 0.11-0.62).

Conclusions Our meta-analysis indicates that upadacitinib may be an effective treatment for patients with prior tofacitinib exposure, demonstrating significant clinical remission, SFCR, and clinical response. Larger clinical trials are needed to establish long-term outcomes.

Keywords Upadacitinib, tofacitinib, inflammatory bowel disease, ulcerative colitis

Ann Gastroenterol 2025; 38 (5): 511-518

Introduction

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) of the large intestine characterized by diarrhea, abdominal pain, rectal bleeding, and weight loss [1]. Conventional therapies for UC, including aminosalicylates, corticosteroids, azathioprine, vedolizumab and anti-tumor necrosis factor agents, are often ineffective in providing sustained remission [2,3]. Over the past 2 decades, small-molecule therapies, such as Janus kinase (JAK) inhibitors, have proven revolutionary in managing UC, exhibiting significantly improved disease outcomes.

JAK/STAT is an intracellular tyrosine kinase signaling pathway that modulates and induces proinflammatory cytokines, such as interleukin (IL)-6, IL-12, IL-13, IL-17, IL-21, IL-23 and IL-33, implicated in the pathogenesis of UC. JAK inhibitors disrupt this signaling pathway by blocking the phosphorylation of JAK, resulting in the anti-inflammatory therapeutic effects seen in UC patients [4,5]. Tofacitinib, a first-generation, non-selective oral pan-JAK inhibitor, was approved by the United States Food and Drug Administration (FDA) for the treatment of UC in 2018. It has induced and maintained remission in patients who had failed treatment with conventional therapies and biologics [6-9]. However, it has been associated with primary and secondary non-response in a subset of patients, as well as adverse effects including hypercholesterolemia, malignancy, cardiovascular events and infections, with particular safety concerns regarding venous thromboembolism (VTE) and herpes zoster reactivation, prompting exploration of alternate options with increased selectivity, greater response rate, and fewer adverse events [10,11].

One such medication, upadacitinib, an oral selective JAK inhibitor associated with better disease-specific outcomes than tofacitinib [12-14], was approved by the FDA in March 2022 [15]. However, initial trials evaluating the effectiveness of upadacitinib in UC patients excluded patients with prior exposure to tofacitinib, leading to a significant knowledge gap and a lack of real-world data on upadacitinib efficacy in tofacitinib-refractory patients. To address this, we conducted a systematic review and meta-analysis to assess disease outcomes with upadacitinib use in patients who had previously failed treatment with tofacitinib, thereby providing evidence-based therapy options to patients who do not respond to non-selective JAK inhibitors.

Materials and methods

This meta-analysis was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Supplementary Table 1) [16,17]. Ethical approval was not required for this analysis.

Data sources and search strategy

A comprehensive electronic search was conducted across multiple databases, including the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase (Elsevier) and Web of Science, covering all records from inception until December 2024. We also manually screened the reference lists of included studies and relevant systematic reviews. The search strategy utilized a combination of keywords and Medical Subject Headings (MeSH) terms, specifically targeting “Upadacitinib,” “Tofacitinib,” and “Ulcerative colitis” (Supplementary Table 2).

Eligibility criteria

Eligible studies included randomized controlled trials, observational studies (case–control, retrospective, or prospective cohort), and case series that assessed disease outcomes with upadacitinib use in UC patients with prior exposure to tofacitinib. No restrictions were applied regarding geographical location or patient age. Studies were excluded if they were literature reviews, editorials, case series with fewer than 10 patients, duplicate studies or animal studies. Additionally, studies that lacked relevant data, addressed different endpoints, or did not have a single-arm study design were excluded. The population consisted of UC patients who had previously been exposed to tofacitinib. The intervention was treatment with upadacitinib. The primary outcomes included clinical remission, steroid-free clinical remission (SFCR) and clinical response, while the secondary outcomes were the mean decrease in fecal calprotectin and the incidence of adverse events.

Study selection and data extraction

Two independent reviewers (LA and FF) selected studies and extracted data; any discrepancies were resolved by a third reviewer (HF). Duplicate records were removed using Mendeley Desktop 1.19.8. Data were extracted using a standardized form that captured information on study characteristics (e.g., authors, study design), patient demographics (e.g., age, sex), and primary and secondary outcomes.

Study definitions

Clinical remission and response were defined based on the simple clinical colitis activity index (SCCAI), Patient-Reported Outcome (PRO-2), and the Mayo score.

Statistical analysis and publication bias

We conducted the statistical analysis in R version 4.4.1 using the package “meta.” We pooled proportions for single-arm studies along with their corresponding 95% confidence intervals (CI), risk ratios (RR) with 95%CIs for dichotomous outcomes, and mean differences with 95%CIs for continuous outcomes. Freeman-Tukey double arcsine transformed proportions were used [18]. RRs were calculated using the Mantel-Haenszel method [19], and mean differences using the inverse variance method in a random-effects model. We used the restricted maximum likelihood estimator to calculate the heterogeneity variance τ2 [20]. The pooled results were represented graphically as forest plots. The chi-square test and the Higgins I2 statistic were calculated to evaluate the statistical heterogeneity, and an I2 value of 25-50% was considered mild, 50-75% as moderate, and >75% as severe heterogeneity [21]. Per the Cochrane guidelines, a publication bias assessment could not be conducted, as fewer than 10 studies were included in the meta-analysis (funnel plots are not sufficiently powered to detect publication bias when the number of studies is <10) [22]. A sensitivity analysis was conducted by sequentially omitting each study from the pooled analysis to assess the robustness of the results. A P-value <0.05 was considered statistically significant in all cases.

Risk-of-bias and quality assessment

The risk of bias in the included cohort studies with available full texts was assessed using the Newcastle-Ottawa Scale (Supplementary Table 3). This scale evaluates studies based on 8 criteria across 3 domains: selection of study groups, comparability, and ascertainment of exposure or outcome. The quality assessment of the included case series was conducted using the Joanna Briggs Institute critical appraisal tool, which comprises 10 questions addressing the internal validity and risk of bias associated with case series designs (Supplementary Table 4).

Results

A total of 804 studies were screened for inclusion in the meta-analysis. After a thorough screening process, 10 studies were shortlisted for full-text review. Five studies did not fulfill the eligibility criteria and were excluded [14,23-26], leaving 4 retrospective studies [12,27-29] and 1 prospective study that were ultimately selected [30]. The PRISMA flow diagram details the study selection process (Fig. 1). All of the included studies observed the impact of upadacitinib in patients with UC after prior treatment with tofacitinib. The study and baseline characteristics of the 127 patients and the outcome data are summarized in Table 1.

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Figure 1 PRISMA flow diagram for included and excluded studies

Table 1 Study and baseline characteristics

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Clinical remission

The analysis, including 4 studies, indicated that the administration of upadacitinib increased the pooled clinical remission by 57% (95%CI 0.32-0.80; I2=84%; P<0.01; Fig. 2). In a sensitivity analysis excluding Gilmore 2024, the clinical remission rate was 47% (95%CI 0.34-0.60; I2=0%; Supplementary Fig. 1).

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Figure 2 Forest plot showing clinical remission in patients on upadacitinib after tofacitinib exposure

CI, confidence interval

Steroid-free clinical remission

The analysis, including 3 studies, revealed that the administration of upadacitinib resulted in a pooled steroid-free clinical remission rate of 52% (95%CI 0.26-0.78; I2=74%; P=0.02; Fig. 3). In a sensitivity analysis excluding Odah 2024, the steroid-free clinical remission rate was 40% (95%CI 0.26-0.54; I2=0%; Supplementary Fig. 2).

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Figure 3 Forest plot showing steroid-free clinical remission in patients on upadacitinib after tofacitinib exposure

CI, confidence interval

Clinical response

The analysis, including 3 studies, indicated that the administration of upadacitinib resulted in a pooled clinical response rate of 75% (95%CI 0.44-0.96; I2=86%; P<0.01; Fig. 4). In a sensitivity analysis excluding Odah 2024, the clinical response rate was 60% (95%CI 0.46-0.74; I2=0%; Supplementary Fig. 3).

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Figure 4 Forest plot showing clinical response in patients on upadacitinib after tofacitinib exposure

CI, confidence interval

Change in the fecal calprotectin

The analysis, including 2 studies, indicated that the administration of upadacitinib decreased the pooled mean fecal calprotectin by 597.59% (95%CI 350.94-844.324; I2=32%; P=0.23; Supplementary Fig. 4).

Adverse events

The analysis, including 3 studies, indicated that the administration of upadacitinib resulted in a pooled adverse event rate of 34% (95%CI 0.11-0.62; I2=80%; P<0.01), encompassing headache, acne vulgaris, rash, nasopharyngitis, and infections such as COVID-19 and herpes zoster, etc. (Fig. 5). In a sensitivity analysis excluding Levine 2024, the rate of adverse events decreased by 23% (95%CI 0.10-0.38; I2=39%; Supplementary Fig. 5).

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Figure 5 Forest plot showing adverse events in patients on upadacitinib after tofacitinib exposure

CI, confidence interval

Discussion

Our systematic review and meta-analysis evaluated the safety and efficacy of upadacitinib in patients with UC who had previously used tofacitinib. The analysis revealed a marked increase in clinical remission and steroid-free clinical remission. The clinical response also demonstrated a notable increase. Additionally, a substantial decline was observed in fecal calprotectin levels.

Our findings reveal a clinical remission rate of 57% and a clinical response rate of 75% with upadacitinib in patients who had previously received and failed tofacitinib therapy. A proportional analysis by Zheng et al reported a clinical remission rate of 38% and a clinical response rate of 61%, regardless of the prior line of therapy [31]. The specific patient population in our study can explain the higher clinical remission and clinical response observed with low heterogeneity. Our findings are consistent with the existing literature. For instance, a network meta-analysis by Zhang et al comparing various drugs used for moderate to severe IBD revealed upadacitinib to be the most effective in achieving the highest clinical remission and clinical response, with cumulative probabilities of 99.3% and 96%, respectively [32]. Another similar study by Shehab et al also reported upadacitinib as the highest-ranking drug in achieving PRO-2 clinical remission [33]. These studies and our findings strengthen the evidence supporting upadacitinib as a superior treatment option for IBD, including UC.

Our study included patients who had previously been treated with tofacitinib. A subgroup analysis by Burr et al demonstrated that upadacitinib not only showed the highest efficacy among other drugs for IBD, but also showed the highest efficacy in previously treated patients—even higher than in the treatment-naive subgroup that received upadacitinib as first-line treatment [34]. Gilmore et al also demonstrated a higher clinical remission rate of 23% with upadacitinib in patients with prior tofacitinib exposure than in tofacitinib-naive patients [27]. A case series by Radcliffe et al, which included patients previously treated with tofacitinib, showed improved clinical remission, steroid-free remission and clinical response [35]. Another case series with patients whose previous JAK inhibitor therapy, specifically filgotinib and tofacitinib, had failed, showed improved outcomes with upadacitinib [25], suggesting a role for a rotation strategy among JAK inhibitors. A study on switching between different JAK inhibitors in rheumatoid arthritis patients showed that it improved outcomes, further strengthening the benefit of JAK inhibitors and suggesting that rotation therapy in inflammatory diseases could be beneficial [36]. Upadacitinib has already shown greater benefits over the other commonly used IBD drugs [32-34]; although the mechanisms of treatment failure may differ between JAK inhibitors and tumor necrosis factor inhibitors (anti-TNF), a study by Wang et al found that upadacitinib effectively modulates inflammatory pathways in anti-TNF non-responders, further supporting its role in refractory IBD [37].

Upadacitinib is a selective JAK1 inhibitor, with over 60 times more selectivity than JAK2 and over 100 times more than JAK3 [38]. This greater selectivity allows upadacitinib to precisely and strongly inhibit proinflammatory cytokines, particularly those implicated in the pathogenesis of IBD [39]. The higher selectivity and potency of upadacitinib can explain its greater efficacy in treating inflammatory diseases compared to other JAK inhibitors. Upadacitinib also more potently inhibits IL-2, IL-3, IL-4, IL-15, IL-21, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-gamma and interferon-alpha, compared to tofacitinib [40]. This greater potency of upadacitinib contributes to its superior efficacy compared to tofacitinib in treating IBD. Tofacitinib, on the other hand, effectively inhibits JAK1 and JAK3, with some activity against JAK2 [41]. This broader inhibition by tofacitinib is implicated as a higher risk of adverse events [40,41]. In comparison, upadacitinib’s precise inhibition of JAK1 could be associated with a reduced risk of adverse events [39-41]. These precise and potent effects of upadacitinib make it a valuable second-line treatment option when tofacitinib has failed as the first-line treatment.

The steroid-free clinical remission rate in our analysis was 52%, highlighting the steroid-sparing effect of upadacitinib. A study by Runde et al, assessing the efficacy of upadacitinib in children and adolescents with IBD who had previously been treated with tofacitinib, showed an 86% steroid-free remission rate and clinical response [42]. Wu et al also found steroid-free remission in 64% of patients receiving upadacitinib for UC after the failure of prior therapies, including tofacitinib, glucocorticoids and biologics [43]. Similar findings were reported by Raine et al in a post hoc analysis, which demonstrated a higher reinitiation of corticosteroids in the placebo group compared to the upadacitinib group [44]. They also demonstrated that patients receiving corticosteroids sustained a higher rate of treatment-emergent adverse events compared to those who did not. Clinical trials have shown that upadacitinib is more effective than tofacitinib in achieving steroid-free clinical remission [13,14]. The efficacy of upadacitinib can be attributed to its precise and targeted action, which effectively suppresses proinflammatory pathways with sustained efficacy.

Our pooled analysis revealed a substantial reduction in fecal calprotectin by 597.59%. This finding is consistent with the existing literature, which supports the role of upadacitinib in resolving inflammation and significantly reducing inflammatory biomarkers [25,42,43]. This is further evidenced by the analysis of Zheng et al, which demonstrated an endoscopic remission rate of 20% in IBD patients with upadacitinib [31]. Zhang et al also found a 99% cumulative probability of achieving endoscopic remission with upadacitinib [32]. This is further supported by the endoscopic findings, which demonstrate an improvement and resolution of inflammation in the intestinal mucosa [25,31,32,43]. The reason lies in the targeted and potent inhibition of the JAK1 pathway by upadacitinib [38]. This reduces inflammation and promotes mucosal healing, significantly decreasing inflammatory cytokines and biomarkers, such as fecal calprotectin and C-reactive protein [39,40,43].

The safety profile exhibited an increase in adverse events, with a proportion of 34%. Levine et al also reported a 31% incidence of adverse events, all of which were infections [29]. Most adverse events encountered are generally mild and manageable, such as headache, acne, nausea, abdominal pain and arthralgia; however, an increased risk of infections, particularly herpes zoster, has been observed with JAK inhibitor therapy [31]. Some studies have reported liver enzyme elevation, leukopenia, neutropenia and anemia [31,43]. The selective inhibition of JAK1 by upadacitinib reduces adverse effects, particularly hematologic side-effects, compared to other JAK inhibitors, by preventing the inhibition of off-target pathways, such as JAK2 and JAK3 [38,39,41].

We acknowledge several limitations in our meta-analysis. First, the absence of a control group limits direct comparison with other therapeutic options. Second, the relatively small sample size of 127 patients may have limited the statistical power of the analysis for certain outcomes. Third, the short follow-up period may not be sufficient to capture long-term outcomes and rare adverse events. It is also important to note that 2 of the 5 included studies were available only in abstract form, which limited access to full methodological details and may have introduced bias. Additionally, there is heterogeneity in the reasons for tofacitinib discontinuation. While most patients discontinued because of non-response (whether primary, secondary, or partial), information about other reasons, such as adverse events or insurance issues, is limited. For instance, in the study by Odah et al adverse events and insurance problems were also cited as reasons for discontinuation.

Despite these limitations, we conducted sensitivity analyses to eliminate heterogeneity and confirm the robustness and reliability of our findings. Therefore, we consider the results of our analysis to be informative within the context of the available data. Moreover, our study focuses on a specific population, i.e., patients who had previously failed treatment with tofacitinib, providing valuable insights for this subgroup.

In conclusion, our systematic review and meta-analysis provide promising evidence that upadacitinib may be an effective treatment option for UC patients who have previously been treated with tofacitinib. While our findings indicate significant improvements in clinical remission and steroid-free remission rates, and a notable reduction in fecal calprotectin, future research should focus on conducting large-scale randomized controlled trials with longer follow-ups and diverse patient populations, comparing the safety and efficacy of upadacitinib with other therapeutic options to establish its long-term outcomes.

Summary Box

What is already known:

  • Tofacitinib, an FDA-approved non-selective oral pan-Janus kinase (JAK) inhibitor for ulcerative colitis (UC), has shown efficacy in inducing and maintaining remission in patients who failed conventional therapies and biologics

  • Limitations include primary and secondary non-response, as well as adverse events such as hypercholesterolemia, malignancy, cardiovascular events, venous thromboembolism, and herpes zoster reactivation

  • Upadacitinib is a recently approved JAK1 inhibitor for moderate-to-severe UC

  • Its efficacy in patients previously treated with tofacitinib remains unclear, as they were excluded from major clinical trials

What the new findings are:

  • This is the first meta-analysis evaluating the efficacy of upadacitinib in patients with prior tofacitinib exposure

  • Upadacitinib shows promising clinical remission (57%), steroid-free remission (52%) and clinical response (75%) rates

  • Treatment with upadacitinib led to a significant reduction in inflammatory markers

  • The study provides initial evidence of upadacitinib’s efficacy in a real-world setting following tofacitinib failure

References

1. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG clinical guideline:ulcerative colitis in adults. Am J Gastroenterol 2019;114:384-413.

2. Garud S, Peppercorn MA. Ulcerative colitis:current treatment strategies and future prospects. Therap Adv Gastroenterol 2009;2:99-108.

3. Singh S, Fumery M, Sandborn WJ, Murad MH. Systematic review with network meta-analysis:first- and second-line pharmacotherapy for moderate-severe ulcerative colitis. Aliment Pharmacol Ther 2018;47:162-175.

4. Fernández-Clotet A, Castro-Poceiro J, Panés J. JAK inhibition:the most promising agents in the IBD pipeline?Curr Pharm Des 2019;25:32-40.

5. Nemeth ZH, Bogdanovski DA, Barratt-Stopper P, Paglinco SR, Antonioli L, Rolandelli RH. Crohn's disease and ulcerative colitis show unique cytokine profiles. Cureus 2017;9:e1177.

6. Sandborn WJ, Su C, Sands BE, et al;OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain Investigators. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2017;376:1723-1736.

7. Uzzan M, Bresteau C, Laharie D, et al;GETAID-TALC Study Group. Tofacitinib as salvage therapy for 55 patients hospitalised with refractory severe ulcerative colitis:A GETAID cohort. Aliment Pharmacol Ther 2021;54:312-319.

8. Berinstein JA, Sheehan JL, Dias M, et al. Tofacitinib for biologic-experienced hospitalized patients with acute severe ulcerative colitis:a retrospective case-control study. Clin Gastroenterol Hepatol 2021;19:2112-2120.

9. Weisshof R, Aharoni Golan M, Sossenheimer PH, et al. Real-world experience with tofacitinib in IBD at a tertiary center. Dig Dis Sci 2019;64:1945-1951.

10. Núñez P, Quera R, Yarur AJ. Safety of Janus kinase inhibitors in inflammatory bowel diseases. Drugs 2023;83:299-314.

11. Wollenhaupt J, Lee EB, Curtis JR, et al. Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis:final results of a global, open-label, long-term extension study. Arthritis Res Ther 2019;21:89.

12. Boneschansker L, Ananthakrishnan AN;Massachusetts General Hospital Crohn's And Colitis Center Collaborators. Comparative effectiveness of upadacitinib and tofacitinib in inducing remission in ulcerative colitis:real-world data. Clin Gastroenterol Hepatol 2023;21:2427-2429.

13. Dalal RS, Kallumkal G, Cabral HJ, Barnes EL, Allegretti JR. One-year comparative effectiveness of upadacitinib vs tofacitinib for ulcerative colitis:a multicenter cohort study. Am J Gastroenterol 2024;119:1628-1631.

14. Kochhar GS, Khataniar H, Jairath V, Farraye FA, Desai A. Comparative effectiveness of upadacitinib and tofacitinib in ulcerative colitis:a US propensity-matched cohort study. Am J Gastroenterol 2024;119:2471-2479.

15. Danese S, Vermeire S, Zhou W, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis:results from three phase 3, multicentre, double-blind, randomised trials. Lancet 2022;399:2113-2128.

16. Moher D, Liberati A, Tetzlaff J, Altman DG;PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses:the PRISMA statement. PLoS Med 2009;6:e1000097.

17. Cochrane Handbook for Systematic Reviews of Interventions. Available from:https://www.cochrane.org/authors/handbooks-and-manuals/handbook [Accessed 14 July 2025].

18. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719-748.

19. Barendregt JJ, Doi SA, Lee YY, Norman RE, Vos T. Meta-analysis of prevalence. J Epidemiol Community Health 2013;67:974-978.

20. Viechtbauer W. Bias and efficiency of meta-analytic variance estimators in the random-effects model. J Educ Behav Stat 2005;30:261-293.

21. West SL, Gartlehner G, Mansfield AJ, et al. Comparative effectiveness review methods:clinical heterogeneity. Table 7 Summary of common statistical approaches to test for heterogeneity. NCBI Bookshelf. Available from:https://www.ncbi.nlm.nih.gov/books/NBK53317/table/ch3.t2/[Accessed 14 July 2025].

22. Page MJ, Higgins JP, Sterne JA. Cochrane. Chapter 13:assessing risk of bias due to missing evidence in a meta-analysis. Available from:https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-13 [Accessed 14 July 2025].

23. Troncone E, Marafini I, Del Vecchio Blanco G, Di Grazia A, Monteleone G. Novel therapeutic options for people with ulcerative colitis:an update on recent developments with Janus kinase (JAK) inhibitors. Clin Exp Gastroenterol 2020;13:131-139.

24. Misselwitz B, Juillerat P, Sulz MC, Siegmund B, Brand S;Swiss IBDnet, an official working group of the Swiss Society of Gastroenterology. Emerging treatment options in inflammatory bowel disease:Janus kinases, stem cells, and more. Digestion 2020;101(Suppl 1):69-82.

25. Hosomi S, Nishida Y, Fujiwara Y. Efficacy of upadacitinib as a second-line JAK inhibitor in ulcerative colitis:a case series. Intern Med 2024;63:1882-1885.

26. Berinstein JA, Karl T, Patel A, et al. Effectiveness of upadacitinib for patients with acute severe ulcerative colitis:a multicenter experience. Am J Gastroenterol 2024;119:1421-1425.

27. Gilmore R, Fernandes R, Hartley I, et al. P1064 Upadacitinib is safe and effective in ulcerative colitis patients with prior exposure to tofacitinib. J Crohns Colitis 2024;18:i1904.

28. Odah T, Karime C, Desai A, et al. Response to upadacitinib in patients with inflammatory bowel disease previously treated with tofacitinib. Dig Dis Sci 2024;69:3911-3919.

29. Levine J, McKibbin J, Ham R, et al. Use of upadacitinib in 16 tofacitinib-refractory ulcerative colitis patients:a single-center case series. Inflamm Bowel Dis 2024;30:2232-2235.

30. Krugliak Cleveland N, Friedberg S, Choi D, et al. P724 Upadacitinib is effective and safe in tofacitinib-experienced patients with ulcerative colitis:a prospective real-world experience. J Crohns Colitis 2023;17(Suppl_1):i854-i856.

31. Zheng DY, Wang YN, Huang YH, Jiang M, Dai C. Effectiveness and safety of upadacitinib for inflammatory bowel disease:a systematic review and meta-analysis of RCT and real-world observational studies. Int Immunopharmacol 2024;126:111229.

32. Zhang W, Zhao S, Li J, Sun Y, Wang X. Network meta-analysis of efficacy and safety of drugs for the treatment of moderate to severe ulcerative colitis. Front Pharmacol 2024;15:1481678.

33. Shehab M, Alrashed F, Alsayegh A, et al. Comparative efficacy of biologics and small molecule in ulcerative colitis:a systematic review and network meta-analysis. Clin Gastroenterol Hepatol 2025;23:250-262.

34. Burr NE, Gracie DJ, Black CJ, Ford AC. Efficacy of biological therapies and small molecules in moderate to severe ulcerative colitis:systematic review and network meta-analysis. Gut 2022;71:1976-1987.

35. Radcliffe M, Long M, Barnes E, Herfarth H, Hansen J, Jain A. Efficacy of upadacitinib in pateints previously treated with tofacitinib for the management of ulcerative colitis. Inflamm Bowel Dis 2023;29:S82.

36. Vassallo C, Sammut L. AB0412 Cycling of JAK-inhibitors in patients with rheumatoid arthritis:a single-centre experience. Ann Rheum Dis 2022;81:1334-1335

37. Wang J, Macoritto M, Guay H, Davis JW, Levesque MC, Cao X. The clinical response of upadacitinib and risankizumab is associated with reduced inflammatory bowel disease anti-TNF- inadequate response mechanisms. Inflamm Bowel Dis 2023;29:771-782.

38. Parmentier JM, Voss J, Graff C, et al. In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494). BMC Rheumatol 2018;2:23.

39. Mohamed MF, Bhatnagar S, Parmentier JM, Nakasato P, Wung P. Upadacitinib:mechanism of action, clinical, and translational science. Clin Transl Sci 2024;17:e13688.

40. Irani M, Fan C, Glassner K, Abraham BP. Clinical evaluation of upadacitinib in the treatment of adults with moderately to severely active ulcerative colitis (UC):patient selection and reported outcomes. Clin Exp Gastroenterol 2023;16:21-28.

41. Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT signaling as a target for inflammatory and autoimmune diseases:current and future prospects. Drugs 2017;77:521-546.

42. Runde J, Ryan K, Hirst J, et al. Upadacitinib is associated with clinical response and steroid-free remission for children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2025;80:133-140.

43. Wu H, Xie T, Yu Q, et al. An analysis of the effectiveness and safety of upadacitinib in the treatment of inflammatory bowel disease:a multicenter real-world study. Biomedicines 2025;13:190.

44. Raine T, Ishiguro Y, Rubin DT, et al. Impact of baseline corticosteroid use on the efficacy and safety of upadacitinib in patients with ulcerative colitis:a post hoc analysis of the phase 3 clinical trial programme. J Crohns Colitis 2024;18:695-707.

Notes

Conflict of Interest: None