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HOME > Intest Res > Volume 23(3); 2025 > Article
Original Article
IBD Upadacitinib induction is effective and safe in ulcerative colitis patients including those with prior exposure to tofacitinib: a multicenter real-world cohort study
Robert Gilmore1,2orcid, Richard Fernandes1,2orcid, Imogen Hartley3orcid, Arteen Arzivian4orcid, Rupert Leong4orcid, Bridgette Andrew5orcid, Abhinav Vasudevan5,6orcid, Tessa Greeve7orcid, Gregory Thomas Moore7,8orcid, Steven Kim9, Daniel Lightowler10,11, Abhey Singh9,10, Gillian Mahy12orcid, Aditya Mithanthaya13orcid, Kannan Venugopaul13, Sangwoo Han14orcid, Robert Bryant14orcid, Jack West15orcid, Jonathan Segal15,16orcid, Britt Christensen15,16orcid, Crispin Corte17,18, Nik Ding3orcid, Yoon-Kyo An1,2orcid, Jakob Begun1,2orcid
Intestinal Research 2025;23(3):347-357.
DOI: https://doi.org/10.5217/ir.2024.00127
Published online: December 20, 2024

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Correspondence to Jakob Begun, Department of Gastroenterology Mater Hospital, Brisbane Raymond Terrace South, Brisbane QLD 4101, Australia. E-mail: Jakob.begun@mater.uq.edu.au
• Received: August 12, 2024   • Revised: October 2, 2024   • Accepted: October 7, 2024

© 2025 Korean Association for the Study of Intestinal Diseases.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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See letter "Upadacitinib after tofacitinib in ulcerative colitis" in Volume 23 on page 229.
  • Background/Aims
    Upadacitinib is a novel selective Janus kinase inhibitor approved for use in ulcerative colitis. Clinical trials had rigorous criteria and excluded many patient subgroups. Given limited real-world effectiveness data, we examined outcomes of patients treated with upadacitinib for ulcerative colitis in a real-world population.
  • Methods
    Patients that commenced upadacitinib for moderate-to-severe ulcerative colitis from September 2022 until March 2023 were identified at 13 inflammatory bowel disease centers across Australia. Clinical, biochemical, endoscopic, and intestinal ultrasound outcomes were recorded retrospectively at baseline, week 8, and week 16.
  • Results
    One hundred and fifty-two patients (61 female [40%], median age 38 years [interquartile range, 28–50]) were included. The primary endpoint of clinical remission was met in 79% at week 8, and 84% at week 16. A total of 42 patients (28%) with prior tofacitinib exposure were included. No significant difference in clinical remission was observed by week 16 between tofacitinib experienced compared to tofacitinib naïve patients (86% vs. 84%, P=0.67). Complete intestinal ultrasound data was available for 36 patients, showing transmural remission in 64% at week 8 and 81% at week 16, with a decrease in median bowel wall thickness of 2.3 mm and 2.4 mm, respectively.
  • Conclusions
    Upadacitinib resulted in high rates of clinical remission at 8 and 16 weeks in this large real-world cohort of ulcerative colitis patients. Upadacitinib is effective in patients with prior tofacitinib exposure. Intestinal ultrasound shows significant rates of transmural remission at week 8, sustained through week 16.
  • Keywords: Ulcerative colitis; Upadacitinib; Janus kinase inhibitors; Tofacitinib; Intestinal ultrasound
Ulcerative colitis (UC) is a chronic, relapsing inflammatory condition affecting the colon, resulting in mucosal ulceration with associated increased stool frequency, loose motions, fecal urgency, and rectal bleeding [1]. For mild to moderate UC, current guidelines recommend the early use of aminosalicylates followed by immunomodulator (IM) drugs such as thiopurines. For moderate-to-severe disease, advanced drug therapies (ADT) may be required [2].
Janus kinase (JAK) inhibitors are orally available, small molecule therapies that inhibit pro-inflammatory cytokine signaling dependent on signal transduction and activation of transcription pathways transcription factors [3]. Tofacitinib, a “panJAK” inhibitor potently inhibits JAK1 and JAK3, whereas upadacitinib is more selective for JAK1. Both tofacitinib and upadacitinib have been approved for the treatment of moderateto-severe UC. In the phase 3 clinical trials, upadacitinib 45 mg daily was significantly more effective than placebo for induction of remission with 26% to 34% of patients demonstrating clinical remission by week 8. After week 8, upadacitinib responders from the induction trials were re-randomized to maintenance upadacitinib 15 mg or 30 mg daily, or placebo. Patients who had not responded by week 8 completed an additional 8 weeks of induction therapy with 45 mg upadacitinib daily. The proportion of initial non-responders who subsequently responded by week 16 was not reported [4]. Upadacitinib appears to have a rapid onset of clinical efficacy, with a significant reduction in stool frequency, urgency, and rectal bleeding observed as early as day 1 post-induction.
Patients’ outcomes in clinical trials do not necessarily reflect real-world experience for a variety of reasons including rigorous patient inclusion and exclusion criteria. Accordingly, clinical trial outcomes can differ significantly from real-world cohort studies. In the upadacitinib clinical trial program for UC, among other exclusions including age, prior surgery and geographic restrictions, patients with prior exposure to tofacitinib and those with isolated proctitis were excluded. These exclusions in particular leave a gap in our understanding of the efficacy of upadacitinib in these patient groups, which can only be addressed through real-world clinical experience. Furthermore, there is limited real-world data examining the effectiveness and safety of upadacitinib when used in routine clinical practice. Two studies reported clinical remission rates > 80% at week 8 for UC, but generalizability of these data is limited by small cohorts of patients, especially regarding tofacitinib-exposed patients [5,6].
This study aimed to assess the real-world effectiveness and safety of upadacitinib in UC, also capturing those patients with prior tofacitinib exposure.
1. Study Design
We performed a nation-wide, multicenter, retrospective cohort study of upadacitinib for moderate-to-severe UC. The study included patients from 13 Australian inflammatory bowel disease centers, who commenced upadacitinib for UC between September 2022 and March 2023. The target population consisted of men and women aged 18 and above with UC of at least 3-month duration since diagnosis. Patients must have at least 16 weeks of clinical data available post upadacitinib induction for moderate-to-severe UC to be eligible for inclusion. Patients who ceased upadacitinib prior to week 16 for active disease were treated as non-responders, and included in the analysis. Patients with indeterminate colitis, Crohn’s disease, prior colectomy including pouchitis, pregnancy, breastfeeding, recent venous thromboembolism or solid organ malignancy were excluded. Ethical approval for this research project including a waiver of consent has been granted for all study sites by Mater Misericordiae Ltd Human Research Ethics Committee (HREC/MML/97196).
2. Outcomes and Definitions
The primary outcome was clinical remission at weeks 8 and 16. Clinical remission was defined using Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) II guidelines [7] using a patient-reported outcome (PRO2) score of ≤ 1 with a rectal bleeding subscore of 0. Secondary outcomes of the study were to determine the proportion of patients achieving the following endpoints at both week 8 and week 16: (1) clinical response (defined as active disease at baseline [PRO2 ≥ 3] with a reduction in PRO2 of ≥ 50%); (2) corticosteroid-free clinical remission (as per definition of clinical remission, plus corticosteroid cessation for a minimum of 2 weeks prior to time of review in patients who were receiving corticosteroid at baseline); (3) biochemical remission (C-reactive protein [CRP] and fecal calprotectin [FC] level normalization [ ≤ 5 mg/L and < 150 μg/g, respectively] where at least one was abnormal at baseline); (4) endoscopic remission (defined as a Ulcerative Colitis Endoscopic Index of Severity [UCEIS] of ≤ 1); and (5) transmural remission assessed sonographically by intestinal ultrasound (IUS) (defined as bowel wall thickness [BWT] < 3 mm in all segments plus a modified Limberg score [mLS] of 0). Safety outcomes included reported adverse events (AEs) and serious AEs (defined as AE leading to discontinuation of drugs or hospitalization) at weeks 8 and 16.
3. Demographic and Clinical Data
Demographic and clinical data was collected by retrospective chart review. The following demographic data was collected: age, sex, smoking history, age at diagnosis, duration of disease, extent of disease, prior endoscopic severity, surgical history, prior admissions with acute severe ulcerative colitis (ASUC), presence of extraintestinal manifestations, prior and current medications including total number of ADT failures (ADT was defined as biologic medication or small molecule). All prior inflammatory disease medications accounted for with current use defined as any use within 8 weeks of upadacitinib induction. Concurrent medications throughout study follow-up were documented, including use of corticosteroid and cumulative dose. Clinical and biochemical data were collected at set timepoints: at baseline (prior to commencement of upadacitinib), week 8 (± 7 days), and week 16 (± 14 days) after commencement of upadacitinib therapy. All endoscopic and IUS data conducted during the 16-week study follow-up period were collected. Endoscopic data included both Mayo endoscopic subscore (MES) and UCEIS. IUS data collected included BWT of the most affected segment and modified Limberg score for Doppler signal interpretation.
4. Statistical Analysis
Continuous variables were summarized using medians and interquartile ranges (IQRs). For normally distributed data comparison of means was performed using the Student t test for parametric variables and the Wilcoxon rank-sum test for nonparametric variables. Categoric variables were expressed as the percentage and number of the cohort and analyzed using the chi-square test.
A total of 152 patients were identified that met inclusion criteria. The clinical and demographic characteristics of the cohort are summarized in Table 1. The median age was 38 years (IQR, 25–50 years), 40% were female, the median duration of disease was 8 years (IQR, 4–15 years), and 5% were active smokers. Twenty-one (14%) had isolated proctitis (E1), 39 (25%) had left-sided colitis (E2), and 92 (61%) had extensive colitis (E3). Fifty-six (37%) had at least 1 episode of ASUC prior to induction, and 34 (22%) had a history of extraintestinal manifestations. The median PRO2 score at baseline was 3 (IQR, 2–4).
Upadacitinib was used as the first-line ADT in 22 bio-naïve patients (14%). A total of 130 patients (86%) had been previously exposed to biologics (90 infliximab [59%], 91 vedolizumab [60%], and 35 adalimumab [23%]) and 42 patients (28%) were previously exposed to tofacitinib. Among those who were exposed to ADT, 27% of patients were exposed to 1 therapy, 29% of patients were exposed to 2 therapies, 17% of patients were exposed to 3 therapies, and 13% of patients were exposed to 4 or more therapies.
At induction, upadacitinib was given concomitantly with oral corticosteroids in 42% (64 of 152) patients, and oral aminosalicylate in 51% (77 of 152) patients, with 38% (52 of 152) of patients receiving a combination of both. Ninety-three percent (141 of 152) of patients had prior exposure to IM therapy, and 54% (82 of 152) were on an IM immediately prior to upadacitinib induction. These patients ceased IM therapy at induction. All patients received upadacitinib induction therapy of 45 mg once daily for 8 weeks. After standard induction therapy, 38% (58 of 152) of patients received extended induction by continuing 45 mg once daily for a further 8 weeks. The remainder received maintenance therapy; 51% (77 of 152) of patients received 30 mg once a daily and 11% (17 of 152) 15 mg once a daily at the discretion of the treating clinicians. All 17 patients who were de-escalated to 15 mg once daily dosing were in corticosteroid-free clinical remission at week 8.
1. Clinical Effectiveness
All 152 patients had complete clinical data available for assessment at both weeks 8 and 16. Outcomes are summarized in Table 2. The primary endpoint of clinical remission was met by 79% (120 of 152) patients at week 8, and 84% (128 of 152) patients at week 16 after upadacitinib initiation (Fig. 1). At baseline 20% (30 of 152) of patients were in clinical remission and were excluded from secondary clinical response analysis. Clinical response in those with active disease at baseline was observed in 75% (92 of 122) of patients at week 8, and 85% (104 of 122) patients at week 16 (Fig. 2). Five percent (7 of 152) of patients ceased upadacitinib prior to week 16 due to active disease. Among 100 patients with rectal bleeding at baseline, complete resolution was seen in 82% of patients at week 8, and 84% at week 16. Similarly, among 132 patients who reported increased stool frequency at baseline, complete resolution was seen in 62% of patients at week 8, and 71% at week 16.
At baseline 64 patients were receiving corticosteroid therapy, with corticosteroid-free clinical remission being achieved in 63% (40 of 64) of patients at week 8 and 83% (53 of 64) at week 16. At week 8, 30% (19 of 64) of patients were still corticosteroid dependent, with this number decreasing to 8% (5 of 64) by week 16.
Isolated proctitis (E1 disease) was present in 14% (21 of 152) of patients at baseline, all patients had active disease at baseline. Clinical remission was seen in 67% (14 of 21) at week 8, increasing to 86% (18 of 21) by week 16. There was no significant difference in rate of clinical remission at week 8 or week 16 between those with isolated proctitis compared with more extensive disease.
2. Biochemical Outcomes
A total of 62 patients had complete biochemical data at baseline, week 8, and week 16. There were no significant differences in rate of clinical remission between those with complete biochemical data and the remainder of the cohort (16% vs. 19%, P=0.24), week 8 (81% vs. 77%, P=0.31), or week 16 (83% vs. 86%, P=0.18). CRP decreased significantly from 6.0 mg/L (IQR, 2.4–16.1 mg/L) at baseline to 1.3 mg/L (IQR, 1.0–5.1 mg/L; P<0.01) at week 8, and 1.7 mg/L (IQR, 1.0–4.9 mg/L; P<0.01) at week 16. There was no significant reduction in CRP from week 8 to 16 (P=0.16).
Similarly, FC decreased significantly from 626 μg/g (IQR, 318–1,381 μg/g) at baseline to 127 μg/g (IQR, 35–488 μg/g; P<0.01) at week 8, and 121 μg/g (IQR, 43–588 μg/g; P<0.01) at week 16. There was no significant reduction in FC from week 8 to 16 (P=0.49).
At baseline, 6% of patients (4 of 62) were in biochemical remission and were excluded from the analysis. Biochemical remission improved significantly to 59% (32 of 54, P<0.01) at week 8 and 66% (38 of 58, P<0.01) at week 16. There was a trend toward increased biochemical remission from week 8 to week 16, but this did not meet statistical significance (P=0.09).
3. Endoscopic Remission
Among the 79 patients who underwent baseline endoscopy within 1 month prior to upadacitinib induction, 41 had a repeat endoscopy (30 complete colonoscopy and 11 flexible sigmoidoscopy) within the 16-week follow-up study period and were included in the analysis. Median time to endoscopy was 13 weeks with an IQR of 4 weeks. The baseline median UCEIS was 4 (IQR, 3–5) and MES was 2 (IQR, 2–3) which reduced significantly to UCEIS 3 (IQR, 1–4; P<0.01) and MES 1 (IQR, 0–1) respectively on repeat endoscopy. At baseline, 6% of patients (3 of 41) were in endoscopic remission (UCEIS of ≤ 1), and were excluded from the analysis. Endoscopic remission was attained in 55% (21 of 38) of follow-up endoscopy within the 16-week induction window.
4. Transmural Healing by IUS
A total of 36 patients underwent IUS examination at baseline, week 8, and week 16. The median BWT reduced significantly from 4.7 mm (IQR, 4.0–5.5 mm) at baseline to 2.4 mm (IQR, 2.0–3.9 mm; P<0.01) at week 8 and 2.3 mm (IQR, 1.9–2.9 mm; P<0.01) at week 16. There was no significant reduction in BWT from week 8 to week 16 (P=0.34). The median mLS reduced significantly from mLS 2 (IQR, 1–3) at baseline to mLS 0 (IQR, 0–1; P<0.01) at week 8 and mLS 0 (IQR, 0–1; P<0.01) at week 16. There was no significant reduction in mLS from week 8 to 16 (P=0.31). At baseline, 1 patient (3%) had no active disease sonographically on IUS and was excluded from the analysis. Transmural healing improved significantly to 63% (22 of 35, P<0.01) on IUS by week 8, increasing to 80% (28 of 35, P<0.01) of patients by week 16. The increase in the proportion of patients with transmural healing from week 8 to week 16 did not meet statistical significance (P=0.06). Of the 28 patients with transmural remission on IUS, all were also in clinical, as well as biochemical and endoscopic remission where data was available (74% of these patients had complete data).
5. Effect of Prior ADT Exposure
Previous exposure to one or more ADT was seen in 86% (130 of 152) of patients and 14% (22 of 152) were ADT-naïve. Among bio-exposed patients, the breakdown of prior therapies is shown in Table 1. When considering upadacitinib induction, there was no significant difference in proportion of patients requiring 16-week 45 mg upadacitinib induction therapy between the cohorts, with 27% (6 of 22) of the ADT-naïve cohort requiring extended induction compared to 33% (45 of 152) of the ADT-exposed cohort. The proportion of ADT-naïve and ADT-exposed patients achieving clinical remission at week 8 was 77% (17 of 22) and 78% (101 of 130) respectively and at week 16 was 82% (18 of 22) and 86% (112 of 130). There was no significant difference in effectiveness of induction of clinical remission at week 8 (P=0.36) or week 16 (P=0.12) when comparing ADT naïve with experienced. Furthermore, when comparing week 8 and week 16 remission rates by number of prior ADT failures there were no significant differences.
6. Tofacitinib Exposed versus Naïve
Among the overall cohort, 33% (42 of 152) had prior exposure to tofacitinib. Patients’ baseline characteristics are summarized in Table 3 stratified by tofacitinib exposure status, with no significant differences between groups except for disease duration and number of prior ADT.
Among the patients with prior tofacitinib exposure, 74% (31 of 42) were receiving tofacitinib immediately prior to upadacitinib induction and 76% (32 of 42) were switched due to loss of response with active disease at induction, while the remaining 24% (10 of 42) of patients were in clinical remission and switched for other reasons (primarily patient preference for once daily therapy [60%] or tofacitinib intolerance due to side effects [40%]). In the tofacitinib-naïve cohort, 81% (91 of 110) of patients had active disease at baseline.
When considering clinical remission between the cohorts, the proportion of tofacitinib-exposed patients in clinical remission was 24% (10 of 42) at baseline, 72% (30 of 42) at week 8, and 86% (36 of 42) at week 16 (Fig. 3). In tofacitinib-naïve patients, the rate of clinical remission was 19% (21 of 110) at baseline, 78% (86 of 110) at week 8 and 84% (92 of 110) at week 16. There was no statistically significant difference in the proportion of patients in clinical remission at baseline (P=0.42), week 8 (P=0.17), or week 16 (P=0.67).
When considering biochemical remission between the cohorts, the proportion of tofacitinib-exposed patients in biochemical remission was 10% (2 of 21) at baseline, 62% (13 of 21) at week 8, and 76% (16 of 21) at week 16. In tofacitinib-naïve patients, the rate of biochemical remission was 5% (2 of 41) at baseline, 56% (23 of 41) at week 8, and 64% (26 of 41) at week 16. There was no statistically significant difference in the proportion of patients in biochemical remission at baseline (P=0.11), week 8 (P=0.14) or week 16 (P=0.24).
When considering transmural remission between the cohorts, the proportion of tofacitinib-exposed patients in transmural remission by IUS was 0% (0 of 15) at baseline, 67% (10 of 15) at week 8, and 80% (12 of 15) at week 16. In tofacitinib-naïve patients, the rate of transmural remission was 5% (1 of 21) at baseline, 62% (13 of 21) at week 8, and 81% (17 of 21) at week 16. There was no statistically significant difference in the proportion of patients in transmural remission at baseline (P=0.19), week 8 (P=0.33) or week 16 (P=0.43).
When considering endoscopic remission between the cohorts, the proportion of tofacitinib-exposed patients in endoscopic remission was 5% (1 of 18) at baseline and 55% (10 of 18) by week 16. In tofacitinib-naïve patients, the rate of endoscopic remission was 9% (2 of 23) at baseline and 48% (11 of 23) by week 16. There was no statistically significant difference in the proportion of patients in endoscopic remission at baseline (P=0.62) or week 16 (P=0.20).
Given the numbers of patients in clinical remission in both groups at baseline, we analyzed only the subset of patients with active disease at baseline. In tofacitinib-exposed patients with active disease at baseline, 63% (20 of 32) met criteria for clinical remission at week 8, increasing to 81% (26 of 32) by week 16. In tofacitinib-naïve patients with active disease at baseline, 79% (72 of 91) met criteria for clinical remission at week 8, increasing to 82% (75 of 91) by week 16 (Fig. 4).
At week 8, the tofacitinib-naïve patients had a significantly higher rate of clinical remission than those in the tofacitinib-exposed cohort (P=0.02). However, at week 16 there was no significant difference in rate of clinical remission (P=0.42) between both cohorts when restricting the analysis to those with disease activity at baseline.
7. Safety and AEs
AEs were seen in 30% (45 of 152) patients over the course of 16 weeks follow-up. Most common were acne (12%), rash (4%), and nasopharyngitis (4%). Two patients reported herpes zoster, neither having received varicella zoster vaccination. Both patients were young females, reported infection during the initial induction with 45 mg upadacitinib, both continued drug and one completed a 7-day course of concurrent antiviral therapy. There were no reports of drug interruption or discontinuation within the 16-week follow-up window. AEs were seen in 26% (11 of 42) of tofacitinib-exposed patients, none severe, compared with 31% (34 of 110) in the tofacitinib-naïve cohort (P=0.24). Serious AEs were reported in 3% (4 of 152) of patients, all requiring admission for intravenous corticosteroid for ASUC. These were not attributed by the treating clinicians to upadacitinib related side-effects. One patient underwent colectomy within the follow-up period after a lack of response to upadacitinib. There were no reported episodes of venous thromboembolism, major adverse cardiac events or malignancy.
We present the largest study focused on real-world outcomes of upadacitinib in UC. In keeping with prior real-world studies, rates of clinical remission seen in this cohort are significantly higher than observed in the clinical trials, even when excluding patients in remission at baseline who were commenced on upadacitinib for reasons other than active disease. At week 8 the clinical remission rates seen in the phase 3 induction trials were 26% to 33%, with other real-world studies demonstrating rates between 71% to 82%. In our cohort, clinical remission at week 8 was seen in 79% in all patients, and 75% in patients who had active disease at baseline. As expected, the observed corticosteroid-free clinical remission rate of 63% was only slightly lower than the overall remission rates in patients with active disease, indicating that the majority of patients in this relatively refractory cohort of UC patients were able to discontinue steroids. Our results confirm that upadacitinib is effective for induction of clinical remission, corticosteroid-free clinical remission, and clinical response in a real-world cohort of patients.
Differences in the rates of remission seen between clinical trials and our real-world data are likely related to several key factors. We used PRO-2 criteria to define clinical remission as recommended by the most recent STRIDE 2 guidelines, while the phase 3 induction studies used modified Mayo criteria with endoscopic subscore included. This lack of endoscopic data as a component of remission likely contributes to the higher reported rates of symptomatic remission in our study, as well as other real-world studies. In the patients in our cohort with endoscopic data baseline disease was moderate (UCEIS = 4, MES = 2), and the endoscopic remission rates (UCEIS ≤ 1) were high at 47% by week 16. We also noted a significant number of patients in clinical remission at baseline (23%), which reflects the practice pattern of clinicians switching therapies for reasons other than active disease including reduction of pill burden, medication intolerance, or safety considerations. Other differences relate to the uncontrolled nature of real-world practice, and potentially the tendency for patients enrolling in clinical trials to have a more complex or refractory disease phenotype.
Of particular interest, we saw no significant difference in clinical remission at week 8 or 16 in the overall cohort of patients with prior tofacitinib exposure compared to unexposed patients. However, when looking at patients with clinically active disease prior to commencing upadacitinib, patients with prior tofacitinib exposure had significantly lower rates of clinical remission at week 8, however, by 16 weeks post-induction remission rates were similar (81% vs. 82%). This supports the efficacy of upadacitinib for patients with prior tofacitinib exposure, and for patients with active disease despite tofacitinib use, extended induction with 45 mg dosing may be required. The tofacitinib exposed versus naïve cohorts differed significantly in some key aspects, primarily duration of disease (longer duration in tofacitinib exposed) and prior ADT exposure, with more ADT failures in the tofacitinib-exposed patients (including tofacitinib exposure). In patients in clinical remission on tofacitinib who were transitioned to upadacitinib, all patients maintained remission and AEs were consistent with the cohort as a whole. These data collectively provide reassurance that switching patients who have been previously exposed to tofacitinib, with or without a clinical response, results in high rates of clinical remission with no additional safety risks.
Tofacitinib has been used as salvage therapy for the most unwell UC patients with ASUC for a number of years. Case series have shown effectiveness when used in infliximab experienced patients or sequentially after failure of infliximab salvage therapy [8-10]. Upadacitinib now has emerging evidence to support its use in a similar cohort of patients [11,12]. Our study identifies a cohort of patients that may not benefit from this approach. The lower rate of clinical remission observed at week 8 in tofacitinib-exposed patients with active disease compared to tofacitinib naïve patients indicates a potentially slower speed of onset in tofacitinib-exposed patients, which is an important consideration in ASUC. Therefore, patients with past or recent tofacitinib exposure presenting with ASUC may not respond rapidly enough to derive benefit from upadacitinib salvage therapy.
Another cohort not included in clinical trials is patients with isolated proctitis, who we found responded equally well to those with more extensive disease distribution. While this may not be unexpected, it confirms clinical practice where refractory proctitis frequently requires and responds to initiation of advanced therapy, and provides reassurance to patients and clinicians using upadacitinib in this patient population.
While the clinical and endoscopic outcomes of upadacitinib have been well documented in this and other studies, the use of IUS in this cohort has not previously been examined. IUS plays a valuable role as an early noninvasive disease marker for induction of remission in UC [13], and has been shown to predict response in ASUC as early as 36 hours after commencing intravenous corticosteroids [14]. This is the first study to explore the IUS outcomes of patients with UC treated with upadacitinib. Our results show the effectiveness of upadacitinib for induction of transmural remission as early as week 8, sustained through 16 weeks of therapy. We observed complete concordance with endoscopic findings, suggesting IUS may be a viable and cost-effective investigation to confirm mucosal healing. Where available, IUS can provide a noninvasive and objective marker of disease activity at the point of care which correlates well with endoscopic features.
The rate of AEs seen in this real-world cohort is in keeping with the observed rates in the phase 3 induction trials. Acne, rash, and nasopharyngitis were most common, the majority being mild and self-limiting that did not require interruption of upadacitinib therapy. The rate of acne seen in our trial was higher than in the clinical trials. Among patients experiencing acne, 88% of these cases occurred within the first 8 weeks of therapy, and 93% of cases occurred with the higher 45 mg dose. No patients required cessation of therapy or admission to emergency or hospital for any AE. Most AEs were seen in patients on 45 mg daily dosing, although this did represent a majority of the exposure time in this cohort, and this dose dependent effect appears to be borne out in a number of other trials and real-world studies across indications. Significantly, we noted no cases of venous thromboembolism, cardiovascular events or malignancies which are of particular concern given the class-wide warning for JAK inhibitors, although the follow-up period in this study was relatively short.
There were several limitations in this real-world study. Due to its retrospective design, there is a risk of recall bias regarding patient inclusion, however, this is partially addressed by the inclusion of all consecutively treated patients from multiple centers. There is no control arm, again due to the project’s retrospective nature. While 13 sites throughout Australia were included, the majority were tertiary referral centers in major cities and patient demographics and prescribing patterns may not be representative of the entire country. Endoscopic and biochemical data is partial due to the real-world nature of the cohort, which may bias results towards the null as endoscopy or biochemical markers may be more likely to be ordered and completed in those with active clinical disease. The generalisability and significance of the endoscopic and sonographic data to the entire cohort may be limited by the fact that only 79 (53%) patients underwent baseline endoscopy within 1 month of upadacitinib induction and only 36 (24%) had complete IUS data. With only 16 weeks of follow-up available, treatment persistence and durability of response cannot be assessed. Furthermore, rare AEs are less likely to be captured given sample size and duration of follow-up.
In conclusion, upadacitinib is effective with an acceptable safety profile in this Australian real-world study of UC. Upadacitinib is equally effective for tofacitinib naïve or experienced patients, but may take up to 16 weeks to demonstrate full effectiveness in patients with prior tofacitinib exposure and active clinical symptoms at upadacitinib induction. Upadacitinib appears similarly effective in ADT naïve or experienced patients and in patients with isolated proctitis compared to more extensive disease. Upadacitinib resulted in transmural sonographic remission as early as week 8, sustained through week 16, with complete concordance with clinical remission.

Funding Source

The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

An YK reports grants from Janssen, during the conduct of the study; has received speaking and consulting fees from AbbVie, Bristol Myers Squibb, Celltrion, Chiesi, Dr Falk, Ferring, Janssen, Pfizer, Sandoz, Shire and Takeda; served on advisory boards member for AbbVie, Bristol Myers Squibb, Chiesi, Janssen, NPS Medicine wise; received research and educational funding from AbbVie, Celltrion, Dr Falk, Janssen, Pfizer, Sandoz and Takeda. Begun J has received speaking and consulting fees from AbbVie, Bristol Myers Squibb, Celltrion, Chiesi, Dr Falk, Ferring, Janssen, Pfizer, Sandoz, Shire, and Takeda; served on advisory boards member for AbbVie, Takeda, Ferring, Celltrion, Bristol Myers Squibb, Chiesi, Janssen, NPS Medicine wise, Anatara, Microba; received research and educational funding from AbbVie, Janssen, Pfizer, Ferring and Takeda. Segal J has received speaker fees for Takeda, Pfizer, Sandoz, BMS, Dr Falk. He has received conference fees from BMS, Takeda and Pfizer. Leong R reports advisory board membership, speakers fees or research grants with AbbVie, Aspen, Ferring, Hospira/Pfizer, Janssen, Takeda, Shire, Celgene, Dr Falk Pharma, Novartis, MSD, Chiesi, BMS, Glutagen, Celltrion, McKusker Charitable Foundation, Joanna Tiddy University of Sydney grant, MRFF, NHMRC. Lightowler D reports advisory board membership, speaker fees or research grants with AbbVie, Janssen, Eli-Lilly, Pfizer. Singh A has received speaker or consultancy fees from AbbVie, Takeda, Janssen, Pfizer and Dr Falk Pharma. Moore GT has received speaker or consultancy fees or advisory board fees for AbbVie, BMS, Celgene, Celltrion, Chiesi, Dr Falk Pharma, Eli-Lilly, Ferring, Janssen, MSD, Pfizer, Takeda and research support from CCA, The Gutsy Group and MRFF. Bryant R has received grant/research support/speaker fees from AbbVie, Ferring, Janssen, BMS, Shire, Takeda, Dr Falk Pharma, GSK and Emerge Health; and is a shareholder in Biomebank. Corte C has received grant/research support/speaker fees from Janssen, AbbVie, Chiesi, Takeda, Ferring, Falk and GESA.

Leong R 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

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Author Contributions

Conceptualization: Gilmore R, Fernandes R, Hartley I, Ding N, An YK, Begun J. Data curation: Gilmore R, Hartley I, Arzivian A, Andrew B, Greeve T, Kim S, Lightowler D, Mahy G, Mithanthaya A, Han S, West J, Corte C. Formal analysis: Gilmore R, Fernandes R, An YK, Begun J. Methodology: Gilmore R, Fernandes R, Hartley I, Ding N, An YK, Begun J. Project administration: Gilmore R, An YK, Begun J. Resources: Vasudevan A, Mahy G, Singh A, Leong R, Moore GT, Venugopaul K, Bryant R, Segal J, Christensen B, Corte C, Ding N, An YK, Segal J. Software: Gilmore R, Fernandes R, Begun J. Supervision: Vasudevan A, Mahy G, Singh A, Leong R, Moore GT, Venugopaul K, Bryant R, Segal J, Christensen B, Corte C, Ding N, An YK, Begun J. Validation: Vasudevan A, Mahy G, Singh A, Leong R, Moore GT, Venugopaul K, Bryant R, Segal J, Christensen B, Corte C. Visualization: Gilmore R, Fernandes R, Hartley I, Ding N, An YK, Begun J. Writing - original draft: Gilmore R, Fernandes R, An YK, Begun J. Writing - review & editing: all authors. Approval of final manuscript: all authors.

Fig. 1.
Clinical remission at baseline, week 8 and week 16.
ir-2024-00127f1.jpg
Fig. 2.
Clinical response at week 8 and week 16.
ir-2024-00127f2.jpg
Fig. 3.
Clinical remission at baseline, week 8, and week 16 stratified by prior tofacitinib exposure.
ir-2024-00127f3.jpg
Fig. 4.
Clinical remission at week 8 and week 16 stratified by prior tofacitinib exposure in those with active disease at baseline.
ir-2024-00127f4.jpg
Table 1.
Baseline Patient Demographics
Demographics Cohort (n = 152)
Female sex 61 (40)
Age at time of induction (yr), median (IQR) 38 (25–50)
Disease duration (yr), median (IQR) 8 (4–15)
Montreal classification (disease extent)
 E1 (proctitis) 21 (14)
 E2 (left-sided UC) 39 (25)
 E3 (extensive UC) 92 (61)
Montreal classification (disease severity)
 S1 (mild) 20 (13)
 S2 (moderate) 61 (40)
 S3 (severe) 71 (47)
History of extraintestinal manifestations 34 (22)
Prior ASUC 56 (37)
Current smoker 7 (5)
Advanced drug therapy naïve 22 (14)
No. of prior advanced drug therapies
 1 41 (27)
 2 46 (29)
 3 25 (17)
 ≥4 18 (13)
Prior advanced drug therapy
 Infliximab 90 (59)
 Vedolizumab 91 (60)
 Tofacitinib 42 (28)
 Adalimumab 35 (23)
Baseline concomitant medications
 Oral corticosteroid 30 (20)
 Oral 5-ASA 74 (49)

Values are presented as number (%) unless indicated otherwise.

IQR, interquartile range; UC, ulcerative colitis; ASUC, acute severe ulcerative colitis; 5-ASA, 5-aminosalicylate.

Table 2.
Primary and Secondary Outcomes
Primary and secondary outcomes Baseline Week 8 Week 16
Clinical response - 91/122 (75) 104/122 (85)
Clinical remission 30/152 (20) 120/152 (79) 128/152 (84)
Corticosteroid-free clinical remission - 40/64 (68) 53/64 (83)
Resolution of rectal bleeding - 82/100 (82) 84/100 (84)
Resolution of stool frequency - 82/132 (62) 94/132 (71)
Biochemical outcomes
 Biochemical remission 4/62 (6) 36/62 (58) 42/62 (68)
 CRP (mg/L), median (IQR) 6.0 (2.4-16.1) 1.3 (1.0–5.1) 1.7 (1.0-4.9)
 FC (μg/g), median (IQR) 626 (318-1381) 137 (35-488) 121 (43-588)
Intestinal ultrasound outcomes
 Transmural remission 1/36 (3) 23/36 (64) 29/36 (81)
 Bowel wall thickness (mm), median (IQR) 4.7 (4.0-5.5) 2.4 (2.0-3.9) 2.3 (1.9-2.9)
Clinical remission in tofacitinib experienced 10/42 (24) 30/42 (72) 36/42 (86)

Values are presented as number/number (%) unless indicated otherwise.

CRP, C-reactive protein; IQR, interquartile range; FC, fecal calprotectin.

Table 3.
Demographics Stratified by Tofacitinib Exposure
Demographics Tofacitinib exposed (n = 42) Tofacitinib naïve (n = 110) P-value
Female sex 16 (38) 45 (41) 0.39
Age at time of induction (yr), median (IQR) 38 (31–52) 37 (27–50) 0.47
Disease duration (yr), median (IQR) 10 (7–17) 7 (4–12) 0.04
Montreal classification (disease extent)
 E1 (proctitis) 7 (17) 14 (13) 0.20
 E2 (left-sided UC) 8 (19) 31 (27) 0.11
 E3 (extensive UC) 27 (64) 65 (59) 0.32
Montreal classification (disease severity)
 S1 (mild) 0 9 (8) 0.07
 S2 (moderate) 24 (57) 44 (40) 0.11
 S3 (severe) 18 (43) 57 (52) 0.13
Extraintestinal manifestations 8 (19) 26 (24) 0.23
Prior ASUC 14 (33) 42 (38) 0.27
Current smoker 3 (7) 4 (4) 0.26
No. of prior advanced drug therapies
 0 0 21 (19) < 0.01
 1 3 (7) 43 (39) < 0.01
 2 7 (17) 39 (35) < 0.01
 3 18 (43) 7 (6) < 0.01
 ≥4 14 (33) 2 (2) < 0.01
Prior advanced drug therapy
 Infliximab 30 (71) 60 (55) 0.07
 Vedolizumab 28 (67) 58 (53) 0.10
 Adalimumab 14 (33) 21 (19) 0.06
Baseline concomitant medications
 Oral corticosteroid 6 (14) 24 (22) 0.11
 Oral 5-ASA 20 (48) 57 (52) 0.31

Values are presented as number (%) unless indicated otherwise.

IQR, interquartile range; UC, ulcerative colitis; ASUC, acute severe ulcerative colitis; 5-ASA, 5-aminosalicylate.

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Figure & Data

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      Upadacitinib induction is effective and safe in ulcerative colitis patients including those with prior exposure to tofacitinib: a multicenter real-world cohort study
      Intest Res. 2025;23(3):347-357.   Published online December 20, 2024
      DOI: https://doi.org/10.5217/ir.2024.00127
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    Upadacitinib induction is effective and safe in ulcerative colitis patients including those with prior exposure to tofacitinib: a multicenter real-world cohort study
    Image Image Image Image
    Fig. 1. Clinical remission at baseline, week 8 and week 16.
    Fig. 2. Clinical response at week 8 and week 16.
    Fig. 3. Clinical remission at baseline, week 8, and week 16 stratified by prior tofacitinib exposure.
    Fig. 4. Clinical remission at week 8 and week 16 stratified by prior tofacitinib exposure in those with active disease at baseline.

    Fig. 1.

    Fig. 2.

    Fig. 3.

    Fig. 4.

    Upadacitinib induction is effective and safe in ulcerative colitis patients including those with prior exposure to tofacitinib: a multicenter real-world cohort study
    Demographics Cohort (n = 152)
    Female sex 61 (40)
    Age at time of induction (yr), median (IQR) 38 (25–50)
    Disease duration (yr), median (IQR) 8 (4–15)
    Montreal classification (disease extent)
     E1 (proctitis) 21 (14)
     E2 (left-sided UC) 39 (25)
     E3 (extensive UC) 92 (61)
    Montreal classification (disease severity)
     S1 (mild) 20 (13)
     S2 (moderate) 61 (40)
     S3 (severe) 71 (47)
    History of extraintestinal manifestations 34 (22)
    Prior ASUC 56 (37)
    Current smoker 7 (5)
    Advanced drug therapy naïve 22 (14)
    No. of prior advanced drug therapies
     1 41 (27)
     2 46 (29)
     3 25 (17)
     ≥4 18 (13)
    Prior advanced drug therapy
     Infliximab 90 (59)
     Vedolizumab 91 (60)
     Tofacitinib 42 (28)
     Adalimumab 35 (23)
    Baseline concomitant medications
     Oral corticosteroid 30 (20)
     Oral 5-ASA 74 (49)
    Primary and secondary outcomes Baseline Week 8 Week 16
    Clinical response - 91/122 (75) 104/122 (85)
    Clinical remission 30/152 (20) 120/152 (79) 128/152 (84)
    Corticosteroid-free clinical remission - 40/64 (68) 53/64 (83)
    Resolution of rectal bleeding - 82/100 (82) 84/100 (84)
    Resolution of stool frequency - 82/132 (62) 94/132 (71)
    Biochemical outcomes
     Biochemical remission 4/62 (6) 36/62 (58) 42/62 (68)
     CRP (mg/L), median (IQR) 6.0 (2.4-16.1) 1.3 (1.0–5.1) 1.7 (1.0-4.9)
     FC (μg/g), median (IQR) 626 (318-1381) 137 (35-488) 121 (43-588)
    Intestinal ultrasound outcomes
     Transmural remission 1/36 (3) 23/36 (64) 29/36 (81)
     Bowel wall thickness (mm), median (IQR) 4.7 (4.0-5.5) 2.4 (2.0-3.9) 2.3 (1.9-2.9)
    Clinical remission in tofacitinib experienced 10/42 (24) 30/42 (72) 36/42 (86)
    Demographics Tofacitinib exposed (n = 42) Tofacitinib naïve (n = 110) P-value
    Female sex 16 (38) 45 (41) 0.39
    Age at time of induction (yr), median (IQR) 38 (31–52) 37 (27–50) 0.47
    Disease duration (yr), median (IQR) 10 (7–17) 7 (4–12) 0.04
    Montreal classification (disease extent)
     E1 (proctitis) 7 (17) 14 (13) 0.20
     E2 (left-sided UC) 8 (19) 31 (27) 0.11
     E3 (extensive UC) 27 (64) 65 (59) 0.32
    Montreal classification (disease severity)
     S1 (mild) 0 9 (8) 0.07
     S2 (moderate) 24 (57) 44 (40) 0.11
     S3 (severe) 18 (43) 57 (52) 0.13
    Extraintestinal manifestations 8 (19) 26 (24) 0.23
    Prior ASUC 14 (33) 42 (38) 0.27
    Current smoker 3 (7) 4 (4) 0.26
    No. of prior advanced drug therapies
     0 0 21 (19) < 0.01
     1 3 (7) 43 (39) < 0.01
     2 7 (17) 39 (35) < 0.01
     3 18 (43) 7 (6) < 0.01
     ≥4 14 (33) 2 (2) < 0.01
    Prior advanced drug therapy
     Infliximab 30 (71) 60 (55) 0.07
     Vedolizumab 28 (67) 58 (53) 0.10
     Adalimumab 14 (33) 21 (19) 0.06
    Baseline concomitant medications
     Oral corticosteroid 6 (14) 24 (22) 0.11
     Oral 5-ASA 20 (48) 57 (52) 0.31
    Table 1. Baseline Patient Demographics

    Values are presented as number (%) unless indicated otherwise.

    IQR, interquartile range; UC, ulcerative colitis; ASUC, acute severe ulcerative colitis; 5-ASA, 5-aminosalicylate.

    Table 2. Primary and Secondary Outcomes

    Values are presented as number/number (%) unless indicated otherwise.

    CRP, C-reactive protein; IQR, interquartile range; FC, fecal calprotectin.

    Table 3. Demographics Stratified by Tofacitinib Exposure

    Values are presented as number (%) unless indicated otherwise.

    IQR, interquartile range; UC, ulcerative colitis; ASUC, acute severe ulcerative colitis; 5-ASA, 5-aminosalicylate.

    Table 1.

    Table 2.

    Table 3.

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