Abstract
Introduction
Upadacitinib and tofacitinib, oral Janus kinase inhibitors, have demonstrated efficacy and safety in ulcerative colitis (UC) in clinical trials. However, real-world comparative data are limited. We conducted a systematic review and meta-analysis of studies directly comparing upadacitinib to tofacitinib in UC management.
Methods
We conducted a systematic search of multiple databases through August 2025 for studies comparing upadacitinib and tofacitinib for UC management. The primary outcome was steroid-free clinical remission (SFCR) at weeks 8–14. Secondary outcomes included SFCR at later timepoints, clinical and endoscopic remission, biochemical remission, treatment discontinuation, colectomy, and safety. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using a random effects model. Heterogeneity was assessed using the I2% statistic.
Results
Ten retrospective studies with 2,021 patients (879 upadacitinib and 1,142 tofacitinib) were analyzed. Upadacitinib was associated with significantly higher SFCR at weeks 8–14 (OR 1.98; 95% CI: 1.32–3.97; I2 = 30%), 48–60 weeks (OR 2.32; 95% CI: 1.50–3.58; I2 = 0%), and at the end of study follow-up (OR 3.60; 95% CI: 1.73–3.92; I2 = 0%). Rates of endoscopic and biochemical remission did not differ significantly. Treatment discontinuation was less frequent with upadacitinib (OR 0.51; 95% CI: 0.34–0.77; I2 = 22%). Overall safety was comparable, except for higher odds of acne with upadacitinib (OR 4.30; 95% CI: 1.86–9.95; I2 = 0%).
Conclusion
Upadacitinib may be more effective than tofacitinib in achieving and sustaining SFCR, with better treatment persistence and similar overall safety. Larger, prospective head-to-head trials are needed to validate these findings.
Keywords: Inflammatory bowel disease, Ulcerative colitis, Biologics, Clinical pharmacology, Immunosuppression
Introduction
Ulcerative colitis (UC) incidence continues to rise globally, with the highest prevalence in North America and Europe and a rapidly increasing burden in Asia and other developing regions [1]. Traditional therapies, including aminosalicylates, corticosteroids, and immunomodulators, remain part of UC management but have limited long-term efficacy and safety [2, 3]. Furthermore, biologic therapies that target tumor necrosis factor (TNF) and interleukins are effective but can be limited by primary nonresponse, secondary loss of response, immunogenicity, and adverse events [3]. In this context, small-molecule therapies such as Janus kinase inhibitors (JAKi) have emerged as promising alternatives by exerting broad immunomodulatory effects with the advantage of oral administration and rapid onset of action [4, 5]. Tofacitinib a pan-JAKi with activity against JAK1 and JAK3 became the first JAKi approved for UC in 2018 [6].
Upadacitinib, a second-generation JAKi with preferential JAK1 selectivity, was approved in 2022 for UC after demonstrating robust efficacy randomized controlled trials (RCTs) [7]. Compared to tofacitinib, its selective JAK1 activity may enhance therapeutic potency while potentially mitigating off-target adverse events [8].
Although clinical trials confirm the efficacy of both agents, direct head-to-head randomized trials are lacking. Furthermore, real-world evidence (RWE), which reflects heterogeneous patient populations, varied treatment exposures, and pragmatic clinical practice patterns, remains sparse. Real-world comparative data are particularly important because UC patients often have long disease duration, multiple prior biologic exposures, and comorbidities not fully represented in RCTs. To address this critical knowledge gap, we conducted a systematic review and meta-analysis of studies directly comparing the efficacy of upadacitinib to tofacitinib in the management of UC.
Materials and Methods
Protocol and Registration
This meta-analysis adheres to the guidelines of the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement (online suppl. Table S1; for all online suppl. material, see https://doi.org/10.1159/000549088) [9]. The review protocol was registered on PROSPERO (CRD420251066256).
Eligibility Criteria
Studies and Participants
The eligible studies included prospective, retrospective, and cross-sectional observational studies directly comparing the clinical, endoscopic, and biochemical response and remission of UC in patients treated with upadacitinib and tofacitinib. The study population comprised adult patients with UC. Studies that only reported safety data or cost analysis, systematic reviews, review articles, single-arm studies, post hoc analyses, database studies, and case reports were excluded.
Primary and Secondary Outcomes
Assessment of clinical outcomes was based on the definitions provided by each study.
-
a.
Primary outcome: the primary outcome was steroid-free clinical remission (SFCR) at weeks 8–14. This time window was chosen as real-world observational studies often assess clinical outcomes at variable timepoints due to differences in clinical follow-up schedules and data availability outside of controlled trial settings [10]. When studies reported SFCR at multiple intervals within that window, the timepoint closest to 8 weeks was chosen to reflect the timepoint used to assess induction in published clinical trials [5, 6]. Subgroup analysis was performed excluding abstracts.
-
b.
Secondary outcomes: the secondary outcomes included other clinical endpoints reported by three or more studies. These comprised SFCR at 48–60 weeks, clinical remission, clinical response, biochemical remission, endoscopic remission, treatment discontinuation, safety, and colectomy rates. Adverse events were pooled as the number of participants with ≥1 event, regardless of event count.
Data Sources and Search Strategy
A systematic search was conducted in PubMed, Web of Science, EMBASE, Cochrane, and Scopus through August 19, 2025. When studies had overlapping cohorts, the study with larger and more updated data was included. To ensure a comprehensive and inclusive search strategy, we used the following key terms across the databases: “ulcerative colitis” (as medical subject heading and as free-text term) combined using the Boolean operator “AND” with “Upadacitinib” and “tofacitinib.” No language or date restrictions were used (Supplement). Two investigators, T.A. and M.E., independently screened citations. Initially, the titles and abstracts were screened for potential eligibility, followed by evaluation of full texts of publications for final inclusion. Discrepancies in article screening decisions were resolved through a discussion between the two authors, and any disagreements were resolved by a third author (A.M.). Conference abstracts were included if they provided adequate data, and non-English articles were translated and reviewed.
Data Extraction and Quality Assessment
Data were extracted into a standardized extraction form by two independent investigators, T.A. and M.E., with a third investigator, A.M., resolving discrepancies. We collected data from each eligible study, including the author’s name, publication year, country, type of publication, study design, number of patients, demographics, UC characteristics, prior advanced treatments, current steroid use, and clinical outcomes. Data from propensity score-matched cohorts were used when available. The Newcastle-Ottawa Scale (NOS), a critical appraisal tool consisting of eight domains with a total score of 0–9 stars, was used. Studies were classified by risk of bias: low (7–9 stars), moderate (4–6 stars), and high (0–3 stars) [11].
Statistical Analysis
Data from each study were pooled to calculate the effect sizes for outcomes using the Mantel-Haenszel random effects meta-analysis model [12]. Outcomes were expressed as odds ratios (OR) with 95% confidence intervals (CI) and depicted in forest plots. The I2 statistics was used to assess study heterogeneity as per the Cochrane Handbook guidelines: 0–40% indicates low importance, 30–60% moderate heterogeneity, 50–90% substantial heterogeneity, and 75–100% considerable heterogeneity [13]. The variability in effect estimates due to heterogeneity was evaluated with the Cochrane Q test, with a p value <0.10 considered statistically significant. For outcomes reported in nine or more studies, publication bias was assessed using Egger weighted regression, with a p value <0.05 indicating bias. To assess the reliability of our findings, a sensitivity analysis was performed to assess the impact of each study on the cumulative effect size for the primary endpoint. Age and follow-up times provided by authors as median and interquartile ranges were converted into means and standard deviations [14]. The mean follow-up time was calculated as the mean of means. We considered a p value of 0.05 or lower as statistically significant unless otherwise stated. The meta-analysis was performed using Review Manager 5.4 [15].
Results
Search Results and Population Characteristics
Our search resulted in 1,367 citations across the five databases. Following the removal of 737 duplicate records, the titles and abstracts of the remaining 630 records were screened. Finally, the full texts of 51 citations were evaluated, yielding a total of 10 studies eligible for inclusion in this systematic review (Fig. 1) [16–25].
Fig. 1.
PRISMA flowchart of systematic review process. “Other (n = 4)” included one study of pouchitis patients, a study of Crohn’s disease, a database study, and a post hoc analysis.
A total of 2,021 patients were included across the two cohorts. The upadacitinib cohort had 879 patients, 39.6% female, with a mean age of 39.1 years. Similarly, the tofacitinib cohort had 1,149 patients, 44.3% female, with a mean age of 39.5 years. At baseline, clinical features showed slight imbalances. The mean UC duration was longer with upadacitinib (12.6 vs. 10.1 years), and pancolitis was more frequent (64.1% vs. 60.1%). On the other hand, prior biologic exposure (84.7% vs. 80.7%) and baseline steroid use (33.7% vs. 28.0%) were more common with tofacitinib. The mean follow-up differed significantly, with 45.1 weeks for upadacitinib and 81.5 weeks for tofacitinib. Further details of the population characteristics are summarized in Tables 1 and 2.
Table 1.
Characteristics of included studies and patient demographics
| Study | Design | Location | Patients, n | Females, n (%) | Mean age | Smokers (%) | Mean LFU, weeks | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| UPA | TOF | UPA | TOF | UPA | TOF | UPA | TOF | UPA | TOF | |||
| Akiyam et al. [16] (2025) | Retrospective | Japan | 228 | 159 | 83 (36) | 66 (42) | 41.74 | 41.35 | 31 (16) | 6 (3.8) | 59.8 | 133.7 |
| Multicenter | ||||||||||||
| Dalal et al. [17] (2024) | Retrospective | USA | 81 | 74 | 38 (47) | 43 (58) | 41.32 | 43.74 | 1 (1) | 1 (1) | 52 | |
| Multicenter | ||||||||||||
| Osty et al. [18] (2025) | Retrospective | International | 105 | 10 | 39 (37) | 2 (20) | 39.14 | 34.9 | 5 (4.8) | 2 (20) | 36.28 | |
| Multicenter | ||||||||||||
| Al-Zarrad et al. [19] (2024) | Retrospective | UK | 22 | 15 | 6 (27.3) | 5 (33.3) | NA | NA | NA | NA | 8 to 12 | |
| Single center | ||||||||||||
| Bertin et al. [20] (2025) | Retrospective | Italy | 13 | 23 | NA | NA | 34.5 | 44.87 | 1 (7.7) | 1 (6.7) | 52.1 | |
| Single center | ||||||||||||
| Chaparro et al. [21] (2025) | Retrospective | Spain | 168 | 369 | 71 (42) | 166 (45) | 45.92 | 43.15 | 45 (27) | 82 (22) | 47.1 | 124.1 |
| Multicenter | ||||||||||||
| Farkas et al. [22] (2025) | Retrospective | International | 104 | 246 | 42 (40.4) | 103 (41.9) | 39.3 | 38.3 | NA | NA | 12 | |
| Multicenter | ||||||||||||
| Kumar et al. [23] (2025) | Retrospective | UK | 70 | 149 | 26 (37.1) | 73 (49) | NA | NA | 1 (0.7) | 1 (1.4) | 26.1 | |
| Multicenter | ||||||||||||
| Baranova et al. [24] (2025) | Retrospective | Russia | 37 | 37 | 12 (32) | 18 (49) | 34 | 30.6 | NA | NA | 56 | 56 |
| Single center | ||||||||||||
| Honap et al. [25] (2025) | Retrospective | International | 51 | 60 | 26 (51) | 20 (33) | 36.7 | 39.4 | NA | NA | 31.3 | 171.9 |
| Multicenter | ||||||||||||
| Total | 879 | 1,142 | 343/866 (39.6) | 496/1,119 (44.3) | 39.1 | 39.5 | 84/665 (12.6) | 93/784 (11.9) | 45.1 | 81.5 | ||
LFU, length of follow-up; UPA, upadacitinib; TOF, tofacitinib.
Table 2.
Baseline disease characteristics of the upadacitinib and tofacitinib cohorts in the individual studies
| Study | Mean UC duration, years | Extension Montreal classification, n (%) | Prior biologic treatment, n (%) | Current steroids (%) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| E1 | E2 | E3 | any biologic | = 1 biologic | ≥2 biologic | anti-TNF | VED | UST | JAKi | |||
| Akiyam et al. [16] (2025) | UPA: 8.95 | UPA: 52 (23) | UPA: 176 (77) | UPA: 188 (82) | UPA: 67 (29) | UPA: 121 (53) | UPA: 132 (58) | UPA: 52 (23) | UPA: 69 (30) | UPA: 106 (46) | UPA: 37 (16) | |
| TOF: 9.69 | TOF: 55 (35) | TOF: 104 (65) | TOF: 124 (78) | TOF: 70 (44) | TOF: 54 (33.5) | TOF: 120 (75) | TOF: 20 (13) | TOF: 1 (0.6) | TOF: 0 (0) | TOF: 45 (28.3) | ||
| Dalal et al. [17] (2024) | UPA: 11.61 | NA | UPA: 61 (75) | NA | NA | NA | UPA: 73 (90) | UPA: 60 (74) | UPA: 25 (31) | UPA: 24 (30) | UPA: 45 (56) | |
| TOF: 12.29 | TOF: 61 (82) | TOF: 68 (92) | TOF: 44 (59) | TOF: 6 (8) | TOF: 0 (0) | TOF: 39 (53) | ||||||
| Osty et al. [18] (2025) | UPA: 10.12 | UPA: 4 (3) | UPA: 42 (40) | UPA: 57 (54) | NA | NA | UPA: 99 (94) | UPA – IFX: 92 (88); ADA: 56 (53); GOL: 25 (24) | UPA: 89 (85) | UPA: 74 (71) | UPA: 105 (100) | UPA: 31 (29.5) |
| TOF: 10.59 | TOF: 1 (10) | TOF: 6 (60) | TOF: 3 (30) | TOF: 9 (90) | TOF – IFX: 7 (70); ADA: 4 (4); GOL: 1 (10) | TOF: 9 (90) | TOF: 6 (60) | TOF: 10 (100) | TOF: 2 (20) | |||
| Al-Zarrad et al. [19] (2024) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| Bertin et al. [20] (2025) | NA | UPA: 4 (25) | UPA: 1 (6.25) | UPA: 11 (68.7) | UPA: 16 (100) | NA | NA | UPA – IFX: 13 (81.25); ADA: 6 (37.5) | UPA: 11 (68.7) | UPA: 8 (50) | NA | NA |
| TOF: 7 (30.4) | TOF: 5 (21.7) | TOF: 14 (60.8) | TOF: 22 (95.6) | TOF – IFX: 21 (91.3); ADA: 8 (34.8) | TOF: 16 (69.6) | TOF: 9 (39.1) | ||||||
| Chaparro et al. [21] (2025) | NA | UPA: 5 (2.9) | UPA: 68 (40) | UPA: 95 (57) | NA | NA | NA | UPA: 153 (91) | UPA: 89 (51) | UPA: 89 (53) | UPA: 80 (48) | UPA: 21 (13) |
| TOF: 17 (4.6) | TOF: 133 (36) | TOF: 217 (59) | TOF: 346 (94) | TOF: 147 (40) | TOF: 71 (19) | TOF: 2 (0.5) | TOF: 64 (17) | |||||
| Farkas et al. [22] (2025) | UPA: 10.2 | UPA: 4 (3.8) | UPA: 32 (30.8) | UPA: 68 (65.4) | NA | NA | NA | NA | NA | NA | UPA: 47 (45.2) | UPA: 47 (45.2) |
| TOF: 8.9 | TOF: 6 (2.4) | TOF: 82 (33.3) | TOF: 158 (64.2) | TOF: 0 (0) | TOF: 141 (57.3) | |||||||
| Kumar et al. [23] (2025) | NA | UPA: 7 (10) | UPA: 34 (48.6) | UPA: 26 (37.1) | UPA: 56 (80) | UPA: 28 (40) | UPA: 28 (40) | NA | NA | NA | NA | NA |
| TOF: 12 (8.1) | TOF: 64 (43) | TOF: 72 (48.3) | TOF: 129 (86.6) | TOF: 67 (45) | TOF: 62 (41.6) | |||||||
| Baranova et al. [24] (2025) | NA | UPA: 5 (14) | UPA: 32 (86) | UPA: 21 (57) | UPA: 13 (35) | UPA: 5 (14) | NA | UPA: 12 (32) | UPA: 1 (2.7) | UPA: 5 (14) | UPA: 14 (38) | |
| TOF: 8 (22) | TOF: 29 (78) | TOF: 20 (54) | TOF: 13 (35) | TOF: 7 (19) | TOF: 2 (5.4) | TOF: 0 (0) | TOF: 0 (0) | TOF: 12 (32) | ||||
| Honap et al. [25] (2025) | UPA: 16.3 | NA | UPA: 51 (100) | NA | NA | NA | UPA: 39 (76) | UPA: 25 (49) | UPA: 18 (35) | UPA: 9 (18) | UPA: 22 (43) | |
| TOF: 8.8 | TOF: 58 (97) | TOF: 54 (90) | TOF: 38 (63) | TOF: 13 (22) | TOF: 5 (8) | TOF: 19 (32) | ||||||
| Total | UPA: 12.59 | UPA: 24/460 (5.2) | UPA: 177/460 (38.5) | UPA: 465/725 (64.1) | UPA: 281/348 (80.7) | UPA: 108/335 (32.2) | UPA: 253/440 (57.5) | UPA: 397/528 (75.2) | UPA: 338/683 (49.5) | UPA: 284/683 (41.6) | UPA: 376/774 (48.6) | UPA: 217/774 (28) |
| TOF: 10.05 | TOF: 43/797 (5.4) | TOF: 290/797 (36.4) | TOF: 597/993 (60.1) | TOF: 312/368 (84.7) | TOF: 140/345 (40.6) | TOF: 132/355 (37.1) | TOF: 588/662 (88.8) | TOF: 276/732 (37.7) | TOF: 106/732 (14.4) | TOF: 17/955 (1.7) | TOF: 322/955 (33.7) | |
UC, ulcerative colitis; UPA, upadacitinib; TOF, tofacitinib; TNF, Tumor necrosis factor; VED, vedolizumab; UST, Ustekinumab; JAKi, Janus kinase inhibitor; IFX, infliximab; ADA, adalimumab; GOL, golimumab.
Characteristics and Quality of Included Studies
The ten included studies comprised of five journal articles and five conference abstracts, all of which were retrospective in design. With regard to the setting, seven studies were multicenter, while three were single center. Geographically, three studies were international, two were in the UK and one was in the USA, Japan, Spain, Russia, and Italy. There was a moderate variation in the reporting and consistency of outcome definition, summarized in online supplementary Tables S2 and S3. According to the Newcastle-Ottawa Scale (NOS), the risk of bias was low in eight studies and moderate in two (online suppl. Table S4).
Meta-Analysis Outcomes
Primary Outcome: SFCR (8–14 Weeks)
A total of five studies (780 patients) reported on SFCR between weeks 8 and 14 of follow-up. Upadacitinib was given to 367 patients, while 413 patients received tofacitinib. The pooled OR of SFCR at weeks 8–14 was 1.98 (95% CI: 1.32–3.97; I2 = 30%) when comparing upadacitinib to tofacitinib (Fig. 2a) [16–18, 22, 25].
Fig. 2.
Forest plots displaying the pooled OR of SFCR at 8–14 weeks (a), 48–60 weeks (b), and the end of study follow-up (c) in UC patients taking upadacitinib compared to tofacitinib.
Secondary Outcomes
-
a.
SFCR (48–60 weeks): similarly, there was a statistically significant increase in the odds of SFCR during the maintenance period (48–60 weeks) in the upadacitinib group compared to the tofacitinib group (OR 2.32; 95% CI: 1.50–3.58; I2 = 0%) [3 studies; 519 patients] (Fig. 2b) [16, 17, 21]. The odds of SFCR at the end of study follow-up were also significantly higher in the upadacitinib group compared to the tofacitinib group (OR 3.60; 95% CI: 1.73–3.92; I2 = 0%) [6 studies; 910 patients] (Fig. 2c) [16–18, 21, 22, 25].
-
b.
Clinical remission: the odds of clinical remission was significantly higher in the upadacitinib group compared to the tofacitinib group at 8–14 weeks (OR 1.77; 95% CI: 1.18–2.66; I2 = 32%) [6 studies; 903 patients] (Fig. 3a) [16, 18, 19, 22, 23, 25] but not at the end of study follow-up (OR 1.71; 95% CI: 0.92–3.16; I2 = 68%) [7 studies; 949 patients] (Fig. 3b) [16, 18–20, 22, 23, 25].
-
c.
Clinical response: there was no significant difference in odds of the clinical response between the two cohorts at 8–14 weeks (OR 1.14; 95% CI: 0.73–1.77; I2 = 0%) [5 studies, 569 patients] (Fig. 3c) [16, 18, 19, 23, 25] or end of study follow-up (OR 1.85; 95% CI: 0.87–3.92; I2 = 61%) [5 studies; 569 patients] (Fig. 3d) [16, 18, 19, 23, 25].
-
d.
Endoscopic remission: three studies, including 96 patients, reported rates of endoscopic remission at follow-up. There was no statistically significant difference in the odds between the upadacitinib and tofacitinib cohorts (OR 1.07; 95% CI: 0.36–3.17; I2 = 49%) (Fig. 4a) [17, 20, 24].
-
e.
Biochemical remission: at the end of the study follow-up, there was no statistically significant difference in the pooled odds of biochemical remission between the two groups (OR 1.18; 95%: 0.39–3.60; I2 = 44%) [3 studies; 389 patients] (Fig. 4b) [19, 20, 22].
-
f.
Discontinuation: by the end of study follow-up, patients taking upadacitinib had significantly lower odds of drug discontinuation compared to patients taking tofacitinib (OR 0.51; 95% CI: 0.34–0.77; I2 = 22%) [8 studies; 823 patients] (Fig. 4c) [16–21, 24, 25].
-
g.
Colectomy: there was a nonsignificant trend toward fewer colectomies in the upadacitinib cohort at the end of study follow-up (OR 0.70; 95% CI: 0.39–1.28; I2 = 0%) [6 studies; 1,071 patients] (Fig. 4d) [16, 17, 22–25].
-
h.
Safety: no significant difference in the odds of adverse events was observed (OR 1.16; 95% CI: 0.81–1.66; I2 = 0%) [17, 18, 20, 21, 24, 25]. There was a significantly higher odds of acne in the upadacitinib cohort (OR 4.30; 95% CI: 1.86–9.95; I2 = 0%) [4 studies; 560 patients] [16–19, 25]. However, there was no significant difference in odds of infections, shingles, dyslipidemia, or venous thromboembolism between the two groups (Fig. 5).
Fig. 3.
Forest plots displaying the pooled OR of clinical remission at 8–14 weeks (a), clinical remission at the end of study follow-up (b), clinical response at 8–14 weeks (c), and clinical response at the end of study follow-up (d) in UC patients taking upadacitinib compared to tofacitinib.
Fig. 4.
Forest plots displaying the pooled OR of endoscopic remission (a), biochemical remission (b), drug discontinuation (c), and colectomy (d) at the end of study follow-up in UC patients taking upadacitinib compared to tofacitinib.
Fig. 5.
Forest plots of the pooled OR of any adverse events (a), acne (b), infections (c), shingles (d), dyslipidemia (e), and venous thromboembolism (f) in UC patients taking upadacitinib compared to tofacitinib.
Validation of Meta-Analysis
Sensitivity and Subgroup Analyses
Sensitivity Analysis
Leave-one-out sensitivity analysis revealed that the odds of SFCR in upadacitinib in the cohort remained significantly higher than in tofacitinib across the three timepoints with individual study exclusion, highlighting the robustness of the pooled estimate (online suppl. Fig. S1) [16–18, 21, 22, 25].
Subgroup Analysis
Subgroup analysis that only included journal articles still showed significantly higher odds of SFCR with upadacitinib at weeks 8–14 (OR 1.60; 95% CI: 1.05–2.45; I2 = 0%) [4 studies; 430 patients] [16–18, 25] and end of study follow-up (OR 2.17; 95% CI: 1.13–4.20; I2 = 51%) [4 studies; n = 439] (online suppl. Fig. S2) [16–18, 25]. To address the difference in mean follow-up, a subgroup analysis of studies with similar follow-up was conducted for discontinuation and colectomy. The pooled odds of discontinuation remained significantly lower in the upadacitinib group (OR 0.39; 95% CI 0.22–0.69; I2 = 16%) [17–20, 24]. Furthermore, there was still a nonsignificant trend toward fewer colectomies in the upadacitinib group (OR 0.44; 95% CI 0.19–1.05; I2 = 0%) (online suppl. Fig. S3) [17, 22–24].
Heterogeneity
The variation of the pooled estimates was assessed using CI and I2 percentage values. For most pooled estimates, including the primary endpoint, the overall distribution of effects was low based on the 95% CI and I2% values.
Publication Bias and Quality of Evidence
All outcomes were reported by fewer than ten studies, precluding a formal assessment of publication bias. Furthermore, a formal assessment of the certainty of evidence was deferred due to the retrospective design of all included studies.
Discussion
This systematic review and meta-analysis provides the first comprehensive synthesis of RWE directly comparing upadacitinib and tofacitinib for the treatment of UC. Across more than 2,000 patients, our findings demonstrate that upadacitinib is consistently associated with higher rates of SFCR during both induction and maintenance, reduced treatment discontinuation, and similar overall safety compared with tofacitinib. These results, while constrained by retrospective data and limited objective endpoints, suggest a potential advantage of upadacitinib for UC management in routine clinical practice.
Upadacitinib’s superiority in achieving SFCR is supported by its significantly higher odds of early clinical remission, along with nonsignificant trends toward higher clinical response and late clinical remission. The consistency of these outcomes increases confidence in the findings. Treatment persistence was also significantly higher with upadacitinib, aligning with individual real-world studies from Japan, Europe, and the USA [26, 27]. Taken together, these findings suggest that patients treated with upadacitinib are more likely to achieve and maintain remission and less likely to discontinue therapy, outcomes that are particularly meaningful in the context of our population, which was largely biologic experienced and suffering from extensive disease.
The observed efficacy advantage of upadacitinib may be attributable to its preferential inhibition of JAK1. JAK1 mediates signaling for multiple cytokines integral to UC pathogenesis, including interleukin-6, interleukin-12, and interleukin-23 [28]. By selectively targeting JAK1 while sparing JAK3 and JAK2 to some extent, upadacitinib may deliver more focused immunosuppression with fewer off-target effects. This contrasts with tofacitinib’s broader but less selective inhibition, which may dilute its potency against the key cytokines driving UC inflammation. Supporting this pharmacologic rationale, small case series have shown clinical benefit with upadacitinib in patients who previously failed tofacitinib [29]. Aligning with these observations, nearly half of the upadacitinib cohort in our patient population had prior JAK exposure, yet they still achieved favorable outcomes.
The implications of these findings are significant for clinical practice. Both the American Gastroenterological Association (AGA) and the British Society of Gastroenterology (BSG) designate JAKis as high-efficacy options for biologic-experienced patients. However, the BSG guidelines emphasize greater certainty of evidence for upadacitinib, which aligns with our pooled data [8, 30]. By demonstrating superior SFCR and treatment persistence without increased overall safety risks, our results provide practical evidence to support preferential use of upadacitinib in many patients, particularly those with extensive disease, prior biologic failure, or the need for rapid induction of remission.
Importantly, the overall safety profile was similar between agents, including rates of infections, shingles, and dyslipidemia. While JAKi use has been associated with major adverse cardiovascular events and malignancy, it is encouraging that no such events were observed across the ten studies [31]. However, this likely reflects short follow-up and small samples of the included studies rather than the absence of risk. The one notable difference was a higher incidence of acne with upadacitinib, a finding consistently reported in RCTs and real-world cohorts [26, 32]. Although acne is typically mild and manageable, it may affect the quality of life and adherence, particularly among younger patients. Clinicians should proactively counsel patients on this side effect and offer supportive dermatologic management when needed.
Although our pooled analysis suggests no major safety differences, caution is warranted. Several studies from Japan have reported higher rates of adverse events with upadacitinib than with tofacitinib [26, 33]. Moreover, the long-term risks of JAKis, including cardiovascular events, malignancy, and venous thromboembolism, remain under active investigation. Continuous pharmacovigilance and registry-based monitoring will be essential as the use of these agents expands.
This analysis has several strengths. It directly compares two JAKis from the same pharmacologic class, addressing a key clinical question not answered by head-to-head RCTs. It synthesizes data from more than 2,000 patients across multiple countries, increasing generalizability. Robust sensitivity and subgroup analyses confirmed the stability of findings. Most included studies were rated at low risk of bias. Studies were conducted across multiple countries on three continents, which enhances generalizability. Finally, baseline characteristics were similar between cohorts for age, sex, disease extent, disease duration, and prior therapies, which reduces confounding.
Nonetheless, several limitations merit consideration. All included studies were retrospective, introducing the potential for residual confounding and selection bias inherent to this study design. Five were available only as conference abstracts, limiting detail and peer-review validation. Additionally, the small number of studies prevented formal testing for publication bias. Consequently, small‐study effects, selective reporting, or nonpublication of null results may have influenced the pooled estimates. The heterogeneity in follow-up duration, substantially shorter for upadacitinib, may bias discontinuation and colectomy outcomes. Furthermore, the use of a time range for the primary endpoint introduces between-study variation. However, it reflects inconsistent follow-up in real-world cohorts and allows inclusion of more studies, improving statistical power. In addition, the limited reporting of endoscopic and biochemical outcomes, as well as the absence of histological data, precluded robust conclusions regarding objective mucosal healing. We were also unable to test concordance across clinical, endoscopic, biochemical, and histological endpoints in a sensitivity analysis. Finally, differences in outcome definitions, the lack of reporting of dosing regimens, treatment sequencing, and baseline disease activity across studies may contribute to variability in outcomes. The primary endpoint, SFCR, may be affected by baseline steroid use (28.0% with upadacitinib vs. 33.7% with tofacitinib). In a sensitivity analysis excluding Farkas et al. (45.2% vs. 57.3%), where the remaining studies had similar baseline steroid use, the pooled SFCR OR at 8–14 weeks fell from 1.98 (p = 0.001) to 1.60 (p = 0.03) but remained statistically significant.
In summary, this systematic review and meta-analysis of emerging RWE suggests that upadacitinib may be more effective than tofacitinib for inducing and maintaining SFCR in UC, with higher treatment persistence and comparable overall safety. Although acne is more frequent with upadacitinib, it is generally mild and manageable. These findings support the positioning of upadacitinib as a preferred JAKi for many patients with moderate-to-severe UC, particularly those with refractory disease. However, the absence of head-to-head RCTs highlights the need for prospective comparative studies to assess both biologic-naïve and biologic-exposed populations. These studies should incorporate standardized definitions of remission, consistent timepoints, and robust evaluation of endoscopic and histological outcomes. Cost-effectiveness analyses and patient-reported outcomes, including quality of life and work productivity, are also critical to fully capture the value of these therapies. Finally, biomarker-driven studies may help identify predictors of response, guiding more personalized treatment strategies.
Statement of Ethics
This is a meta-analysis of studies already published and with data that are available for public view. Hence, ethical approval was not required for this study.
Conflict of Interest Statement
Dr. Jennifer Seminerio reports consulting fees from AbbVie, Johnson & Johnson, Bristol-Myers Squibb, Takeda Pharmaceuticals, Inc., and Eli Lilly and Company. The other authors have no conflicts of interest to declare.
Funding Sources
The authors received no financial support for the research, authorship, and/or publication of this article.
Author Contributions
Tareq Alsaleh: study conceptualization, data collection, formal analysis, data interpretation, and manuscript preparation. Abdul Mohammed and Aimen Farooq: data interpretation, manuscript preparation, and supervision. Magda Elamin, Amr Akl, Karim Mohamed Yassin, and Ahmed Elnaggar: data collection, formal analysis, and manuscript editing. Jennifer Seminerio: methodology, data review, supervision, and manuscript preparation.
Funding Statement
The authors received no financial support for the research, authorship, and/or publication of this article.
Data Availability Statement
This work is a systematic review and meta-analysis of previously published observational studies. All data analyzed were obtained from peer-reviewed articles, and no new raw data was generated. The manuscript and supplementary materials contain the complete list of included studies and the extracted datasets. Additional details are available from the corresponding author upon reasonable request.
Supplementary Material.
Supplementary Material.
Supplementary Material.
Supplementary Material.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
This work is a systematic review and meta-analysis of previously published observational studies. All data analyzed were obtained from peer-reviewed articles, and no new raw data was generated. The manuscript and supplementary materials contain the complete list of included studies and the extracted datasets. Additional details are available from the corresponding author upon reasonable request.