Upadacitinib After Advanced-Therapy Failure in Ulcerative Colitis: What Real-World TRIDENT-UC Data Suggest

For gastroenterologists treating moderate-to-severe ulcerative colitis, the first advanced therapy is often only the beginning of a longer therapeutic sequence. A patient may lose response to an anti-TNF agent, fail to achieve steroid-free remission on a biologic, or require a mechanistically different option after persistent inflammation. The clinical question then becomes practical and difficult: after one advanced therapy has failed, which next treatment is most likely to deliver steroid-free remission without adding unacceptable risk?

A real-world multicenter study now provides useful comparative data for that exact scenario. The study, summarized by GI & Hepatology News on August 28, 2026, evaluated outcomes with upadacitinib, tofacitinib, and ustekinumab in adults with moderate-to-severe ulcerative colitis who had experienced failure of at least one prior advanced therapy. The original retrospective study was published in Clinical Gastroenterology and Hepatology and is referred to in the news report as the TRIDENT-UC study.

The headline finding was that upadacitinib was associated with higher rates of steroid-free clinical remission at both week 16 and week 52 compared with tofacitinib or ustekinumab. However, the interpretation requires caution. TRIDENT-UC was retrospective, conducted in Portuguese centers, and had more missing longer-term biochemical and endoscopic data at week 52. The study provides clinically relevant real-world comparative evidence, but it does not prove that upadacitinib should universally replace other options after advanced-therapy failure.

The sequencing problem in modern UC care

The treatment landscape for ulcerative colitis has expanded substantially, but the sequencing question remains unsettled. Clinicians now choose among biologics and small molecules with different mechanisms, speeds of onset, safety considerations, monitoring requirements, pregnancy implications, and access barriers. This is especially challenging after the first advanced therapy fails, because trial populations, regulatory labels, and real-world patient characteristics do not always align neatly.

The TRIDENT-UC investigators framed this issue directly. According to the GI & Hepatology News report, co-first and corresponding author Joana Camões Neves, MD, stated that treatment sequencing after failure of an advanced therapy remains a major challenge in ulcerative colitis, and that TRIDENT-UC offers real-world comparative data that may help clinicians make more informed treatment decisions.

This framing is important. The study is not asking whether upadacitinib works in UC in isolation. It asks a more practice-facing question: among patients who have already failed at least one advanced therapy, how do outcomes appear when clinicians use upadacitinib, tofacitinib, or ustekinumab in real-world care?

What TRIDENT-UC investigated

TRIDENT-UC was a retrospective multicenter real-world study involving 312 adults with moderate-to-severe ulcerative colitis treated at nine centers in Portugal. All included patients had experienced failure of at least one previous advanced therapy. The treatment groups were not equal in size: 103 patients received upadacitinib, 74 received tofacitinib, and 135 received ustekinumab.

The primary outcome was steroid-free clinical remission at weeks 16 and 52. Steroid-free clinical remission was defined as a Patient-Reported Outcome-2 score of 0 while off corticosteroids for at least 30 days at week 16 and at least 90 days at week 52. Secondary outcomes included biochemical remission, defined as fecal calprotectin of 250 µg/g or less, and endoscopic remission, defined as a Mayo endoscopic subscore of 0.

These endpoints are clinically meaningful because they move beyond symptom improvement alone. In UC, steroid-free remission is a practical marker of treatment success, while fecal calprotectin and endoscopic remission help clinicians assess inflammatory control more directly. Still, because this was a retrospective study, the availability and timing of objective assessments were not as controlled as in a prospective randomized trial.

Steroid-free remission: the central signal

At week 16, 48% of patients receiving upadacitinib achieved remission without steroids, compared with 27% of patients receiving tofacitinib and 27% receiving ustekinumab. Among patients with evaluable data at week 52, steroid-free remission rates were 75% with upadacitinib, 52% with tofacitinib, and 53% with ustekinumab.

After adjustment for baseline differences between treatment groups, upadacitinib remained associated with higher odds of steroid-free remission. Compared with tofacitinib, the adjusted odds ratio was 2.56 at week 16 and 3.14 at week 52. Compared with ustekinumab, the adjusted odds ratio was 3.71 at week 16 and 4.68 at week 52. There was no significant difference between tofacitinib and ustekinumab.

Clinically, this is the most important finding. For patients who have already failed an advanced therapy, steroid-free remission is a meaningful therapeutic goal. Persistent corticosteroid exposure remains undesirable because it reflects uncontrolled disease and carries cumulative toxicity. The TRIDENT-UC data suggest that upadacitinib may offer a higher likelihood of achieving this target in a treatment-experienced UC population.

However, the word associated is essential. The study was not randomized. Treatment selection may have been influenced by disease severity, comorbidities, physician preference, timing of drug availability, access, and other unmeasured factors. Statistical adjustment can reduce confounding, but it cannot eliminate it.

Biochemical remission and inflammatory signal

The biochemical remission findings followed a similar pattern. At week 16, biochemical remission was observed in 64% of patients receiving upadacitinib, compared with 47% receiving tofacitinib and 41% receiving ustekinumab. At week 52, the observed rates were 73%, 48%, and 43%, respectively.

After adjustment, upadacitinib was associated with higher odds of biochemical remission than both tofacitinib and ustekinumab at week 16. At week 52, adjusted analysis showed higher odds with upadacitinib compared with ustekinumab, but not a statistically significant advantage compared with tofacitinib. The report also notes that upadacitinib showed the largest reduction in fecal calprotectin over time.

These findings support the clinical remission signal by suggesting that symptom-based outcomes were accompanied by evidence of reduced intestinal inflammation. But the missing-data issue matters. Biochemical data were available for 84% of patients at week 16 and 64% at week 52. That makes the week-52 biochemical findings less secure than the earlier time point and supports the authors’ caution that longer-term secondary results should be interpreted carefully.

Endoscopic remission: promising, but limited by data availability

Endoscopic remission was also more common with upadacitinib in observed analyses. At week 16, 38% of patients receiving upadacitinib achieved endoscopic remission, compared with 13% receiving tofacitinib and 25% receiving ustekinumab. At week 52, endoscopic remission rates were 57%, 33%, and 23%, respectively. After adjustment, upadacitinib was associated with higher odds of endoscopic remission than either comparator at both time points.

For clinicians, endoscopic remission is particularly compelling because it is closer to objective disease control than symptoms alone. A Mayo endoscopic subscore of 0 represents a stringent endpoint. If replicated prospectively, these results would strengthen the argument for upadacitinib when early and deep inflammatory control is a priority.

But this part of the study also carries a major limitation: endoscopy results were available for only 58% of patients at week 16 and 55% at week 52. Patients who undergo follow-up endoscopy in real-world care may differ systematically from those who do not. Some may have persistent symptoms prompting evaluation; others may be assessed because they are doing well and clinicians are confirming mucosal healing. Without controlled assessment schedules, selection bias is difficult to exclude.

Second advanced therapy subgroup: closer to the common clinic scenario

The investigators also examined a subgroup of 146 patients who received one of the three drugs as their second advanced therapy. This subgroup is especially relevant because clinicians frequently face the decision immediately after failure of a first biologic or small molecule.

At week 16 in this subgroup, steroid-free remission occurred in 52% of patients receiving upadacitinib, compared with 15% receiving tofacitinib and 35% receiving ustekinumab. After adjustment, upadacitinib was associated with higher odds of steroid-free remission compared with tofacitinib and ustekinumab. The adjusted odds ratios were 6.30 versus tofacitinib and 3.04 versus ustekinumab.

Upadacitinib also had the highest observed rates of biochemical remission and endoscopic remission in this subgroup. However, the endoscopic remission analysis in the subgroup was descriptive, which means it should not be treated as definitive comparative evidence.

The subgroup result reinforces the main finding but should not be overinterpreted. Subgroup analyses can be clinically informative, especially when aligned with the primary result, but smaller sample sizes widen uncertainty and increase vulnerability to imbalance between groups.

Safety: similar serious adverse events, more acne with upadacitinib

Serious adverse events were uncommon across all three groups: 1.9% with upadacitinib, 2.7% with tofacitinib, and 1.5% with ustekinumab. The report states that there was no significant difference among groups and that no major cardiovascular events were reported.

Nonserious skin-related adverse events were more common with upadacitinib. Acne occurred in 11% of patients receiving upadacitinib. It cleared after dose reduction in five patients, while six patients were evaluated by a dermatologist.

These safety findings are reassuring within the limits of the study, but they should not be read as definitive comparative safety evidence. The cohort was retrospective, and the sample size may be insufficient to detect uncommon but clinically important events. Follow-up duration and patient selection also matter. JAK inhibitors require individualized safety assessment, especially in patients with cardiovascular, thromboembolic, malignancy, infection, smoking, age-related, or pregnancy-related considerations.

The expert interview in the GI & Hepatology News report makes this point directly. Dr. Camões Neves emphasized that treatment choice should remain individualized and that clinicians should consider comorbidities, patient preferences, safety profile, and local availability. She specifically noted scenarios in which ustekinumab may be favored over a JAK inhibitor, such as an older patient with significant cardiovascular or thromboembolic risk factors or a young woman planning pregnancy in the near future.

How this evidence may influence practice

The practical impact of TRIDENT-UC is that it gives clinicians comparative real-world data in a scenario where decision-making is often uncertain. For a patient with moderate-to-severe UC who has failed one advanced therapy, especially when steroid-free remission and early inflammatory control are priorities, upadacitinib may deserve strong consideration.

But this does not mean the study establishes a universal sequencing rule. It does not prove that upadacitinib is the best choice for every bio-experienced patient. It does not override safety considerations, pregnancy planning, prior adverse events, comorbidity profile, patient preference, access, or local prescribing constraints. It also does not replace guideline-based decision-making.

A more accurate interpretation is that TRIDENT-UC adds supportive evidence to a growing clinical impression: upadacitinib may be a particularly effective option after prior advanced-therapy failure in UC. Its use should be individualized, and the level of confidence should be higher for the week-16 steroid-free remission endpoint than for week-52 biochemical and endoscopic findings, which were affected by missing data and described as exploratory.

What clinicians should not conclude

Clinicians should not conclude that upadacitinib caused superior outcomes solely because higher remission rates were observed. The retrospective design means treatment groups may have differed in ways that were not fully measurable. Drug availability over time may also have influenced results because upadacitinib became available later than the other therapies. The authors noted that this could have affected results and contributed to less complete follow-up.

Clinicians should also not conclude that tofacitinib and ustekinumab are ineffective after advanced-therapy failure. Both were associated with remission in meaningful proportions of patients. The absence of significant difference between tofacitinib and ustekinumab in this study does not prove equivalence across all patient populations or clinical contexts.

Finally, clinicians should not use these data to ignore safety stratification. Upadacitinib’s apparent effectiveness advantage must be weighed against individual risk factors. The decision remains a clinical balance, not a simple ranking exercise.

Strengths that make TRIDENT-UC useful

TRIDENT-UC has several strengths for everyday practice. It reflects real-world patients treated across multiple centers rather than highly selected trial conditions. It directly compares three therapies commonly considered after advanced-therapy failure. It uses clinically relevant outcomes: steroid-free remission, biochemical remission, and endoscopic remission. It also includes both early and one-year time points.

Another strength is that the study assessed a subgroup receiving the drugs as second advanced therapy, a situation frequently encountered in IBD clinics. The consistency of the upadacitinib signal across the overall cohort and this subgroup makes the findings more clinically interesting.

The report also states that the authors declared no external funding and no relevant financial, professional, or personal conflicts of interest.

Limitations that should shape interpretation

The main limitation is the retrospective design. Retrospective real-world studies are valuable, but they are vulnerable to selection bias, confounding by indication, incomplete data capture, and variation in assessment timing. Even after statistical adjustment, unmeasured differences between groups may remain.

The second limitation is missing follow-up data, especially at week 52. This affects confidence in longer-term biochemical and endoscopic outcomes. The report notes that biochemical data were available for 64% of patients at week 52, while endoscopy data were available for 55%. The authors characterized week-52 biochemical and endoscopic findings as exploratory.

The third limitation is geographic and health-system context. The study included nine centers in Portugal. Results may not fully generalize to other countries with different access pathways, monitoring practices, prescribing patterns, and patient characteristics.

Future research priorities

TRIDENT-UC should encourage larger prospective cohorts and, ideally, carefully designed comparative studies focused on post–advanced-therapy failure sequencing. Key questions remain: which patient characteristics predict response to upadacitinib after prior biologic failure? Does prior mechanism of failure matter? How should JAK inhibitor risks be incorporated into sequencing algorithms? Which patients may be better served by ustekinumab despite lower observed remission rates in this cohort? Can biomarkers, disease extent, inflammatory burden, prior drug exposure, or pharmacodynamic features help identify the right therapy for the right patient?

Dr. Camões Neves highlighted the need to validate the findings in larger prospective cohorts and to better understand which patient characteristics can guide therapy selection.

Clinical Takeaway

TRIDENT-UC provides clinically relevant real-world evidence that upadacitinib was associated with higher steroid-free clinical remission than tofacitinib or ustekinumab at weeks 16 and 52 in adults with moderate-to-severe ulcerative colitis after failure of at least one advanced therapy. The study also showed higher observed biochemical and endoscopic remission rates with upadacitinib, although longer-term secondary findings were affected by missing data and should be interpreted cautiously.

For clinicians, the message is not that upadacitinib should automatically replace other therapies after advanced-therapy failure. Rather, it should be strongly considered when effectiveness, steroid-free remission, and rapid inflammatory control are major priorities, provided the patient’s safety profile is appropriate. Treatment selection must remain individualized, incorporating comorbidities, thromboembolic and cardiovascular risk, infection risk, malignancy history, pregnancy planning, patient preference, and local availability.

TRIDENT-UC is useful, practice-relevant evidence—but it remains observational. It supports a stronger role for upadacitinib in UC sequencing discussions, while leaving important questions for prospective validation and individualized care.

Five key clinical takeaways

1. TRIDENT-UC was a retrospective multicenter real-world study of 312 adults with moderate-to-severe UC after failure of at least one advanced therapy.

2. Upadacitinib was associated with higher steroid-free clinical remission than tofacitinib or ustekinumab at both week 16 and week 52.

3. Biochemical and endoscopic remission also favored upadacitinib, but week-52 objective outcomes had substantial missing data and were considered exploratory.

4. Serious adverse events were uncommon and similar across groups, but nonserious acne was more frequent with upadacitinib.

5. The findings should inform, not dictate, sequencing decisions; individual safety profile, comorbidities, pregnancy planning, patient preference, and access remain central.

Source reference and link

Primary source: GI & Hepatology News. “Upadacitinib linked to higher remission after UC therapy failure.” Published August 28, 2026.

Original study source cited by GI & Hepatology News: Clinical Gastroenterology and Hepatology, retrospective TRIDENT-UC study of upadacitinib, tofacitinib, and ustekinumab after advanced-therapy failure in ulcerative colitis.