Abstract
Tofacitinib, an oral Janus kinase (JAK) inhibitor, shows promise as a rescue therapy for acute severe ulcerative colitis (ASUC), a life-threatening condition marked by high colectomy rates. This narrative review synthesizes evidence from randomized controlled trials (RCTs), observational studies, and systematic reviews. The efficacy of tofacitinib has been documented, with an 83.01% day-7 response rate in the TACOS trial and 79.9%–86% 90-day colectomy-free survival in steroid-refractory ASUC. However, seven unmet needs impede the adoption of tofacitinib treatment for managing ASUC: (1) a lack of head-to-head RCTs comparing tofacitinib not only to standard rescue therapies like infliximab and ciclosporin but also to other JAK inhibitors like upadacitinib, (2) uncertainty in optimal dosing and duration, (3) ambiguity in positioning tofacitinib in the treatment algorithm, (4) undefined patient selection criteria, notably for those with prior biologic exposure, (5) limited long-term efficacy and cost-utilization data, (6) unresolved safety risks (e.g., infections, thrombosis), and (7) underexplored potential for combination therapy. These gaps undermine the widespread use of tofacitinib in reducing surgical burden and improving outcomes. Collaborative research—especially multi-center RCTs comparing tofacitinib to infliximab, ciclosporin, and next-generation JAK inhibitors—is vital for establishing evidence-based protocols. Addressing these needs could optimize tofacitinib-based ASUC management, offering a rapid, oral alternative to enhance patient care.
Plain language summary
Acute severe ulcerative colitis (ASUC) is a serious condition where the large intestine becomes very inflamed, causing symptoms like frequent bloody diarrhea. It is a medical emergency that often requires a hospital stay and sometimes surgery to remove the colon. When first-line treatments are not effective, doctors use powerful “rescue therapies” in an attempt to prevent urgent surgery to remove the colon. Finding better treatments could help patients avoid surgery and lower healthcare costs.
Tofacitinib is a pill that reduces inflammation and is already approved for moderate-to-severe outpatient ulcerative colitis. This review explores whether its potential effectiveness for the more serious condition of ASUC. Unlike some treatments that need injections, it is taken by mouth, which might make it easier to use.
The review looked at existing studies and found tofacitinib might work well for ASUC. Some research showed that a significant number of patients avoided surgery soon after starting it. But there are still seven big questions:
1. How does it compare? We need studies comparing tofacitinib to other common treatments like infliximab or ciclosporin.
2. How much and how long? It is unclear what dose to use or how long to take it for ASUC.
3. When to use it? Should it be the first treatment or only used after others fail?
4. Who benefits most? We do not know which patients benefit the most, especially those who have tried other drugs.
5. Does it work long-term? There is little information on its long-term effectiveness or cost savings.
6. Is it safe? There are concerns about infections or blood clots, but its risks have not been fully compared to those of other treatments.
7. Can it be combined with other drugs? Combining it with other treatments might work, but we need more research.
The review says tofacitinib could be a helpful option for ASUC, but more studies are needed to answer these questions and make it a standard treatment.
Keywords
Introduction
Acute severe ulcerative colitis (ASUC) represents a medical emergency within the spectrum of inflammatory bowel disease (IBD) and is historically defined by the Truelove and Witts criteria—specifically, the presence of six or more bloody stools per day accompanied by systemic signs such as fever, tachycardia, or anemia. 1 ASUC affects approximately 20% of patients with ulcerative colitis (UC) over their disease course and requires urgent hospitalization. It carries a significant colectomy risk—around 20% within 3 months of the first admission, rising to 30.2% by 12 months, and potentially reaching up to 85% in steroid non-responders without rescue therapy.2,3 Despite advances in management, the pooled mortality rate in ASUC remains at around 1% in patients treated with infliximab or ciclosporin salvage therapy.2,4 The economic burden is equally stark, with per-admission costs for UC ranging from approximately $5000 to $14,000 in Canada. 5 Similar figures are reported globally; for instance, a 2023 study from Australia identified a median index admission cost of 7829 AUD (approximately $5200), with these costs being primarily driven by the length of stay and need for colectomy. 6 Current guidelines from the American College of Gastroenterology (ACG) and the European Crohn’s and Colitis Organization (ECCO) advocate a stepwise approach: intravenous (IV) steroids as first line, followed by infliximab or ciclosporin for non-responders.7,8 Although overall colectomy rates for UC have seen some reduction in recent decades, rates for acute severe cases remain persistently high, highlighting an ongoing need for therapies that effectively halt disease progression and prevent surgery.8,9
Tofacitinib, an oral Janus kinase (JAK) inhibitor approved for moderate-to-severe UC since 2018, targets pro-inflammatory cytokines (e.g., interleukin-6 (IL-6), IL-23) via JAK1/JAK3 blockade, offering a rapid onset of action, whereas biologics may require weeks.8,10,11 The TACOS randomized controlled trial (RCT) reported an 83.01% day-7 clinical response rate in hospitalized patients, significantly outperforming placebo (58.82%), 12 while retrospective observational studies show 79.9%–86% colectomy-free survival at 90 days in steroid-refractory cases.13–15 Unlike infliximab infusion-based delivery, tofacitinib’s oral administration may simplify treatment logistics in the hospital setting for ASUC patients, reducing the burden on infusion-related resources. However, its application in ASUC remains nascent compared to outpatient moderate-to-severe UC, where long-term remission rates are well documented in real-world studies.16,17 Several reviews and reports (including the TRIUMPH study) have pointed to insufficient RCTs and unclear safety profiles that hinder tofacitinib’s integration into standard protocols.14,15,18
We aimed to collate current evidence on tofacitinib-based management of ASUC and highlight seven unmet needs, namely, trial design/comparison, dosing/duration, treatment positioning, patient selection criteria, outcome data, including cost-effectiveness, safety, and combination therapy (Table 1). However, beyond these established gaps, the emergence of newer, more selective JAK inhibitors like upadacitinib has introduced a critical new question: is tofacitinib the optimal agent within its class for ASUC? Therefore, this review will address these seven needs while framing them within the evolving therapeutic landscape. To address this broad, multifaceted scope, the article is structured as a narrative review, synthesizing evidence from targeted research of medical literature and major conference proceedings rather than adhering to a formal systematic review protocol. Given the persistent surgical burden and morbidity of ASUC, resolving these gaps could position tofacitinib as an integral transformative therapy.15,19,20
Seven unmet needs for tofacitinib in ASUC.
ASUC, acute severe ulcerative colitis; HR, hazard ratio; RCT, randomized controlled trials; TB, tuberculosis; TID, thrice daily; UC, ulcerative colitis; VTE, venous thromboembolism.
Seven unmet needs of tofacitinib in ASUC
Trial design and comparisons
The 2024 TACOS RCT in India comprised 104 patients with ASUC treated with a tofacitinib regimen of 30 mg/day (10 mg thrice daily, TID) or placebo with IV steroids. Notably, tofacitinib was administered as a first-line therapy upon admission in combination with IV steroids, not as a day-3 rescue therapy, a key design element that distinguishes it from many ASUC salvage studies. This achieved a high response rate by day 7 (83.01% vs 58.82%, respectively; odds ratio (OR) 3.42, 95% confidence interval (CI) 1.37–8.48, p = 0.007) and reduced rescue therapy by day 90 (0.13 vs 0.38, respectively; log-rank p = 0.003). 12 Critically, patients in the tofacitinib arm continued this advanced therapy post-discharge, while the control group primarily used conventional therapies. This difference in post-discharge management may confound the interpretation of the 90-day outcomes.
A significant omission in current research is the lack of head-to-head comparisons with established rescue therapies like infliximab and ciclosporin. The TACOS trial compared tofacitinib to placebo, not active comparators, leaving its relative efficacy untested against standards of care. 12 An RCT found comparable efficacy between infliximab and ciclosporin in steroid-refractory ASUC (day-7 response rate = 85%). 21 In the absence of such comparative data, the position of tofacitinib remains speculative in the context of widespread infliximab use and cost-effective ciclosporin application. 22 Finally, the TACOS trial’s design was unusual because it did not use colectomy as the primary endpoint. This is noteworthy, as colectomy-free survival is typically the key outcome in ASUC studies. Instead, the primary endpoint was clinical response at day 7, with secondary endpoints including the need for rescue therapy by day 90. This design choice may limit direct comparisons with trials focusing on colectomy avoidance.
Perhaps a more pressing unmet need in trial design is the lack of comparison between different JAK inhibitors themselves. While tofacitinib is the most studied JAK inhibitor in ASUC, upadacitinib has shown promise in moderate-to-severe UC and is increasingly being explored in ASUC. In the broader context of moderate-to-severe UC, evidence from multiple network meta-analyses and real-world studies consistently suggests that upadacitinib is more effective than tofacitinib in inducing clinical and endoscopic remission.23–27 However, in the specific high-inflammation setting of ASUC, this superiority has not been established; the most direct comparative evidence from a 2025 Australian multicenter retrospective study found no significant difference in 1-year colectomy rates between the two agents. 28 This discrepancy has led to two main hypotheses. One is that the broad pan-JAK inhibition of tofacitinib might be more effective in controlling the “cytokine storm” of ASUC. The other is that a “treatment ceiling effect” may exist, where both drugs are sufficiently potent for this acute indication. It is plausible that the broad, pan-JAK inhibition of tofacitinib (targeting JAK1/3 and to a lesser extent, JAK2) may offer more comprehensive cytokine blockade in this hyper-inflammatory state compared to the more targeted JAK1-selectivity of upadacitinib. However, this remains a clinical hypothesis, and further preclinical studies using organoid models or in vitro cytokine stimulation assays are warranted to test the differential effects of pan-JAK versus selective JAK1 inhibition in a hyper-inflammatory environment. Future research should include comparative studies of different JAK inhibitors to determine their relative efficacy and safety profiles in ASUC, addressing a significant gap in the current evidence base.
The evidentiary foundation for tofacitinib in ASUC is further constrained by an overreliance on small or single-center studies. The TACOS trial, while a landmark RCT, is a key example of this limitation. Its single-center design is a critical concern, as such trials are well documented to be susceptible to selection bias and may report larger treatment effects that are not always replicated in broader, multi-center research.29,30 This is particularly relevant given that the demographic and genetic profile of the cohort in India may not be representative of the global ASUC population seen in North America and Europe.31–34 Other evidence, such as the prospective TRIUMPH study, is also limited by a small sample size. 18 Therefore, to move beyond these preliminary findings, a unified, global effort is required. Future progress will likely depend on the establishment of international research consortia to conduct the large-scale, multi-center RCTs needed to definitively validate tofacitinib’s efficacy across diverse populations and avoid biases inherent to localized clinical practices. Until such trials, supported by the International Organization for the Study of Inflammatory Bowel Disease, bridge these gaps, tofacitinib’s potential remains to be fully established. 35
Optimal dosing and duration
The rapid onset and oral delivery of tofacitinib make it a compelling rescue therapy for ASUC, yet its optimal dosing and duration remain unsettled, hindering standardized adoption. For moderate-to-severe UC, a standard induction regimen of 20 mg/day (10 mg twice daily, BID) for 8 weeks is the standard induction, 11 but ASUC may demand faster, higher dosing, with debate centering on how long to sustain 30 mg/day (Table 2).
Summary of tofacitinib dosing and outcomes in ASUC studies.
Tofacitinib dose escalated to 30 mg/day (15 mg BID) after 10 days due to insufficient improvement in one patient, continued for 11 days until discharge.
One patient received high-intensity tofacitinib at 30 mg/day (10 mg TID) for 3 days alongside IV steroids, showing initial symptom improvement and CRP decline, but after dose reduction to 10 mg/day (5 mg BID) on day 5, experienced a rapid symptom resurgence and CRP rise, necessitating urgent colectomy.
Not all ASUC patients.
ASUC, acute severe ulcerative colitis; BID, twice daily; CI, confidence interval; CRP, C-reactive protein; HR, hazard ratio; TID, thrice daily.
High-dose approaches (30 mg/day) aim for rapid disease suppression. The TACOS trial employed a 7-day tofacitinib regimen of 30 mg/day
The peak concentration of tofacitinib at 1 h and 70% hepatic/30% renal clearance support frequent dosing (TID) to maximize exposure in ASUC’s acute window, in contrast to the 20 mg/day 8-week UC regimen.12,36 A 30 mg/day tofacitinib regimen achieved a 78% response rate at 8 weeks for moderate-to-severe UC cases 41 while achieving steady-state trough concentrations of 17.1 ± 12.1 ng/mL in healthy participants that support high-dose regimens. 36
Steenholdt et al. 15 reviewed 148 ASUC cases, using tofacitinib (20–30 mg/day) with an 85% colectomy-free survival rate at 30 days, though variable dosing and low evidence quality limit broader adoption. In the TACOS trial, a 7-day 30 mg/day tofacitinib regimen correlated with adverse events such as infections (3.77%) and thrombosis (1.88%), suggesting that extending this high-dose regimen beyond 7 days could heighten these risks, necessitating further study. 12 Conversely, a prolonged 20 mg/day regimen may fail to address urgent ASUC treatment needs. RCTs are warranted to compare 20 versus 30 mg/day regimens over fixed 3-, 7-, or 14-day spans in steroid-refractory, biologic-experienced, and comorbid patients.
Treatment positioning
ASUC requires fast, effective treatment to avoid colectomy. Here, we review tofacitinib as a first-line treatment and in rescue settings to place it among current options (Figure 1).
A proposed algorithm for integrating tofacitinib into the management of ASUC.
First-line therapy: steroids alone versus tofacitinib + steroids
Administering tofacitinib with IV steroids may be an ASUC first-line choice that pairs JAK inhibition with anti-inflammatory steroid effects. The TACOS trial findings demonstrated significant short-term efficacy and reduced long-term escalation by employing 30 mg/day tofacitinib plus IV hydrocortisone. 12 Berinstein et al. 14 studied 40 biologic-experienced ASUC patients who received IV methylprednisolone (60 mg/day) and were treated with either a high-dose tofacitinib regimen of 30 mg/day (10 mg TID) for 3 days followed by 20 mg/day (10 mg BID), or a standard-dose regimen of 20 mg/day (10 mg BID). The 90-day colectomy rate was 15% versus 20.4% in controls (HR 0.28, 95% CI 0.10–0.81, p = 0.018), with TID dosing more protective (HR 0.11, p = 0.008). 14 In another case series by Berinstein et al., 37 30 mg/day tofacitinib plus 60 mg/day IV methylprednisolone regimen achieved rapid symptom improvement and reduced CRP levels in ASUC patients with prior treatment failure. This low-grade evidence appears most applicable to biologic-naïve, newly diagnosed ASUC patients. 12 These patients may respond better because their inflammatory pathways are less adapted. 11 Biologic-experienced patients, often steroid-refractory, have altered cytokine profiles where high IL-1β, IL-6, and interferon-gamma levels post-tumor necrosis factor inhibitor failure may reduce efficacy. 42 Yet, higher TID dosing in such cases can improve outcomes, as seen in Berinstein et al. 14 A crucial, related unmet need is the potential for a steroid-free induction regimen using tofacitinib monotherapy. While current evidence focuses on combining tofacitinib with corticosteroids, the ultimate goal in IBD management is to minimize steroid exposure. The phase IIIb ORCHID trial in moderate active UC, for instance, demonstrated that tofacitinib monotherapy was effective, though not superior to steroids for inducing short-term remission. 43 However, this principle has not been tested in the high-acuity setting of ASUC, where IV corticosteroids remain the unwavering standard of care. Investigating whether tofacitinib alone could be a viable first-line option, thereby avoiding steroid-related toxicities, represents a significant avenue for future research.
Post-steroid failure: infliximab/ciclosporin versus tofacitinib
In steroid-refractory ASUC, infliximab and ciclosporin are the standard rescue therapies because they avert colectomy, especially in biologic-naïve patients.7,8 In an RCT by Laharie et al., 21 infliximab achieved a ~46% success rate in ASUC cases, with efficacy and safety profiles comparable to those of ciclosporin. Tofacitinib has demonstrated efficacy as a rescue therapy for steroid-refractory ASUC. One systematic review found pooled colectomy-free survival rates of 79.9% at 90 days and 71.6% at 6 months, 13 while another study found 75% colectomy-free survival with tofacitinib therapy. 44 Another case series showed 75% of biologic-naïve, steroid-refractory patients with ASUC achieving remission and remaining colectomy-free. 45 While biologic-naïve patients may derive significant benefit from JAK inhibitors like tofacitinib, these patients also respond well to established therapies such as infliximab or cyclosporine. Despite emerging data, JAK inhibitors have not yet been incorporated into formal management guidelines for ASUC. Even the most up-to-date international guidelines, such as the 2025 ACG clinical guideline, do not recommend them as a routine rescue therapy, continuing to prioritize infliximab or cyclosporine. 7 Hypoalbuminemia (<30 g/L) increases infliximab renal clearance and may reduce efficacy, 46 while tofacitinib has ~70% hepatic and 30% renal clearance, with a fraction unbound in plasma of 0.6, 36 which suggests limited albumin dependence compared with biologics leading to consistent pharmacokinetics. Future studies should carefully weigh the ethical implications of prioritizing JAK inhibitors over proven therapies in treatment-naïve patients, balancing innovation with evidence-based practice.
Post-infliximab or ciclosporin failure: ciclosporin/infliximab/colectomy versus tofacitinib
Current guidelines recommend ciclosporin treatment if infliximab salvage therapy fails (or vice versa) or colectomy in steroid-refractory ASUC.7,8 However, it is important to be mindful of the risks for patients who decline colectomy and opt for consecutive medical rescue therapies. In these cases, complications persist, particularly the risk of infection, which has occasionally led to fatal outcomes. Tofacitinib is under investigation as a third-line therapy to potentially delay or avoid colectomy in ASUC patients refractory to infliximab. In a series by Gilmore et al., 47 five young male patients with ASUC refractory to both IV steroids and infliximab were treated with high-dose tofacitinib. This approach resulted in a 90-day colectomy-free survival rate of 80% (4/5). 47 Khan et al. 48 reported one ASUC patient, similarly failing steroids and infliximab, who avoided colectomy with tofacitinib (30 mg/day then 20 mg/day) over 90 days. Xiao et al. 49 reported three hospitalized patients with ASUC refractory to both steroids and infliximab who achieved clinical response with tofacitinib, with a median discharge time of 5 days post-initiation. By contrast, Jena et al. 50 documented two ASUC patients failing steroids and infliximab: one responded to tofacitinib at the dose of 20 mg/day (10 mg BID) and avoided colectomy, while the other failed to respond and required urgent colectomy. In addition, authors also documented a patient with ASUC who failed steroid and ciclosporin therapy responded to 20 mg/day tofacitinib treatment. Tofacitinib may offer a bridge for surgery-averse or unfit patients, yet this benefit must be weighed against the risks of delaying surgery. Prolonged preoperative medical therapy increased postoperative complications (OR 1.12 per day). 51 The utility of tofacitinib depends on assessing its rapid onset response (within 3–5 days) to balance colectomy avoidance against surgical morbidity, and its role post-steroid-infliximab failure warrants multi-center RCTs.
Safety concerns
ASUC management during hospitalization requires assessment of short-term safety concerns, particularly venous thromboembolism (VTE) and infections.3,7,8 In the TACOS trial, the tofacitinib arm showed a 3.77% infection rate and a 1.88% thrombosis rate, while the overall risk of adverse events was 24.52% in the tofacitinib and 13.72% in the placebo arms, with no severe infections in either arm. 12 A study of ASUC cases treated with tofacitinib reported a 10% total infection rate (herpes zoster: 1.4%; any infection: 8.8%) with 2.03% discontinuing therapy, though no infection-related deaths were reported. 15 One VTE event (0.7% incidence) was recorded, a fatal suspected pulmonary thromboembolism occurring 1 month post-discharge, though not definitively confirmed to be related to tofacitinib. 15 One RCT in ASUC reported an ~9% infliximab- and 7% ciclosporin-related severe infection rate. 21 These data suggest that tofacitinib-based ASUC therapy may have reduced infection rates compared with those for infliximab and ciclosporin. However, inconsistent definitions of infection severity and the absence of direct comparative trials in ASUC limit a clear understanding of their relative risks.
Korean guidelines recommend cautious use of tofacitinib in elderly patients with moderate-to-severe UC due to heightened risks of thrombosis and cardiovascular events, 52 as highlighted by studies in rheumatoid arthritis that identified a potential tofacitinib-associated risk.53,54 However, ASUC-specific data from TACOS and a Korean cohort show no consistent VTE signal,12,55 suggesting that the disease’s hypercoagulable state—driven by inflammation, immobility, and dehydration—may dominate over drug-specific effects.
Optimal patient selection
Identifying ASUC cases most likely to benefit from tofacitinib treatment remains a key clinical question. Prior biologics exposure may be a key determinant. The impressive TACOS results likely stem from the predominant enrollment of biologic-naïve patients, with only 4.8% having tumor necrosis factor inhibitor exposure. 12 Conversely, a systematic review by Berinstein et al. reported efficacy in both biologic-naïve and experienced patients but without a direct comparison between these groups. 15 Tofacitinib therapy for biologic-experienced ASUC cases resulted in a lowered 90-day colectomy risk (HR 0.28, 95% CI 0.10–0.81, p = 0.018) compared to controls. 14 As it excluded biologic-naïve patients, direct comparisons with the TACOS trial, which predominantly enrolled biologic-naïve patients, are limited. 12 Nonetheless, this study provided strong evidence that the number of prior biologic failures impacts tofacitinib efficacy, with each additional failure significantly increasing colectomy risk (HR 1.61, 95% CI 1.13–2.29, p = 0.009). 14 Notably, infliximab failure was the most prevalent prior biologic exposure in the tofacitinib group of Berinstein et al. 14 ’s study, with a rate of 85%, compared to only 27.4% in the control group. This predominance can be attributed to infliximab being the first biologic approved for UC in 2005, based on the landmark ACT 1 and ACT 2 trials. 56 However, existing studies have not stratified outcomes by specific prior biologic failures. Therefore, it remains unclear which biologic exposure most significantly impacts tofacitinib efficacy.
Although the overall serious infection rates associated with tofacitinib and infliximab appear comparable, their distinct infectious risk profiles may impact treatment selection. Tofacitinib suppresses cytokine signaling, compromising antiviral immunity and increasing the risk of herpes zoster reactivation. In the OCTAVE trials, evaluating a 20 mg/day tofacitinib regimen in moderate-to-severe UC over 8 weeks, the herpes zoster incidence rate was ~3.59 per 100 patient-years with 5 cases among 905 patients (0.55%). 11 This low rate is similar to the 1.4% and 0% incidence reported in ASUC cases treated with various tofacitinib regimens.12,15 Preemptive herpes zoster vaccination is impractical in ASUC due to urgency, and high-dose steroid requirements may impact the efficacy of the vaccination. However, this low incidence supports the short-term safety of tofacitinib as a rescue therapy, with monitoring indicated for extended use. Conversely, infliximab increases tuberculosis (TB) infection susceptibility. 57 TB risk varies from 0.02%–0.21% (low/intermediate TB incidence regions) to 1.59%–11.6% (high TB incidence regions).58–60 Although these TB risk data are derived from the broader UC population rather than specifically from ASUC cohorts, they remain relevant as patients who successfully achieve remission with infliximab will continue it as long-term maintenance therapy. Tailored decision-making with consideration of TB prevalence may favor using tofacitinib over infliximab in TB-endemic areas. However, the absence of ASUC-specific head-to-head trials limits risk stratification in this acute context. These insights not only shape urgent therapeutic decisions in ASUC but also emphasize the critical need for prospective studies to optimize treatment selection based on individual risk profiles and infectious susceptibility.
Comprehensive outcome data
The scarcity of outcome data for tofacitinib-treated ASUC cases, especially for long-term efficacy and cost-effectiveness, limits its routine adoption. Short-term outcomes show 79.9%–86% for 90-day colectomy-free survival.12–15 However, data for long-term tofacitinib therapy for ASUC cases are limited, and UC-based data may suggest its potential. The OCTAVE Open study found that 66.9% and 40.3% of patients achieved response at 36 months to 5 and 10 mg/day tofacitinib regimens, respectively, when tracked for 7 years. 61 Similarly, real-world UC data showed a 50.0% remission rate at 3 years, with 54.3% continuing tofacitinib. 16 For ASUC cases achieving initial control with tofacitinib, these findings imply long-term benefits, yet ASUC’s distinct severity—marked by rapid progression and intense inflammation—necessitates caution in extrapolation.
Beyond long-term efficacy, long-term safety warrants consideration, particularly for these patients who continue on maintenance therapy. Data from post-marketing surveillance in rheumatoid arthritis have raised concerns about increased risks of major adverse cardiovascular events and malignancies compared to TNF inhibitors.53,54 While long-term extension studies in UC, such as OCTAVE Open, have not demonstrated the same definitive risk signals, 61 the patient populations and follow-up durations differ. Therefore, extrapolating these long-term risks to the ASUC population requires caution, and continuous vigilance is necessary for patients remaining on prolonged tofacitinib therapy post-induction.
In moderate-to-severe UC, lifetime Markov models have established tofacitinib’s superior cost-effectiveness over most biologics, yielding substantial cost savings (ranging from €4228 to €17,184) and gains in quality-adjusted life years (QALYs; 0.035–0.083). 62 Others found that tofacitinib followed by infliximab ($505,373, 22.325 QALYs) outperforms infliximab–tofacitinib (Incremental Cost-Effectiveness Ratio $2,149,157/QALY) in Japan, with 100% cost-effectiveness at $38,023/QALY. 63 This gap potentially widens in ASUC with infliximab’s accelerated regimen as salvage therapy in certain cases. 64 Also, short-term colectomy reduction by tofacitinib could lower surgical costs (median: $40,300; range: $26,400–$65,000 USD per procedure). 65 To address these gaps, prospective, multi-center cohort studies are needed. These studies should compare tofacitinib directly against established therapies like infliximab, tracking meaningful long-term, ASUC-specific endpoints such as the rate and timing of disease relapse, duration of corticosteroid-free remission, and long-term colectomy-free survival. Economic evaluations should use a lifetime horizon Markov model, capturing direct costs (drugs, hospitalizations, surgeries) and indirect costs (productivity losses), with sensitivity analyses to explore uncertainty, as outlined in established frameworks. 66 Such robust data could illuminate tofacitinib’s long-term role and economic value in ASUC, reinforcing its potential as a transformative therapy.
Potential of combination therapies
Tofacitinib combination therapies show promise; however, the only direct evidence comes from a case report where ciclosporin (3 mg/kg/day) plus tofacitinib (20 mg/day) achieved clinical remission within 10 days and sustained healing at 6 months. 67 This case underscores a potential mechanistic synergy, whereby ciclosporin’s rapid, calcineurin-mediated T-cell immunosuppression may complement tofacitinib’s broader blockade of multiple pro-inflammatory cytokine pathways.8,11
Beyond ASUC, combination approaches in severe UC provide indirect insights. A patient with refractory UC, failing multiple therapies (e.g., infliximab, vedolizumab, ustekinumab), who achieved clinical, endoscopic, and histologic remission after 4 years of tofacitinib and ustekinumab. 68 Similarly, tofacitinib with infliximab has shown safety and efficacy in refractory UC. 69 These examples underscore the potential of tofacitinib to complement biologics or immunosuppressants. However, safety concerns remain with these combinations, given the immunosuppressive profiles of drugs like ciclosporin, tofacitinib, and biologics. Yang et al. 67 and Bucheeri et al. 68 cases reported no serious adverse events, while case series by Gilmore et al. 69 demonstrated that one patient developed varicella zoster but was successfully managed. Currently, the evidence is weak, largely derived from case reports and small studies, and not robust RCTs. Large-scale RCTs are essential to evaluate these combinations—such as ciclosporin + tofacitinib or tofacitinib + ustekinumab—against standard ASUC salvage therapies like infliximab or ciclosporin alone. To maximize efficiency and relevance, future trials could employ sophisticated methodologies, such as an adaptive design that begins with combination therapy in highly refractory patients before de-escalating to monotherapy, utilizing co-primary endpoints of short-term clinical response and long-term safety.
Conclusion
Tofacitinib holds promise for ASUC owing to 83.01% day-7 response rate and 79.9%–86% 90-day colectomy-free survival in steroid-refractory cases. Its rapid onset of action and oral delivery offer advantages over infliximab by reducing costs and surgical burden. However, the seven unmet needs identified above persist. Crucially, the debate has expanded beyond tofacitinib versus biologics to include its standing against newer JAK inhibitors like upadacitinib. The lack of a clear efficacy advantage for either agent in the ASUC setting—despite upadacitinib’s apparent superiority in moderate-to-severe UC—underscores that a direct comparative trial has become arguably the most critical unmet need. Addressing these scientific gaps through robust, collaborative research is vital to refine treatment algorithms and significantly enhance patient care in ASUC.
However, translating this scientific potential into clinical practice requires overcoming significant implementation barriers. These include the high cost of therapy, the need for rigorous safety monitoring (e.g., for lipid profile changes and herpes zoster risk), and variable accessibility, particularly in resource-limited settings where it may paradoxically be a more feasible option than biologics. Addressing these practical challenges is as critical as resolving the remaining scientific gaps.
