Introduction

Tofacitinib is an oral janus kinase inhibitor (JAK) approved for patients with moderate to severe ulcerative colitis (UC) and either inadequate response or loss of response or intolerance to conventional or biologic therapy. The 5-year and 10-year cumulative risk of colectomy in UC is 10%–15%.¹ Due to the increasing number of anti tumor necrosis factor (TNF)-alfa non responders, tofacitinib seems a valuable therapeutic alternative. This study aims to assess the effectiveness of tofacitinib in preventing colectomy in patients with moderate-to-severe UC refractory to anti TNF-alfa agents.

Aims & Methods

We performed an observational retrospective and prospective multicenter study in five Italian IBD referral units including adult patients with confirmed diagnosis of moderate-to-severe UC (defined by a total Mayo score ≥ 6), treated with tofacitinib because of response failure or intolerance to anti TNF-alfa agents. Primary aim was the effectiveness of tofacitinib in preventing colectomy during a follow-up of 52 weeks. Secondary aims were: survival without colectomy, survival without tofacitinib discontinuation, clinical remission (defined as Mayo partial score ≤ 2) at week 8, 24 and 52, endoscopic remission (defined as Mayo endoscopic score ≤ 1) and steroid-free clinical remission (Mayo Partial score ≤ 2 without steroid) at week 52; adverse events (AE) to tofacitinib. Descriptive statistics and Kaplan Meier analyses of survival were performed.

Results

From January 2021 to October 2022 45 patients were included. During the follow-up, 6 patients (13%) underwent colectomy and all of them before week 24. Survival without colectomy and survival without tofacitinib discontinuation are represented in Figs.1-2. Clinical remission was reached by 17 patients (37.7%) at week 8, by 20 (44.4%) at week 24, and by 22 patients (48.8%) at week 52. Among the 11 patients with an endoscopic evaluation available after completing 52-week treatment, 9 (82%) achieved endoscopic remission. At week 52, 22 patients (49%) maintained steroid-free clinical remission. In eighteen patients (40%) tofacitinib was interrupted, because of failure in 15 and because of a severe AE in 3. AE occurred in 9 patients (20%), but in 3 only (6.7%) were severe and entailed treatment interruption.

Conclusion

These data confirm effectiveness and safety of tofacitinib in preventing colectomy in moderate-to-severe UC refractory to anti TNF-alfa agents.

References

1. Fumery M, Singh S, Sandborn WJ et al. Natural History of Adult Ulcerative Colitis in Population-based Cohorts: A Systematic Review. Clin Gastroenterol Hepatol 2018;16:343–356.

Introduction

Anti-TNF agents play a significant role in the induction and maintenance therapy of moderate to severe ulcerative colitis. However, at least 30% of patients experience loss of response within the first year of treatment.

Aims & Methods

This study aims to compare Tofacitinib versus Vedolizumab in patients with ulcerative colitis in the setting of previous anti-TNF failure. We performed a systematic review in PubMed, Embase and Cochrane databases, searching for randomized and non-randomized studies comparing Tofacetinib versus Vedolizumab in this population. The primary outcome was colectomy rate. The secondary outcomes were thromboembolic event rate and infectious incidence. The odds ratio (OR) was used for binary outcomes with their respective 95% confidence interval (CI). Heterogeneity was assessed using the Cochran Q test and I² statistics.

Results

The meta-analyses included 6 studies and 2,241 patients. There was a significant difference favoring Vedolizumab in colectomy rate (OR 2.03; 95% CI 1.30 to 3.16, p=0.002; I2=0%). There were no difference in thromboembolic event rate (OR 0.90; 95% CI 0.39 to 2.06; p=0.798; I2=0%) and infection incidence (OR 0.83; 95% CI 0.56 to 1.25; p=0.378; I2=0%).

Conclusion

In patients with ulcerative colitis with prior anti-TNF failure, tofacitinib showed higher colectomy rate compared to vedolizumab, with no difference in thromboembolic and infectious events between both groups. Considering this, vedolizumab seems to be a reasonable option in this population.

References

1. Straatmijer T, Biemans V, Visschedijk MC, Hoentjen F, De Vries A, Van Bodegraven AA, et al. SUPERIOR EFFECTIVENESS OF TOFACITINIB COMPARED TO VEDOLIZUMAB IN ANTI-TNF EXPERIENCED ULCERATIVE COLITIS PATIENTS: A NATIONWIDE DUTCH REGISTRY STUDY. United Eur Gastroenterol J. 2022;10((Straatmijer T., t.straatmijer@amsterdamumc.nl; De Boer K.H.N.) Amsterdam UMC, Amsterdam, Netherlands):390–1.
2. Buisson A, Serrero M, Altwegg R, Guilmoteau T, Bouguen G, Nachury M, et al. Real-world comparison of effectiveness between tofacitinib and ustekinumab in patients with ulcerative colitis exposed to at least one anti-TNF agent: Results from the TORUS study. J Crohns Colitis. 2023;17((Buisson A.; Guilmoteau T.) CHU Clermont-Ferrand, IBD Unit, Clermont-Ferrand, France):i707.
3. Adimadhyam S, Lewis JD, Simon AL, Wolfe AE, Smith S, Hou L, et al. Real-world Evidence Comparing Tofacitinib and Vedolizumab in Anti-TNF-experienced Patients With Ulcerative Colitis. Inflamm Bowel Dis. 2024 Apr 3;30(4):554–62.
4. Hyun HK, Zhang HS, Yu J, Kang EA, Park J, Park SJ, et al. Comparative effectiveness of second-line biological therapies for ulcerative colitis and Crohn’s disease in patients with prior failure of anti-tumour necrosis factor treatment. BMC Gastroenterol. 2022 Mar 27;22(1):143.

Introduction

​While ulcerative proctitis (UP) is considered to be a less severe form of ulcerative colitis (UC) it profoundly impairs quality of life. UP has been understudied with regard to potential treatments as it was historically excluded from UC phase 2 and 3 randomized controlled trials. There is currently limited evidence to support the use of tofacitinib in patients with UP.

Aims & Methods

We aimed to assess the effectiveness and safety of tofacitinib for the treatment of UP.
We conducted a retrospective multicenter study in seventeen GETAID centers. All consecutive patients with chronic anti-TNF refractory UP treated with tofacitinib were included. The primary outcome measure was steroid-free clinical remission at induction (assessed from week 8 to week 14), defined as a partial Mayo score of 2 or less with no individual subscore above 1. Secondary outcomes included clinical response (decrease of at least 30% of the partial Mayo score) at induction and steroid-free clinical remission and response at one year. Persistence rates of tofacitinib were assessed with Kaplan Meier survival analysis. Univariate and multivariate logistic regression with backward selection was performed to identify factors associated with steroid-free remission at induction.

Results

We enrolled 35 patients (median age of 45.9 year-old, interquartile range (IQR) [35-52.3]) who had previously received a median of 2 (IQR [2-3]) lines of biologics for UP, all of whom had been exposed to anti-TNF therapy, 74% to vedolizumab and 25% to ustekinumab. At the time of inclusion, the median partial Mayo score was 7 (IQR [5.5-7]), and all patients had an endoscopic subscore of 2 or 3 (endoscopic assessment available for 26 patients at baseline). After induction, 42.8% (15/35) of patients achieved clinical steroid-free remission, while 60% (21/35) achieved clinical response. At one year, the steroid-free clinical remission and response rates were 39.4% (13/33) and 45.5%, respectively (15/33).In multivariate analysis, the only factor independently inversely associated with steroid-free clinical remission at induction was the baseline partial Mayo (adjusted odds ratio of 0.56, 95%CI (0.33-0.95) for an increase of one unit) (Table 1).
Treatment persistence was estimated at 68% (95% Confidence Interval (CI) [54.1-85.6]) at 6 months, and 50.4% (95% CI [35.5-71.6]) at one year. Five (14.3%) adverse events were reported, with one case leading to treatment withdrawal (septic shock secondary to cholecystitis). In addition, one herpes zoster, one COVID, one bronchitis, and one bartholinitis occurred. No major acute cardiovascular event and no death occurred.

Conclusion

Here we present the largest real-world evidence of tofacitinib in patients with UP. These findings suggest that tofacitinib offers a therapeutic option for patients with anti-TNF refractory UP.

Clinical Case Summary

Introduction: Up to 30% of patients with acute severe ulcerative colitis (ASUC) lack adequate response to intravenous corticosteroid therapy and rescue treatment with infliximab or cyclosporine. Despite rescue therapy, more than 30% of patients with ASUC require surgical intervention. Due to rapid action, tofacitinib may provide additional means for colectomy prevention in patients with ASUC. Rapid tofacitinib effect and clinical improvement may be observed within 3 days.
Case report: A 30-year-old man was presented with ulcerative proctitis endoscopically and histologically in May 2021. The remission is achieved with 5-ASA followed by endoscopic confirmation in May 2022.
In December 2022, the patient suffered another relapse. A colonoscopy revealed an extensive form of ulcerative colitis (Montreal classification E2S3) without clinical response to systemic corticosteroids. Repeated stool test for Clostridium dificile tested positive followed with oral vancomycin addition. Symptoms worsened with 7-8 bloody stools. The disease was classified as severe according to Truelove Witts criteria followed by hospitalization in January 2023. The initial partial Mayo score (pMayo score) was 9. The patient was offered a rescue regimen with inflixmab or tofacitinib. He preferred tofacitinb with corticosteroids, at a dose of 20 mg per day, with regular clinical and laboratory monitoring. On treatment day 3 , the pMayo score decreased to 6, due to less rectal bleeding (RB) Mayo subscore - RBS = 1. The next assessment on treatment day 7 revealed pMayo score 5 (RBS = 1) and stool frequency (SF) Mayo subscore - SFS = 2. The patient was discharged home for further treatment. After 8 weeks of treatment, the pMayo score was 2 with RBS 0 and SFS 1.
Conclusion: Tofacitinib could be considered a promising treatment in patients with steroid-refractory ASUC. Randomized clinical trials are required for further efficacy assesment, safety and optimal dosing tofacitinib in cases of ASUC.

Introduction

Biologic and small-molecule therapies are widely used for ulcerative colitis (UC), but their comparative effectiveness in TNF-exposed patients remains unclear.

Aims & Methods

This study evaluates the clinical and biomarker responses to Vedolizumab, Tofacitinib, and Ustekinumab over 12 months, adjusting for baseline differences using Inverse Probability of Treatment Weighting (IPTW). A multicenter retrospective cohort of TNF-exposed UC patients treated with Vedolizumab (n = 260), Tofacitinib (n = 149), or Ustekinumab (n = 193) was analyzed. Clinical outcomes, including Partial Mayo Score (pMayo), clinical remission, and biomarker response (CRP, ESR, fecal calprotectin), were assessed at baseline (T0), 8 weeks (T1), 24 weeks (T2), and 52 weeks (T3). IPTW balanced baseline characteristics, and longitudinal changes were analyzed using a repeated-measures general linear model (GLM) with post-hoc corrections for multiple comparisons.

Results

Before IPTW, significant baseline differences existed, with Tofacitinib patients being younger (p < 0.001), more frequently female (p = 0.003), and having higher fecal calprotectin levels (p = 0.005). After IPTW, covariate balance was achieved (SMD < 0.10). pMayo scores significantly declined in all treatment groups over time (p < 0.001, η² = 0.469), with no significant main effect of therapy (p = 0.329). A minor time-by-therapy interaction (p = 0.036, η² = 0.026) indicated slight response variations but lacked clinical significance. Before IPTW, Tofacitinib showed superior pMayo improvement versus Ustekinumab (p = 0.008), but this difference lost significance post-IPTW, suggesting baseline confounding. At 52 weeks, clinical remission was highest with Tofacitinib (57%), followed by Vedolizumab (40%) and Ustekinumab (22%) (p = 0.003). Biomarker remission favored Vedolizumab (48.8%) over Tofacitinib (19.5%) and Ustekinumab (21.2%) (p = 0.002). Adverse events were rare but more frequent with Vedolizumab (p < 0.001).

Conclusion

Over 12 months, all therapies significantly improved clinical and biomarker outcomes, with no significant differences in overall pMayo reduction post-IPTW. Tofacitinib achieved the highest clinical remission, while Vedolizumab demonstrated superior biomarker response. These findings highlight the need for individualized treatment selection in TNF-exposed UC patients.

Introduction

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Histological outcomes and the immune landscape were assessed in an UC patient cohort at baseline and after 8 weeks tofacitinib.

Aims & Methods

In this prospective study, 40 patients with moderate to severely active UC received tofacitinib 10 mg twice daily for 8 weeks. Clinical, endoscopic and histological outcomes were assessed at baseline and week 8 and colon biopsies were stained for JAK1-3, Tyrosine kinase 2 (TYK2) and Signal transducer and activator of transcription (STAT) 1-6 total protein expression using immunohistochemistry (IHC). Histological remission was defined as a Robarts Histopathology Index (RHI) ≤3 points without mucosal neutrophils and histological response as 50% decrease in RHI compared to baseline. Response was defined as histological remission and endoscopic Mayo score (EMS) ≤1 (histo-endoscopic mucosal improvement). Biopsies were scored by a blinded pathologist. Whole slide images with multiple biopsies per patients were stained using IHC, analyzed using automated cell detection (QuPath) and quantified in percentages by dividing the number of positive stained cells by the total number of cells on the slide. Outcomes were compared between responders and non-responders (NR).

Results

Out of 40 patients, 26 (65%) had severe endoscopic disease (EMS 3) with a median RHI of 14. Thirty-one patients (78%) had failed prior anti-Tumor Necrosis Factor (anti-TNF) agents and 18 (55%) failed vedolizumab. At week 8, 23 patients (58%) achieved histological remission, 34 (85%) histological response and 15 (38%) histo-endoscopic mucosal improvement. A significant decline in RHI compared to baseline was observed after 8 weeks both in responders (14 vs 0, p<0.001) and NR (15 vs 6, p=0.002). In the entire cohort, total STAT1 (p<0.001), STAT3 (p=0.002) and STAT5 (p=0.026) expression significantly decreased after 8 weeks treatment compared to baseline, which was not different between responders and NR (Table). However, responders to tofacitinib expressed significantly lower total STAT1 levels compared to NR at 8 weeks (p<0.001). Likewise, JAK2 (p=0.008) and total STAT2 expression (p=0.004) were significantly lower in responders compared to NR at 8 weeks, although no significant decrease compared to baseline was observed. A trend towards lower baseline JAK1, JAK2 and total STAT4 expression and higher total STAT6 expression was seen in responders compared to NR.

Conclusion

Tofacitinib resulted in histological response in the majority of UC patients and led to a substantial decline of total STAT1, STAT3 and STAT5 expression both in responders and NR. Yet, after 8 weeks significantly lower total STAT1 levels were observed in responders compared to NR. Responders tended to express lower JAK1, JAK2 and total STAT4 and higher total STAT6 levels at baseline.

Disclosure

This study was funded and supported by Pfizer.