Introduction

Tofacitinib is effective as monotherapy in the treatment of biologic-naive ulcerative colitis (UC) patients; however, available real-world clinical studies are limited by cohort size.

Aim

• To investigate efficacy and safety of tofacitinib in moderate-to-severe colitis and acute severe ulcerative colitis (ASUC)
• To study steroid-free remission (SFR), colectomy-free survival, primary non-response (PNR), and loss of response (LOR) in indications of UC (ASUC and chronic activity [CA])
• To identify predictive factors of efficacy in different outcomes and to assess the prevalence of adverse events (AEs)

Patient Profile

• 391 UC patients (ASUC and CA) receiving tofacitinib with 26 weeks follow-up period

Method

Study Design

• Retrospective international, multicenter collaborative cohort study (23 tertiary centers in Europe, Canada and Israel)
• Vast majority of the cohort had received anti-tumor necrosis factor treatment previously and two-thirds of the patients had received vedolizumab
• All patients received tofacitinib 20 mg/d induction dose and 10 mg/d maintenance dose, treatment escalation was mostly identical to the induction dose. Few cases received a higher dosage (25 and 30 mg/d, respectively)

Endpoints

• Primary outcome: SFR rates (partial Mayo <2 and CRP <5 mg/L with no rectal bleeding and with no concomitant corticosteroid therapy) at weeks 12 and 52
• Secondary outcomes: colectomy rates at weeks 12 and 52, PNR rates (<30% decrease in partial Mayo or ≥2 bleeding score at week 12), LOR rates (need of dose optimization or prolonged induction dose) and persistence of the treatment

Results

Efficacy

• Tofacitinib achieved SFR rates of 23.7% (ASUC: 26%, CA: 22.8%) at week 12 and 41.1% (ASUC: 34.2%, CA: 43.5%) at week 52 (Figure 1); sustained steroid-free clinical remission rate was 17.9%
• Biologic-naive patients significantly achieved week 52 SFR (odds ratio [OR], 2.078; P=0.04), however, baseline partial Mayo score (OR, 0.850; P=0.006) was negatively associated with week 12 SFR
• Week 52 colectomy rate was 8%, PNR rate was 21.5% and LOR was 54.1%; LOR was more common in CA group versus the ASUC group (58.5% vs. 41%; P=0.006).
• Tofacitinib was remarkably efficient as a rescue therapy in ASUC, as the colectomy rate was 7.5 % at week 12 and 17.6% at week 52 (P<0.001)
• Tofacitinib dose optimization was effective in 37.5% patients in LOR group
• CA Patients remained on tofacitinib for a longer period of time versus ASUC patients (35.3 weeks vs. 29.6 weeks; P=0.07)
• Tofacitinib significantly reduced the clinical activity index (from 6.2 to 3.5 at week 12 & 1.8 at week 52; P<0.001)
• It significantly decreased the markers of biochemical activity: CRP (from baseline 19.34 μg/mL to 6.42 μg/mL at week 52; P<0.001) and fecal calprotectin (from baseline 1559.7 mg/g to 313.76 mg/g at week 52; P <0.001)
• Tofacitinib increased the number of patients in endoscopic remission from 3.9% at baseline to 43% at follow-up; P<0.001)

 

Figure 1: Steroid-free remission rates (12 week and 52 week) achieved with tofacitinib in UC patients

  

Safety 

• A total of 17.1% AEs were reported and 17.9% (3.1% of the total cohort) were severe AEs
• All AEs were reversible. Moderate AEs resulting in dose reduction or admission of specific therapeutic agent occurred in 14.3% cases and moderate infections occurred in 52% cases

• Cessation of the tofacitinib was needed in 12% and dose reduction was needed in 8%, or with specific treatment for the AE; tofacitinib cessation was due to severe infection, dyspnea, vertigo, nausea, gastric pain, and skin rash

• One case of thromboembolic event was reported which may be associated with other risk factors

Conclusion

• Tofacitinib was effective in both moderate-to-severe UC and in patients with ASUC as a rescue therapy with high rates of SFR and mucosal healing in the short and long terms even after anti-tumor necrosis factor and vedolizumab failure. No new adverse event signals were found.

• This is the first study to compare the efficacy of tofacitinib in different indications of UC (CA and rescue therapy)
• The study highlights the favorable effects of tofacitinib as almost 90% of patients did not receive it as a first-line treatment. Hence, tofacitinib could be more effective as first-line treatment in biologic-naive patients as a rescue therapy or in a lower therapeutic line in CA due to its outstanding efficacy among available therapeutic options and its reassuring safety profile.

 

Inflamm Bowel Dis 2023 Aug 5; doi: 10.1093/ibd/izad135. Online ahead of print.