Introduction

Despite the proven efficacy of intravenous corticosteroids in hospitalized acute severe ulcerative colitis (ASUC) patients, corticosteroid resistance occurs in 30%-40% of the patients. They need rescue with either medical (infliximab/cyclosporine) or surgical (colectomy) therapies, however, a high incidence of colectomy, shorter colectomy-free survival and adverse events persist in these patients.

Aim

To evaluate whether addition of tofacitinib to corticosteroids was superior to corticosteroids alone in hospitalized ASUC patients

Patient Profile

• 104 patients with ASUC

Method

Study Design

• Single-center, prospective, double-blind, placebo-controlled randomized trial
• Patients received tofacitinib (10 mg thrice daily) or a matching placebo for 7 days while continuing intravenous corticosteroids (hydrocortisone 100 mg every 6 hours)

Endpoints

• Primary end point: response to treatment (decline in the Lichtiger index by >3 points and an absolute score <10 for 2 consecutive days without the need for rescue therapy) by day 7
• Secondary outcome: the cumulative probability of requiring initiation of infliximab or undergoing colectomy within 90 days following randomization
• Safety evaluation: adverse event(s) monitoring, including opportunistic infections and cardiovascular events

Results

Efficacy

• Tofacitinib, as add-on therapy to corticosteroids, significantly achieved the primary outcome of treatment responsiveness at day 7 in 83.01% patients receiving tofacitinib as compared to 58.82% patients receiving placebo (odds ratio, OR 3.42, P = 0.007) (Figure 1)
• Fewer patients in the tofacitinib group required rescue medical or surgical therapy within 7 days of hospitalization (OR 0.27, P = 0.01) versus placebo
• The cumulative probability of need for rescue therapy at day 90 was significantly lower with tofacitinib as compared to placebo (0.13 vs. 0.38, P = 0.003)
• Tofacitinib therapy was associated with lower CRP levels at day 7 (5.17 mg/L vs. 6.18 mg/L) and shorter hospital stay as compared to placebo (total duration 9.69 days vs. 11.01 days)
• The need for rescue therapy was lower in the tofacitinib group of patients on oral corticosteroids at the time of hospitalization versus those in placebo group (19.23% vs. 56.52%)
• Also, in the subgroup of patients with previous exposure to thiopurines, the use of rescue therapy was lower in the tofacitinib arm compared with that in the placebo arm (12.5% vs. 100%)
• Maintenance therapy with tofacitinib was associated with lower rates of use of medical or surgical rescue therapy at day 90 compared with maintenance treatment with azathioprine

Figure 1: Comparison of the effect of tofacitinib and placebo on the primary outcome

Safety 

• Most of the treatment-related adverse effects were mild
• One patient, receiving tofacitinib, developed hemorrhagic venous infarct in the left temporal lobe and dural venous sinus thrombosis
• The adverse effects were experienced in 24.52% patients in the tofacitinib arm (hair loss, acneiform skin eruptions, and upper respiratory tract infection) and 13.72% in the placebo arm (acneiform skin eruptions and facial puffiness)
• Tofacitinib (n=1) was associated with lower disease-related mortality rates as compared to placebo (n=4)

Conclusion

• Tofacitinib, in combination with corticosteroids improved treatment responsiveness and decreased the need for rescue therapy in patients with ASUC
• The continuation of treatment with tofacitinib beyond 7 days, in reduced doses, provides an effective therapeutic option for maintenance of remission in these patients.
• This is the first randomised controlled trial to evaluate the efficacy of tofacitinib, used as an adjunct to corticosteroids, in improving the treatment response in patients with ASUC

Am J Gastroenterol 2024; 119: 1365-1372