P368 Tofacitinib induction efficiency and intracellular cytokine dynamics in ulcerative colitis: Results from clinical practice

Abstract

Background Tofacitinib is an oral JAK inhibitor approved for the treatment of ulcerative colitis (UC). Its efficiency was proven in registration trials; however, data from clinical practice are insufficient. Our aim was to evaluate response to tofacitinib after 8 weeks in UC patients, and to assess potential predictors of response including early cytokine production shifts. Methods Data from consecutive UC patients who started tofacitinib 10 mg b.i.d. were evaluated. Disease activity was assessed by Mayo score at baseline and week 8 together with C-reactive protein (CRP) and faecal calprotectin (FC). Production of IL-4, IL-10, IL-17, TNFα and IFNγ in T-helper cells was determined at baseline and week 4. At week 8, patients with total Mayo 0–5 with endoscopic subscores 0–1 were considered responders. Adverse events were registered at every visit. Results Twenty-four patients (41.7% males, 58.3% females), mean age 35.3 ± 11.8 years were included. Mean disease duration was 8.3 ± 5.2 years. In median, the patients were previously treated with two biologic agents; however, 25% of the patients were naive to any biologic therapy. Systemic corticosteroids were present in 41.7% patients at baseline and no patient had concomitant biologic or other immunosuppressive therapy. At week 8, 52.9% of patients responded to therapy. Total Mayo decreased in responders from mean 5.9 ± 3.5 to 1.1 ± 1.3 (p = 0.01), while in nonresponders it changed from 8.0 ± 2.5 to 8.9 ± 2.1 (p = 0.86). Endoscopic subscore decreased from 2.0 ± 1.0 to 0.6 ± 0.7 (p = 0.02) in responders, however, remained stationary in nonresponders (2.9). CRP and FC dropped significantly in responders (6.7 ± 6.2 vs. 2.0 ± 2.2 mg/l, p = 0.04; 1195 ± 1189 vs. 578 ± 654 μg/g, p = 0.05), but not in nonresponders. The responding and nonresponding groups differed significantly in baseline triglycerides, which were higher in nonresponders. Other baseline parameters were comparable. In responders, there was a significant decrease in IL-4 and no change in IL-10, while in nonresponders, there was no change in IL-4 and a significant decrease in IL-10. Tofacitinib was stopped in 23.5% of patients at week 8 due to insufficient response. Two patients reported headaches after treatment initiation and single events of CMV colitis, C. diff. colitis and oral candidiasis occurred. Conclusion Tofacitinib was efficient in inducing clinical response with mucosal healing in about 50% of UC patients after 8 weeks of therapy. There was no clear baseline predictor of response, however, considering limited sample, there was also no indication of even multiple biologics failure negatively affecting the response. Preliminary results of cytokine dynamics suggest early IL-4 decrease as a potential biomarker of response, warranting further investigation.

Real-World Effectiveness and Safety of Tofacitinib in Patients With Ulcerative Colitis: Systematic Review With Meta-Analysis

“…Of the 202 citations identified with the search strategy, 17 studies including 1162 patients with UC were eligible to be included in this review. [5][6][7][11][12][13][14][15][16][17][18][19][20][21][22][23][24] (Supplementary Table 1). Six studies were reported as full-text articles, and 11 were conference proceedings.…”

“…Mucosal healing was reported in 6 studies 5,7,12,15,18,19 (n = 252; Figure 3). Mucosal healing was achieved in 41.9% of patients at week 8 (95% CI, 18.1-65.6; range, 23.1%-54.2%; 3 studies 12,15,18 ) and in 35.1% of patients at weeks 12 to 16 (95% CI, 11.5-58.7; range, 9.1%-64.9%; 4 studies 5-7, 15, 19 ).…”

Tofacitinib and newer JAK inhibitors in inflammatory bowel disease—where we are and where we are going

“…Kolar et al identified an early decrease in IL-4 levels as a potential biomarker of tofacitinib response. 85 In another study, a tofacitinib-specific mucosal genetic biomarker was identified that was significantly correlated with endoscopic response. The identified hub gene (p=1.5×10 −9 , fold change 2.3) had a predictive accuracy for the response of 100% (p<0.001).…”

Efficacy of JAK inhibitors in Ulcerative Colitis

“…A retrospective cohort study from Prague included 24 patients with UC, including 25% patients who were bio-naïve. 20 After 8 weeks of tofacitinib 10 mg BID, mucosal healing [endoscopic Mayo sub-score ≤1] was demonstrated in 52.9% of the patients. In responders, the mean [±SD] total Mayo score decreased from 5.9 [±3.5] to 1.1 [±1.3] [ p = 0.01], the mean endoscopic sub-score decreased from 2.0 [±1.0] to 0.6 [±0.7] [ p = 0.02], the mean CRP dropped from 6.7 [±6.2] to 2.0 [±2.2] mg/L [ p = 0.04], and the mean faecal calprotectin level dropped from 1195 [±1189] to 578 [±654] µg/g [ p = 0.05].…”