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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.

Background Pharmacokinetics of vedolizumab have been associated with therapy outcome, although real-life data has been contradictory. Thus, we set to examine whether vedolizumab levels before therapy intensification may be associated with clinical, inflammatory and endoscopic outcomes further on. Methods In this retrospective cohort study, vedolizumab drug levels were determined in vedolizumab-treated patients with insufficient therapy response from six medical centers in Israel and Europe, before they underwent dose-intensification. The success of dose-increase gauged by clinical scores, inflammatory (C-reactive protein values, calprotectin) indices and endoscopic data was assessed vis-à-vis pre-escalation drug levels. Results Overall, 161 IBD patients (74, 46% Crohn’s disease) were included, of whom 32 patients underwent intensification at end-of-induction (week 10) and 129 during maintenance period (weeks 14–44, median week 30). In total, 34%, 60% and 30% of the 161 patients reached clinical, inflammatory and endoscopic remission by 6 months after intensification, respectively. Among 129 patients intensified during maintenance period, pre-intensification trough levels were not lower among those reaching clinical and inflammatory remission after dose-escalation (median vedolizumab levels 34.4 vs. 24.4 μg/ml, 30.7 vs. 30.5 μg/ml, p = 0.09, 0.25 respectively). Patients who reached mucosal healing also had higher, rather than lower, vedolizumab levels before intensification (median vedolizumab levels 31.3 vs. 17 μg/ml, p = 0.04 for patients with and without mucosal healing, respectively). Similarly, among 32 patients intensified at week 6 by an extra-dose at week 10, those with higher, while not lower, levels before escalation had higher rates of post-escalation clinical remission (median levels 101 vs. 61.5 μg/ml, p = 0.05). A similar trend was observed in terms of mucosal healing (88.5 vs. 43 μg/ml, p = 0.09) and inflammatory remission (median levels 100 vs. 55 μg/ml p = 0.15). Conclusion Lower vedolizumab trough levels before interval shortening were not predictive of success of the intervention. These results argue against a pharmacokinetic basis for insufficient response to vedolizumab and question the need for dose-escalation. A higher pre-escalation drug-level was associated with better later outcomes, possibly indicating a lower inflammatory burden, and may serve to predict patients with low likelihood to respond to therapy continuation.

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Background Despite significant impact biological treatment had on prospects of patients with ulcerative colitis, there is still a substantial proportion of patients with non-response to multiple drugs. Beside dose optimization and selection of agents with different mechanism of action, combination of two different targeted molecules has recently been proposed in cases where inflammatory activity cannot get under control. This case series provide promising results of vedolizumab in combination with tofacitinib in treatment resistent UC patients. Methods Patients with complicated refractory or acute severe colitis, in whom combined treatment with vedolizumab and tofacitinib based on shared clinical decision was started, were included. Data on demographics, treatment details, persistence and disease activity including laboratory markers, clinical activity index (partial Mayo score) during regular visits every 2 months up to one year after treatment initiation were collected. Currently available data were analyzed at 6 months. Endoscopic disease activity before and 2-6 months after dual therapy start was evaluated. Results In total, 21 UC patients who were started on vedolizumab and tofacitinib dual therapy between Oct 2020 and Sep 2022 were included. Tofacitinib dose was 10mg bid in all patients and all patients on vedolizumab maintenance treatment had intensified dosing regimen. Mean patients age was 36.4±8.1 years, 47.6% were males and 52.4% females. Mean disease duration at baseline was 7.5±5.8 years. All patients had advanced disease including 61.9% with extensive colitis and 38.1% with left-sided colitis. At least 2 previous biologics in monotherapy were used in 85.7% of patients. Mean pMayo score at baseline was 5.6±1.9 and decreased to 0.5±0.9 at 6 months (p=0.0020). Initial fecal calprotectin in the cohort was 1829±2520µg/g vs. 225±257µg/g at 6 months (p=0.0068) and mean CRP changed from 11.4±17.1 to 5.4±7.2mg/l (p=ns). Endoscopic Mayo score before dual treatment initiation averaged 2.8±0.5 indicating mostly severe disease activity and decreased to 1.4±1.2 during follow-up endoscopy (p=0.0005) with half of the patients having only no to mild activity (eMayo 0-1). Up to now, dual therapy had to be terminated in 7 patients – 4 patients failed on the treatment, 1 refused to continue with dual therapy, 1 patient experienced adverse event (liver lesion) and 1 was discontinued for reimbursement reasons. Conclusion In the presented small cohort of patients with refractory ulcerative colitis, in whom other modalities were depleted or colectomy was considered, combined vedolizumab and tofacitinib treatment has proven to be efficient with half of the patients reaching mucosal healing after 6 months and without raising significant safety concerns.