EFFICACY AND SAFETY OF UPADACITINIB FOR THE TREATMENT OF FISTULAS AND FISSURES IN PATIENTS WITH CROHN’S DISEASE

Background and Aims: A treat-to-target (TTT) strategy of striving for symptomatic and endoscopic remission is recommended for the management of inflammatory bowel diseases (IBD). Yet, real-world uptake of TTT strategies has been modest. We sought to assess the feasibility of implementing TTT and improve its uptake in the Crohn’s and Colitis Foundation’s learning health system (LHS), IBD Qorus.

Methods: Through encounter-level provider filled surveys, we examined an ‘intention to TTT’ for each eligible clinic visit (for patients identified as not being in endoscopic remission on most recent endoscopic evaluation) across a multi-center LHS over a 12-month period (November 2020-November 2021). ‘Intention to TTT’ (or TTT score) was defined as an affirmative response to all three of the following: (1) Was treat-to target discussed with patient, (2) Was objective assessment for inflammation (endoscopy, radiology and/or fecal calprotectin) performed within the preceding 12m, (3) Is there an intention to change treatment since target has not been reached. Over a 12-month breakthrough series (BTS) collaborative, we sought to improve implementation of TTT with monthly report cards, webinars, an active listserv and two all-Qorus learning sessions. Changes in rates of ‘intention to TTT’ were examined over 12 months, overall and at each site, with an earliest clinically meaningful signal of improvement defined a priori as 2% increase per month.

Results: Over 12 months, there were 7934 patient visits across 38 sites in the IBD Qorus collaborative; patients in 37% visits (n=2913) were not in endoscopic remission at time of visit. Overall, rates of ‘intention to TTT’ increased from 23% at the beginning of the BTS, to 49% at the end of the BTS, corresponding to a clinically significant 2.4% per month increase in rates of implementing TTT (p<0.01) (Figure 1). While rates of discussion of TTT (88% of eligible visits) and intention to adjust therapy (70% of eligible visits) were consistently high, there was a significant increase in objective evaluation for inflammation during the course of the BTS. There was considerable variability across sites in rates of ‘intention to TTT’ across sites.

Conclusions: Through a quality improvement initiative in a LHS, rates of ‘intention to TTT’ increased significantly over 12-months, though overall rates remained low. Assessing patient-, provider- and practice-level barriers and facilitators for successful implementation of a TTT strategy is warranted to improve clinical outcomes.

Background: For patients with inflammatory bowel disease (IBD) and a history of cancer, retrospective studies suggest that exposure to anti-TNF and/or immunomodulator (IMM) agents did not increase the risk of recurrent or new cancer compared to those not exposed to these medications. The SAPPHIRE Registry was developed to prospectively examine this issue.
Methods: Patients with IBD who had a confirmed first cancer (index cancer) were recruited from centers affiliated with the New York Crohn’s and Colitis Organization (NYCCO) since 2017. Patients receiving chemotherapy or radiation therapy at enrollment, a first cancer more than 10 years prior to study entry, or recurrent cancer within the last 10 years were excluded. Cancers were categorized as gastrointestinal (GI), hematologic, dermatologic, and other solid malignancies. The primary outcome was the development of recurrent or new cancer stratified by immunosuppression exposure.
Results: To date, 306 patients with IBD and an index cancer were enrolled. The average age at IBD diagnosis was 34 years and at cancer diagnosis was 52 years (Table 1). Patients were 48% male, 89% white, and 63% never smokers. Index cancers were solid (140; 46%), dermatologic (99; 32%), GI (32; 10%), and hematologic (23; 8%). The majority of index cancers were diagnosed as stage 1. Following the index cancer, patients were exposed to anti-TNF (98; 32%), vedolizumab (91; 30%), IMM (74; 24%), ustekinumab (58; 19%), and tofacitinib (9; 3%; Table 2). 103 (34%) of patients were exposed to neither immunomodulators nor biologics. During follow-up, 44 (14%) patients developed 53 subsequent cancers (25 new, 28 recurrent) comprising 18 (34%) other solid, 25 (47%) dermatologic, 5 (9%) GI, and 1 (2%) hematologic malignancy. After a mean follow up of 3.4 years (SD 1.4 years), unadjusted bivariate analysis did not reveal increased risk of new or recurrent cancer with exposure to IMM monotherapy (9.2/100 person-years; RR 1.39, 95% CI 0.41-4.37), biologic monotherapy (7.8/100 person-years; RR 1.17, 95% CI 0.52-2.87), combination therapy with an IMM and a biologic (14.0/100 person-years; RR 2.10, 95% CI 0.83-5.57), or tofacitinib (11.2/100 person-years; RR 1.70, 95% CI 0.18-8.19) compared to those not exposed to immunosuppression (6.7/100 person-years).
Conclusion: In this ongoing prospective study, exposure to immunosuppressive IBD therapies in patients with IBD and a history of cancer has so far conferred no increased risk of new or recurrent cancer. Continued prospective study is required to confirm these findings.

Background: Intestinal and perianal fistulas and fissures are associated with significant morbidity and decreased quality of life in patients with Crohn’s disease (CD). We evaluated rates of fistula and fissure improvements with upadacitinib (UPA), an oral selective Janus kinase inhibitor, in patients with CD who had fistulas or fissures at baseline in phase 3 induction and maintenance trials.
Methods: In the U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836) phase 3 induction trials, patients with moderate-to-severe CD were randomized to UPA 45 mg once daily (QD) or placebo (PBO) for 12 weeks. Patients who achieved clinical response after 12 weeks of induction were eligible for U-ENDURE (NCT03345823) and rerandomized to UPA 30 mg QD, UPA 15 mg QD, or PBO for an additional 52 weeks of maintenance treatment. Fistula activity was assessed by presence of external openings and draining upon gentle compression. Presence of perianal fissures was also assessed. The proportion of patients with external closure of fistula openings, complete resolution of draining, and ≥ 50% reduction in draining was recorded at weeks 12 and 52. Endpoints were analyzed using non-responder imputation.
Results: Of 1021 enrolled patients, 143 patients had fistulas (124 [86.7%] perianal; 19 [13.3%] enterocutaneous) and 54 patients had perianal fissures at baseline. The proportion of patients who achieved external closure of fistula openings was higher with UPA vs PBO at week 12 (Fig 1A) and at week 52 (Fig 2A). The proportion of patients who achieved complete resolution of draining and ≥ 50% reduction in draining was higher with UPA vs PBO at week 12 (Fig 1B and 1C) and at week 52 (Fig 2B and 2C). A higher proportion of patients achieved complete resolution of fissures with UPA vs PBO at week 12 (Fig 1D) and at week 52 (Fig 2D). At weeks 12 and 52, a higher proportion of patients with fistulas treated with UPA vs PBO achieved clinical remission and endoscopic response (Fig 1E and 2E). Rates of adverse events (AEs), serious AEs, or AEs leading to study drug discontinuation were similar in UPA groups compared with PBO during the induction and maintenance periods. Rates of abscess formation were 1.8% with UPA 45 mg and 6.8% with PBO at week 12, and 3.0% with UPA 30 mg, 6.4% with UPA 15 mg, and 2.5% with PBO at week 52.
Conclusions: Among patients with CD complicated with fistulas and/or fissures at baseline, UPA treatment led to higher rates of external closure of fistula openings, resolution of draining, and healing of fissures, along with clinical remission and improvements in luminal disease compared with PBO. No new safety concerns were identified.