Comparative study on the effectiveness, durability, and safety of upadacitinib versus risankizumab after anti-TNF failure in Crohn's Disease: The U-PARIS study of ENEIDA

Abstract

Background Upadacitinib (UPA) and risankizumab (RSK) are alternatives for Crohn’s disease (CD) patients refractory to conventional therapies or biologics, although their optimal positioning is unclear.

Aims to compare the durability and effectiveness of UPA and RSK after biologic failure in CD; to identify risk factors for relapse and for therapy discontinuation; and to explore safety profile of UPA and RSK in this scenario.

Methods Adult patients from the prospectively-maintained ENEIDA registry of GETECCU who received UPA or RSK as second- (after 1 anti-TNF) or third-line (after 2 anti-TNFs, after 1 anti-TNF+vedolizumab, or after 1 anti-TNF+ustekinumab) with ≥12 weeks of follow-up, were included. Clinical remission was defined as Harvey-Bradshaw Index (HBI) ≤ 4, and clinical response as a decrease in HBI > 3 points. Biologic remission was considered as faecal calprotectin (FC) ≤ 250 µg/g, and biologic response as a reduction of ≥ 50% in FC levels. Endoscopic activity was graded as quiescent (remission), mild, moderate or severe (as endoscopist’s criteria); and radiologic activity as absence/presence according to radiologist. Outcomes were evaluated at 12, 24, and 48 weeks. Treatment durability was analysed using Kaplan-Meier curves, and factors for therapy discontinuation and relapse were identified by Cox regression. All adverse events (AEs) were recorded.

Results A total of 562 patients from 39 centers were included [UPA: n = 242 (43%), RSK: n = 320 (57%)] (Table 1).

In second-line, 12 and 24-week durability was 70%/59% for UPA and 72%/72% for RSK; in third-line, 61%/40% for UPA, and 80%/76% for RSK (p < 0.05). Outcomes were included in Table 2.

In second-line, predictive factors for therapy discontinuation were stricturing-fistulising behaviour (Hazard Ratio [HR]=1.9, 95% confidence interval [CI]=1.1-3.3), and UPA vs. RSK treatment (HR = 1.8, 95%CI=1.1-3.1). In third-line, UPA treatment was associated with treatment discontinuation (HR = 2.4, 95%CI=1.5-4). The severity of CD at baseline was associated with relapse in second- (HR = 7.1, 95%CI=3.9-12.7) and in third-line (HR = 5.4, 95%CI=3.4-8.7). AEs were reported in 64 (28%) UPA- and 28 (10%) RSK- treated patients (p < 0.05), most commonly acne for UPA, while infections predominated with RSK. Treatment was maintained in 81% of UPA and 91% of RSK patients with AEs (p < 0.05).

Conclusion UPA and RSK are effective options after biologic failure in CD patients. Both agents showed high treatment durability with greater persistence observed for RSK in third-line. CD behaviour and UPA treatment (vs. RSK) were predictive factors for therapy discontinuation, while severity of CD at baseline predicted relapse. AEs occurred more frequently with UPA, leading to a higher rate of treatment discontinuation compared with RSK.