Introduction

Upadacitinib (UPA) is an oral, reversible JAK inhibitor that recently demonstrated efficacy compared with placebo (PBO) in 2 double-blind, multicenter induction studies, U-EXCEED and U-EXCEL, and 1 maintenance study, U-ENDURE.^1-3 UPA is approved for the treatment of patients with moderately to severely active Crohn’s disease (CD).^4,5 The updated STRIDE-II guidelines recommend symptomatic control and mucosal healing as short- and long-term goals, respectively, of therapy.⁶ This post hoc analysis evaluated the durability of clinical, biomarker, and endoscopic improvements in patients with moderately to severely active CD treated with maintenance UPA.

Aims & Methods

In the phase 3 induction studies, U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836), patients with moderately to severely active CD were randomized 2:1 to receive either UPA 45 mg or PBO once daily for 12 weeks. Clinical responders to UPA at week 12 were re-randomized 1:1:1 to the phase 3 maintenance study, U-ENDURE (NCT03345823), in which they received UPA 30 mg, UPA 15 mg, or PBO once daily for an additional 52 weeks. The 52‑week durability (achievement of an outcome at maintenance week 0 and at 52 weeks) of clinical, biomarker, and endoscopic outcomes was assessed amongst patients achieving the specified outcome at the end of induction. Endpoints evaluated included enhanced clinical response (per stool frequency [SF]/abdominal pain score [APS]) , clinical response (CR-100), clinical remission (per SF/APS and CD activity index [CDAI]), endoscopic response, endoscopic remission, achievement of normalized high-sensitivity C-reactive protein (hs-CRP), and achievement of normalized fecal calprotectin (FCP).

Results

Across all endpoints studied, maintenance UPA treatment with both UPA doses provided greater maintenance of response compared with PBO (Table). Compared with PBO, a greater proportion of patients receiving UPA achieved maintenance of CR-100 (UPA 30 mg, 60.8%; UPA 15 mg, 48.8%; PBO, 17.9%; nominal P < .0001 for both doses). Similarly, a greater proportion of patients maintained enhanced clinical response with UPA vs PBO (UPA 30 mg, 61.1%; UPA 15 mg, 44.0%; PBO, 21.8%; nominal P < .0001 for both doses). Maintenance of clinical remission was greater with UPA vs PBO (CDAI: UPA 30 mg, 65.2%; UPA 15 mg, 49.5%; PBO, 21.2%; SF/APS: UPA 30 mg, 60.0%; UPA 15 mg, 50.5%; PBO, 19.6%; nominal P < .0001 for all). Likewise, maintenance of endoscopic response was greater with UPA vs PBO, as was maintenance of endoscopic remission. A greater proportion of patients maintained biomarker normalization with UPA 15 mg or 30 mg vs PBO at week 52.

Conclusion

Maintenance therapy with both UPA doses results in durable clinical, biomarker, and endoscopic improvements amongst patients with moderately to severely active CD. Patients receiving UPA 30 mg QD maintenance achieved key endpoints at a numerically higher rate than did patients receiving UPA 15 mg QD.

References

1. Loftus E, et al. United European Gastroenterol J. 2022;10:OP129.
2. Colombel JF, et al. Gastroenterology. 2022;162:867f.
3. Panés J, et al. Am J Gastroenterol. 2022;117:S10.
4. RINVOQ. Summary of Product Characteristics. AbbVie Deutschland GmbH & Co. KG; 2023. Accessed 24 April 2023. https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf.
5. Electronic Medicines Compendium. Rinvoq (upadacitinib) 30 mg prolonged-release tablets: summary of product characteristics. Updated March 16, 2023. Accessed March 27, 2023. https://www.medicines.org.uk/emc/product/12830/smpc/
6. Turner D, et al. Gastroenterology. 2021;160:1570–1583.

Disclosure

RP has served as consultant for Abbott, AbbVie, Abbivax, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Lilly, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB; speakers fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Lilly, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda; and has received research grants from AbbVie, Janssen, Pfizer, Takeda, and Ventyx.
MTA has served as a consultant for AbbVie, Arena Pharmaceuticals, Bristol-Myers Squibb, Celsius, Focus Medical, Gilead, Janssen, Microba, Lilly, Pfizer, Prometheus Biosciences, UCB, and WebMD Global.
RA has served as a speaker or consultant, or received research grants from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, Falk Foundation, Ferring, Galapagos, Gilead, InDex Pharmaceuticals, Janssen-Cilag, Kiniksa, Lilly, MSD, Novartis, Pandion Therapeutics, Pfizer, Roche Pharma, Samsung Bioepis, Takeda, Tillots Pharma, and Viatris
PB has received financial support for research from AbbVie, Amgen, Celltrion, Mylan, Pfizer, and Takeda; lecture fees from AbbVie, Celltrion, Janssen, Lilly, and Takeda; and consulting fees AbbVie, Arena Pharmaceuticals, Bristol-Myers Squibb, Celltrion, Dr Falk, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda, and Tetrameros.
SDL has served as a consultant for Cornerstones, Janssen, Lilly, Pfizer, and UCB; and received grant and research support from AbbVie, Arena, Celgene, Janssen, Shield Therapeutics, Takeda, Tetherex, and UCB.
GAD reports no conflicts of interest
EL has received research grants from Janssen, Pfizer, and Takeda; received educational grants from AbbVie, Janssen, MSD, and Takeda; received speaker fees from AbbVie, Dr Falk Pharma, Ferring, Hospira, Janssen, MSD, Pfizer, and Takeda; served on advisory boards for AbbVie, Arena, Celgene, Ferring, Galapagos, Gilead, Hospira, Janssen, MSD, Pfizer, and Takeda; and served as a consultant for AbbVie.
ST has received research funding from AbbVie.
APL, ED, CJ, and AG are employees of AbbVie and may own stock and/or options.
JP has received financial support for research from AbbVie and Pfizer; received lecture fees from AbbVie, Ferring, Janssen, and Takeda; and received consultancy fees from AbbVie, Arena Pharmaceuticals, Athos, Boehringer Ingelheim, Celltrion, Ferring, Galapagos, Genentech, GSK, Janssen, Mirum, Morphic, Origo, Pandion, Pfizer, Protagonist, Revolo, Robarts, Roche, Takeda, Theravance, and Wassermann.
Funding
AbbVie Inc. funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of this abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship. AbbVie and the authors thank the patients who participated in the study and all study investigators for their contributions. AbbVie funded the research for this study and provided writing support for this abstract. Medical writing assistance, funded by AbbVie, was provided by Spencer Hughes, PhD, of JB Ashtin.

Introduction

Underwater endoscopic mucosal resection (UEMR) is an alternative to conventional EMR (CEMR) offering consistent negative horizontal margins. However, UEMR does not involve submucosal injection; thus, its ability to achieve a sufficient resection depth comparable to that of CEMR remains uncertain. This randomized controlled trial (RCT) aimed to compare UEMR and CEMR in terms of resection depth.

Aims & Methods

This multicenter, parallel two-arm, open-label, noninferiority RCT was conducted across four Japanese institutions enrolling patients with colorectal tumors measuring 10–20 mm. Participants were randomly assigned in a 1:1 ratio to either to UEMR or CEMR group, using a computerized random-number generator. The primary outcome was the resection depth, which is the distance from the lower edge of the muscularis mucosa to the deep margin of the resected specimen, analyzed based on per-protocol (PP) principles (noninferiority margin of 400 µm).

Results

This study screened 217 patients from September 21, 2022, to December 2, 2024, and randomly assigned them to the UEMR (n =109) or CEMR (n =108) group. The PP analysis revealed that the mean resection depths of the UEMR and CEMR groups were 1688.9 ± 1510.0 µm and 1432.3 ± 1294.2 µm, respectively (mean difference: 256.6 µm, 95% confidence interval: -119.9 µm to 633.1 µm; P = 0.18), indicating the noninferiority of UEMR compared with CEMR in terms of resection depth. Subgroup analyses revealed that the resection depth of lesions by UEMR, especially at the cecum/ascending colon (1822.4 ± 1469.7 µm vs. 1096.5 ± 1007.6 µm; P = 0.01), and those with superficial morphology (1238.7 ± 862.2 µm vs. 731.6 ± 376.1 µm; P < 0.01), was significantly deeper than that achieved by CEMR. Moreover, even for nonexperts, UEMR tended to provide adequate resection depth compared with CEMR, approaching the proficiency level exhibited by experts (1786.6 ± 1471.6 µm vs. 1192.4 ± 1074.7 µm; P = 0.07). There were no significant differences in adverse events between the two groups, including one case of intraoperative perforation (0.9%) in the CEMR group and one case of delayed bleeding (0.9%) in the UEMR group. No EMR-related deaths were reported.

Conclusion

UEMR maintains the equivalent resection depth as CEMR and could become the gold standard endoscopic resection technique for intermediate-size colorectal tumors. UEMR is strongly recommended, especially for lesions at the cecum, ascending colon, and superficial lesions, because it could resect significantly deeper than CEMR. Furthermore, UEMR is recommended for nonexperts as a resection method that provides sufficient resection depth (Clinical trial registration number: UMIN000047432).

Introduction

Complex perianal fistulas represent one of the most challenging manifestations of Crohn’s disease. Combined surgical and medical therapy with biologic drugs represents today the first-line treatment option, but its efficacy does not exceed 60% in terms of healing. Recently, new therapeutic approaches, such as autologous microfragmented adipose tissue (M-Fat) injection, have shown promising results. Indeed, a recent non-profit prospective pilot study on 15 patients has demonstrated that the local injection of M-Fat is a safe and promising “rescue therapy” for patients with multiresistant complex fistulizing Crohn’s disease (PCD), with a 66.7% rate of combined remission in such difficult patients. It has to be highlighted that the M-Fat injection is minimally invasive, with less risk of sphincteric damage and can be carried out in day-surgery setting.

Aims & Methods

The primary aim of this multicentre double-blind randomized controlled trial (ATTIC) is to evaluate the efficacy of the infiltration of M-Fat in the healing of perianal complex fistulas not-responding to treatment with biologics. Consecutive patients referring to the 6 investigation Centers for surgical treatment of persistent complex fistulizing PCD refractory to biosurgical approach were assessed for eligibility. After baseline pelvic magnetic resonance imaging, those included were submitted to surgical drainage with “cone-like” fistulectomy, and then randomized to receive a 15 to 20 cc local injection, at the internal orifice level and along fistula tracts, of M-Fat obtained by a lipoaspiration and processed with an enzyme-free technology (treatment group), or a suture placement and injection of 15 cc of saline solution at the internal orifice (control group). Clinical follow-up were conducted at 2, 4, 8, 12, and 24 weeks; at 24 weeks after surgery, pelvic magnetic resonance was obtained. Success was defined as “combined remission”, combination of clinical (absence of drainage upon gentle finger compression) and radiological healing (absence of residual collections > 3 mm). Clinical remission was defined as clinical healing of all external openings not confirmed at radiological assessment.

Results

An overall 92 patients were screened, and 66 (33 per group) completed the 24-week follow-up. A statistically significant difference in favour of the treatment group in terms of combined remission emerged at the primary endpoint at 24-week follow-up (control group, 18.18%; treatment group: 57.58%; p = 0.0020). No significant differences in clinical outcome measures were encountered at any of the other follow-up points. No significant differences emerged between the groups in terms of recurrence rate, complication rate, and number of adverse events. Clinical remission was 63.64% in the treatment group compared to 51.52% in the control group with no statistically significant difference (p > 0.05).

Conclusion

This multicentre double-blind randomized controlled trial demonstrates that the intraoperative injection of M-Fat, associated with surgical complete drainage of perianal sepsis, is safe, effective, and reproducible in healing complex multirefractory perianal Crohn's disease, while improving the quality of life and significantly reducing the risk of definitive oostomy.