Introduction

Mirikizumab is a monoclonal antibody directed against the p19 subunit of interleukin (IL)-23 approved for the management of patients with moderate-to-severe ulcerative colitis (UC). Currently, there is no large study supporting the effectiveness of mirikizumab in UC in a real-life setting.

Aims & Methods

This study aims to evaluate the effectiveness and safety of mirikizumab in real-life setting. This was a retrospective multicenter cohort study of a prospectively collected database including adult patients with confirmed diagnosis of UC treated with mirikizumab according to clinical practice. Patients were enrolled in three third-level italian centers (San Raffaele Hospital, Humanitas Research Hospital, and Federico II Hospital) from June 2024 to February 2025. All patients with at least 3 months of follow-up after therapy initiation were eligible. The primary outcome was the clinical remission rate (defined as partial Mayo Score (pMS) < 2 with a rectal bleeding subscore of 0) at week 12. Secondary outcomes included changes in bowel urgency (measured by the Numeric Rating Scale (NRS) urgency score), changes in serum C-reactive protein (CRP) and fecal calprotectin (FC) levels from week 0 to 12, safety profile of mirikizumab during induction therapy.

Results

In total 100 patients (60% male, with median age 48.53 ± 15.36) with UC were included. Most patients had a left-sided colitis (55, 55%) or a pancolitis (41, 41%). Most patients (81, 81%) were already treated with at least one advanced therapy before starting mirikizumab (including 28 patients treated with ustekinumab, 28%). A fifth of patients (19, 19%) were exposed to ≥ 4 advanced therapies. A significant reduction in pMS was observed from baseline to week 12 (median [IQR]: 4.0 [1.75–6.0] vs. 2.0 [0.0–4.0]; Wilcoxon signed-rank test: W = 312, Z = -5.35, p < 0.00001, n = 69) with 48 (48%) patients reaching clinical remission at week 12. Moreover, a significant improvement in bowel urgency was observed from baseline to week 12 (t(98) = 6.58, p = 2.28×10⁻⁹), with a moderate-to-large effect size (g = 0.66). From baseline to week 12, both FC and CRP levels showed significant reductions following treatment (FC: V = 1153.00, p = 2.4×10⁻⁵, r = 0.67; CRP: V = 680.00, p = 0.03, r = 0.37). Effect sizes were large for FC and moderate for CRP with paired data from 53 and 47 patients being analyzed, respectively. In total, 39 patients (39%) underwent extended induction while 3 patients (3%) discontinued the drug at week 12. There were no adverse events leading to discontinuation or death. Two mild adverse events were reported (upper respiratory tract infection in 1 patient and pyrexia in 1 patients). No significant changes were observed in liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels over time (AST: χ²(2) = 0.21, p = 0.90, W = 0.005; ALT: χ²(2) = 3.73, p = 0.16, W = 0.08).

Conclusion

This is the largest study demonstrating the effectiveness and safety of mirikizumab in inducing clinical remission in patients with UC in a real-life setting. Patients treated with mirikizumab achieved a significant reduction in bowel urgency, FC and CRP levels. No statistically significant increase in liver toxicity was detected during the induction treatment.

Disclosure

F. D'Amico. OM Nardone, A. Zilli, M. Allocca, S. Danese, L. Peyrin-Biroulet and A. Armuzzi have served as speaker and advisory board member for Lilly

Clinical Case Summary

An 18-year-old female was diagnosed with very early-onset Crohn’s disease (CD) in 2008. Due to steroid dependence, adalimumab 40 mg biweekly was initiated in 2019, with escalation to 40 mg weekly in February 2023 following secondary loss of response. In November 2023, despite clinical and biochemical remission (CRP <0.5 mg/L, fecal calprotectin <50 µg/g), the patient developed painful purpuric and ulcerated lesions on both lower limbs. Histological examination of a skin biopsy confirmed leukocytoclastic vasculitis (LCV), revealing perivascular neutrophilic infiltrates, nuclear debris, and fibrinoid necrosis in post-capillary venules. Infectious and autoimmune screening, including ANA, antiphospholipid antibodies, p-ANCA, and c-ANCA, were negative. Following consultation with an immunologist, adalimumab was discontinued, and oral prednisone 25 mg/day was initiated. However, the clinical course was complicated by a skin abscess, which was treated with oral amoxicillin/clavulanate (1 g three times daily for 3 days). As vasculitic lesions worsened, the patient was hospitalized, and prednisone was increased to 50 mg/day. Intravenous cefazolin (2 g every 8 hours for 5 days) was also administered, resulting in stabilization and partial clinical improvement. A multidisciplinary team, including a gastroenterologist, immunologist, and dermatologist, opted to initiate off-label treatment with upadacitinib 30 mg/day, a selective Janus kinase 1 (JAK1) inhibitor. After four weeks, the patient showed improvement in the vasculitic lesions, and corticosteroid therapy was tapered. At the six-month follow-up, the patient remained on upadacitinib monotherapy, with sustained clinical and biochemical remission of both CD and LCV, without any adverse events. This case highlights the potential of JAK1 inhibition as an effective and safe therapeutic option for leukocytoclastic vasculitis in patients with Crohn’s disease.

References

Photographic documentation of the clinical case:
1. Images showing the initial presentation of petechial and purpuric lesions on the lower limbs.
2. Images of severe vasculitis characterized by confluent and ulcerated lesions.
3. Images documenting cutaneous healing following upadacitinib treatment.

Introduction

Guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor, demonstrated efficacy in participants (pts) with moderately to severely active ulcerative colitis (UC) treated with GUS subcutaneous (SC) induction and maintenance in the Phase 3 ASTRO study. Here we present data for bowel urgency and abdominal pain symptoms as measured by the Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms (UC-PRO/SS) instrument at Week (W) 12 and W24.

Aims & Methods

Eligible pts had a modified Mayo score of 5 to 9, a rectal bleeding subscore of ≥1, and a Mayo endoscopic subscore (MES) ≥2. Pts had a documented inadequate response/intolerance to biologics, Janus kinase (JAK) inhibitors, and/or sphingosine-1-phosphate (S1P) inhibitors (BIO/JAKi/S1Pi-IR) or to corticosteroids, 6-mercaptopurine, or azathioprine. Randomization was stratified by baseline BIO/JAKi/S1Pi-IR status and MES with 418 pts allocated 1:1:1 to GUS 400 mg SC every 4 weeks (q4w) (x3)→GUS 200 mg SC q4w (N=140), GUS 400 mg SC q4w (x3)→GUS 100 mg SC every 8 weeks (q8w) (N=139), or placebo (PBO) (N=139). Pts who met rescue criteria at W16 were rescued: PBO pts switched to GUS; GUS pts stayed on their assigned GUS dose regimen (sham rescue). The prespecified analysis plan compared the combined GUS 400 mg SC group to PBO at W12 (both the GUS 100 mg q8w and 200 mg q4w groups received the same induction dosing regimen through W12) and each GUS group to PBO at W24. The UC-PRO/SS is a validated instrument to assess the severity of bowel-related symptoms.¹ Clinically meaningful improvements (CMI) in bowel signs and symptoms and abdominal symptoms scales were evaluated. Complete resolution of individual core symptoms (bowel urgency and abdominal pain) was assessed.

Results

Baseline mean UC-PRO/SS domain scores were similar across treatment groups (Table). The proportions of pts with bowel urgency at baseline were 81.3% in the GUS 100 mg group, 84.3% in the GUS 200 mg group, 82.8% in the GUS combined group, and 87.1% in the PBO group. Greater proportions of GUS-treated pts had resolution of bowel urgency at W12 (GUS combined vs PBO: 45.0% vs 23.1%, nominal P<0.001) and W24 (GUS 100 mg and GUS 200 mg vs PBO: 47.8% and 41.5% vs 22.3%; nominal P<0.001 for both). The proportions of pts with abdominal pain at baseline were 78.4% in the GUS 100 mg group, 74.3% in the GUS 200 mg group, 76.3% in the GUS combined and 78.4% in the PBO group. Greater proportions of GUS-treated pts had resolution of abdominal pain at W12 (GUS combined vs PBO: 48.8% vs 23.9%, nominal P<0.001) and W24 (GUS 100 mg and GUS 200 mg vs PBO: 45.9% and 45.2% vs 25.7%; nominal P<0.001 for both). The proportions of pts with no bowel urgency and no abdominal pain were greater for GUS vs PBO at W12 and W24 (Table). GUS-treated pts achieved greater improvement from baseline at W12 and W24 in domain and individual core symptoms compared with PBO-treated pts (Table). The proportions of pts achieving CMI in each domain score were greater for GUS vs PBO at both timepoints (Table).

Conclusion

Pts with moderately to severely active UC treated with GUS SC experienced CMI at W12 and W24 in UC signs and symptoms as measured by UC-PRO/SS compared with PBO.

References

Higgins PDR, et.al. J Patient Rep Outcomes. 2017;2:26.

Disclosure

SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen (Johnson & Johnson), Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB, and Vifor and reports lecture fees from AbbVie, Amgen, Ferring, Gilead, Janssen (Johnson & Johnson), Mylan, Pfizer, and Takeda.

LPB reports grants or contracts from Celltrion, Fresenius Kabi, Medac, MSD, and Takeda; consulting and/or payment or honoraria and/or data safety monitoring board or advisory board participation for AbbVie, Abivax, Adacyte, Alfasigma, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GlaxoSmithKline, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen (Johnson & Johnson), Kern Pharma, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, and Ysopia; and meeting attendance/travel support from Abbvie, Alfasigma, Amgen, Celltrion, Connect Biopharm, Ferring, Galapagos, Genentech, Gilead, Gossamer Bio, Janssen (Johnson & Johnson), Lilly, Medac, Morphic, MSD, Pfizer, Sandoz, Takeda, Thermo Fischer, and Tillots.

ML reports research support from Lilly, Pfizer, and Takeda and consulting for AbbVie, Bristol Myers Squibb, Intercept, Janssen (Johnson & Johnson), Lilly, Pfizer, Prometheus, Roivant, Takeda, and Target RWE.

MG, TB, YA, MK, CH, SJ, LJ, and HZ are employees of and may own stock in Johnson & Johnson.

TH reports research grants from AbbVie GK, Boston Scientific Corporation, EA Pharma Co. Ltd., JIMRO Co. Ltd., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Pfizer Inc., Takeda Pharmaceutical Co. Ltd., and Zeria Pharmaceutical Co. Ltd.; consulting fees from AbbVie GK, Abivax, Bristol Myers Squibb, EA Pharma Co. Ltd., Gilead Sciences, Janssen Pharmaceutical K.K., Lilly, Mitsubishi Tanabe Pharma Corporation, and Pfizer Inc.; and lecture fees from AbbVie GK, EA Pharma Co. Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Co. Ltd.

DTR reports consulting and/or speaker fees and/or advisory board participation for AbbVie, Altrubio, Apex, Avalo, Bristol Myers Squibb, Buhlmann Diagnostics, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Janssen (Johnson & Johnson), Lilly, Pfizer, Samsung Neurologica, and Takeda; Altrubio, Datos Health, and Iterative Health stock options; grants from Takeda; and membership on the Board of Directors of Cornerstones Health, Inc and on the Crohn’s & Colitis Foundation’s Board of Trustees.

JRA reports grant support from Janssen (Johnson & Johnson), Merck, and Pfizer; consultancy fees from AbbVie, Adiso, Bristol Myers Squibb, Ferring, Genentech, GlaxoSmithKline, Janssen (Johnson & Johnson), Merck, Pfizer, Roivant, and Seres Therapeutics; payments for speaking from AbbVie, Bristol Myers Squibb, and Janssen (Johnson & Johnson); and is a steering committee member and investigator for Janssen (Johnson & Johnson).