Introduction

Risankizumab (RZB), a monoclonal antibody targeting the interleukin-23 p19 subunit, has previously demonstrated the ability to improve clinical and endoscopic outcomes during induction (ADVANCE, MOTIVATE) and maintenance (FORTIFY) in patients with moderately to severely active Crohn’s disease (CD) regardless of the number of prior biologic failures.^1-3 As sustained clinical and endoscopic improvements are important goals in CD, we evaluated the long-term outcomes of RZB by the number of prior biologic failures in patients who received long-term RZB maintenance treatment in the ongoing FORTIFY open-label extension (OLE) substudy.⁴

Aims & Methods

The FORTIFY OLE enrolled patients who completed 52 wks of maintenance therapy with subcutaneous RZB 180 mg, RZB 360 mg, or placebo (withdrawal) in the FORTIFY substudies or RZB phase 2 OLE. All patients received RZB 180 mg every 8 wks (q8w) starting at wk 56, except for those who received prior rescue therapy (single dose of RZB 1200 mg followed by RZB 360 mg q8w) as they continued RZB 360 mg q8w in the OLE. Patients who demonstrated an inadequate response (increased symptoms plus an objective marker of inflammation) during the OLE could also receive rescue therapy (single dose of RZB 1200 mg followed by RZB 360 mg q8w). This analysis included all patients who completed 2 years of RZB treatment in the FORTIFY OLE (following 1 additional year of randomized maintenance-see footnotes for complete patient population); herein referred to as 152-wk maintenance completers. We assessed clinical and endoscopic outcomes by the number of prior biologic failures (0, 1, ≥2) in each dose group as well as in a pooled dose group. Outcomes assessed at wk 12 (induction) and wk 52 (maintenance) are shown in the Table for reference.

Results

Among the 710 patients who were 152-wk maintenance completers, approximately 1/3 of patients failed 0 (n=210, 30%), 1 (n=227, 32%), ≥2 prior biologics (n=273, 38%), respectively. Baseline demographics and characteristics were similar across subgroups, although patients who failed ≥2 prior biologics generally had more severe disease, as defined by disease duration, SES-CD, FCP, and CRP. Across the subgroups of patients who failed 0, 1, and ≥2 prior biologics, rates of clinical remission (per CDAI and SF/APS), endoscopic response, endoscopic remission, and ulcer-free endoscopy were sustained through wk 152 with RZB maintenance therapy in the pooled RZB 180 mg and RZB 360 mg maintenance groups (Table). Results for the RZB 180 mg and RZB 360 mg groups are also shown in the Table. For almost all endpoints, patients who failed 0 prior biologics demonstrated numerically higher responses, followed by patients who failed 1, and then ≥2 prior biologics (Table).

Conclusion

Patients who completed 2 years of RZB treatment in the FORTIFY OLE demonstrated sustained clinical and endoscopic improvements regardless of the number of prior biologic failures. Biologic naïve patients demonstrated the most improvement, followed by those who failed 1, and then ≥2 prior biologics, suggesting the benefits of RZB in early treatment.

References

D'Haens G, Panaccione R, Baert F, et al. Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials. Lancet. 2022;399(10340):2015-2030. doi:10.1016/s0140-6736(22)00467-6
2. Ferrante M, Panaccione R, Baert F, et al. Risankizumab as maintenance therapy for moderately to severely active Crohn's disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial. Lancet. 2022;399(10340):2031-2046.
3. Ferrante M. Clinical and Endoscopic Improvements with Risankizumab Induction and Maintenance Dosing Versus Placebo are Observed Irrespective of Number of Prior Failed Biologics (Abstract OP128). UEG Journal. 2022:101.
4. Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology. 2021;160:1570-1583. doi:10.1053/j.gastro.2020.12.031

Disclosure

AbbVie Disclosure: AbbVie funded these studies and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, writing of manuscript, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.
Disclosures: Marc Ferrante has received speaker and/or consultant fees from AbbVie, AgomAb Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Dr Falk, Eli Lilly, Ferring, Janssen-Cilag, MRM Health, MSD, Pfizer, Regeneron, Takeda, Thermo Fisher, Truvion Healthcare and Viatris; Research Grants: AbbVie, Biogen, EG, Janssen, Pfizer, Takeda and Viatris.
Laurent Peyrin-Biroulet has received consulting and/or lecture fees from AbbVie, Adacyte, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Nordic Pharma, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, Ysopia, Abivax, Samsung, Ventyx, Roivant, and Vectivbio.
Axel Dignass reports received fees for participation in clinical trials, review activities such as data monitoring boards, statistical analysis and end point committees from Abivax, AbbVie, Bristol Myers Squibb, Dr Falk Foundation, Galapagos, Gilead, Janssen, and Pfizer; consultancy fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Roche, Sandoz, Stada, Takeda, Tillotts, and Vifor Pharma; payment for lectures including service on speakers bureaus from AbbVie, Biogen, CED Service GmbH, Celltrion, Falk Foundation, Ferring, Galapagos, Gilead, High5MD, Janssen, Materia Prima, MedToday, MSD, Pfizer, Sandoz, Takeda, Tillotts, and Vifor Pharma; payment for manuscript preparation from Abbvie, Falk Foundation, Janssen, Takeda, Thieme, and UniMed Verlag.
David T. Rubin has served as a consultant for AbbVie, Altrubio, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Dizal Pharmaceuticals, Galapagos, Ichnos Sciences S.A., InDex Pharmaceuticals, Iterative Health, Janssen, Lilly, Pfizer, Prometheus Biosciences, Reistone, Syneos, and Takeda. He has received grant support from Takeda.
Silvio Danese has received consultancy fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Janssen, Johnson &Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB Inc., and Vifor.
Geert D’Haens has served as an adviser for AbbVie, Alimentiv, AstraZeneca, Bristol Meyers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Galapagos, Pfizer, Immunic, Johnson & Johnson, Takeda, Tillotts, Ventyx, and Vifor Pharma; and has received speaker fees from AbbVie, Johnson & Johnson, Pfizer, Takeda, and Tillotts.
Kristina Kligys, Stijn van Haaren, Alexandra Song, Javier Zambrano, and Yafei Zhang are AbbVie employees and may own AbbVie stock and/or stock options.
Toshimitsu Fujii receives AbbVie GK, Alfresa Corporation, Boehringer Ingelheim GmbH, Bristol Myers Squibb, Celgene, Celltrion, EA Pharma, Eisai, Gilead Sciences, Janssen, Kissei, Lilly, and Takeda. and speaker fees from AbbVie GK, Ajinomoto Pharma, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, EA Pharma, Janssen, Kissei, Kyorin, Kyowa Hakko Kirin, Mitsubishi-Tanabe, Mochida, Nichiiko, Nippon Kayaku, Takeda, and Zeria Pharma.
Remo Panaccione has received consulting fees, speaker fees, and research support from
Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB.

Introduction

Obesity, characterized by low-grade systemic inflammation, is associated with numerous chronic inflammatory conditions including inflammatory bowel diseases (IBD). While accumulating body fat has direct influence on IBD progression, creeping fat (CF) in Crohn’s disease (CD) manifests independently of body weight. As a response of mesenteric adipose tissue (AT) to intestinal inflammation, preadipocytes migrate towards affected intestinal segments to form a distinct immunophenotypic AT comprising hyperplastic adipocytes, preadipocytes and immune cells which exert complex immunologic and metabolic interactions with the adjacent intestine. However, associations between the cellular architecture of CF and CD progression remain unclear.

Aims & Methods

We aim to study gut-AT interactions in the context of IBD, focusing on the role of preadipocytes in CF as well as relevance of metabolic integrity of mesenteric adipocytes for intestinal homeostasis. Ex vivo co-cultures of wild-type murine intestinal organoids and mesenteric mature adipocytes or preadipocytes using a novel 3D culture system allowed us to study direct effects on transcriptional profiles and growth capacity, distinguishably between adipogenic cells of distinct differentiation states. Furthermore, we generated a mouse model of adipocyte-specific mitochondrial dysfunction by genetic deletion of heat shock protein 60 (Hsp60) to investigate mechanisms of metabolic and inflammatory phenotype transmission between mesenteric AT and intestinal epithelium. In addition, we used human mesenteric and CF explants from CD patients undergoing surgical resection to isolate preadipocytes and perform ex vivo proliferation and differentiation studies.

Results

In intestinal organoids from mice, the presence of both, mature adipocytes and preadipocytes induces downregulation of Hsp60 accompanied by induction of mitochondrial stress markers (Trb3, Chop). However, solely preadipocytes were sufficient to induce intestinal epithelial gene signatures involved in oxidative stress (Ido1, Nos2, Duox2) and reduced stemness (Lgr5) as attributable to metabolic impairment and injury phenotypes. Conversely, in response to presence of intestinal organoids, mesenteric adipocytes show upregulated expression of browning markers (Ucp1, Cidea, Cox7a1) accompanied by reduced inflammatory and mitochondrial stress signaling. In mice, genetically induced mitochondrial dysfunction in adipocytes leads to phenotypic AT remodeling of specifically the mesenteric depot, resulting in extensive immune cell infiltration and crown-like structure formation in anatomic relation to the intestinal epithelium. Human CF-derived preadipocytes in comparison to equivalent cells from healthy mesentery of the same patient exhibit distinct morphological features and diminished lipid incorporation after adipogenic differentiation ex vivo.

Conclusion

We demonstrate that exclusively preadipocytes condition the intestinal epithelium to injury-related phenotypic features, suggesting a novel and crucial relevance for IBD research and management. Vice versa, intestinal epithelial cells can stimulate mesenteric adipocytes to recruit thermogenic capacity, which is associated with anti-inflammatory effects, suggesting a protective role of mesenteric AT browning capacity. Disturbing adipocyte mitochondrial function is sufficient to remodel mesenteric AT architecture and induce propagating inflammation. Consequent effects on the adjacent intestine we address in our ongoing studies considering adipocyte mitochondria as target for therapeutic interventions in CD.

Introduction

Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is part of a broader spectrum of immune-mediated inflammatory diseases (IMIDs). Clinical and epidemiological studies indicate a higher prevalence of IMIDs among patients with IBD and their first-degree relatives, with a significant proportion of patients with IBD also diagnosed with conditions such as asthma, psoriasis, and rheumatoid arthritis^1,2. These patterns suggest shared genetic and/or environmental risk factors. The clinical intersections call for a multidisciplinary management strategy in which decisions account for the broader immune landscape rather than focusing on each diagnosis in isolation^1,3.

Aims & Methods

This study aimed to characterize the relationship between IBD and other IMIDs and disentangle genetic and environmental contributions. This was done by analyzing the tetrachoric correlation⁴ between disease codes registered for 107,651 full sibling pairs born between 1910 and 2010 in the Danish nationwide health registries. We then estimated SNP-based correlations based on summary statistics from genome-wide association studies of each disease using LDSC⁵. Lastly, we downloaded and reanalyzed all V3-V4 16S rDNA fecal microbiota samples available from NCBI⁶ in a unified bioinformatical pipeline. We used this data to generate microbiota disease profiles and estimate their correlations across IBD and IMIDs.

Results

We show that CD and UC have distinct patterns of correlations with other IMIDs. Asthma and celiac disease were correlated with CD (asthma: ρ=0.12, 95% CI=0.10-0.13, celiac disease: ρ=0.12, 95% CI=0.08-0.17), but not UC within full siblings. Oppositely, sarcoidosis (ρ=0.16, 95% CI=0.13-0.19), multiple sclerosis (ρ=0.09, 95% CI=0.06-0.12), systemic lupus erythematosus (SLE) (ρ=0.19, 95% CI=0.13-0.25), and Sjögren’s syndrome (ρ=0.15, 95% CI=0.10-0.20) correlated with UC but not CD. The IMIDs Graves’ disease, type 1 diabetes, iridocyclitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis correlated with both CD and UC. Evaluating genetic and gut microbial correlations highlighted that UC exhibits microbiota-linked correlations with multiple sclerosis (ρ=0.11, 95% CI=0.01-0.21) and SLE (ρ=0.15, 95% CI=0.05-0.24) despite an estimated negative genetic overlap (multiple sclerosis: ρ=-0.18, 95% CI=-0.32--0.04, SLE: ρ=-0.21, 95% CI=-0.32--0.09), suggesting a key role for environmental factors, including microbial. In contrast, for both IBD subtypes rheumatoid arthritis showed consistent genetic (CD: ρ=0.12, 95% CI=0.02-0.21, UC: ρ=0.17, 95% CI=0.08-0.27) as well as microbial convergence (CD: ρ=0.30, 95% CI=0.20-0.38, UC: ρ=0.12, 95% CI=0.02-0.22), whereas the correlation with psoriasis appeared to be mainly genetically driven (CD SNP correlation: ρ=0.23, 95% CI=0.14-0.33, CD microbiota correlation: ρ=-0.13, 95% CI=-0.23--0.03, UC SNP correlation: ρ=0.25, 95% CI=0.15-0.35, UC microbiota correlation: ρ=0.06, 95% CI=-0.04-0.16).

Conclusion

These findings uncover heterogeneity in shared etiological pathways across immune diseases, underscoring the need for stratified approaches to diagnosis and therapeutic intervention in IBD. Importantly, our findings demonstrate that CD and UC—though often co-studied—harbor distinct immunogenetic and microbial associations, reinforcing the need for subtype-specific approaches in clinical management and research design. Further, the correlation between IBD and other IMIDs appears to be driven by different genetic and environmental mechanisms, which must be further explored.

References

1. Bezzio C, Corte C Della, Vernero M, et al. Inflammatory bowel disease and immune-mediated inflammatory diseases: looking at the less frequent associations. Therap Adv Gastroenterol 2022;15. Available at: https://journals.sagepub.com/doi/full/10.1177/17562848221115312 [Accessed March 14, 2025].
2. García MJ, Pascual M, Pozo C Del, et al. Impact of immune-mediated diseases in inflammatory bowel disease and implications in therapeutic approach. Sci Rep 2020;10:10731. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC7330038/ [Accessed March 14, 2025].
3. Park SW, Kim TJ, Lee JY, et al. Comorbid immune-mediated diseases in inflammatory bowel disease: a nation-wide population-based study. Aliment Pharmacol Ther 2019;49:165–172. Available at: https://pubmed.ncbi.nlm.nih.gov/30506945/ [Accessed March 14, 2025].
4. Falconer DS, Mackay TFC. Introduction to Quantitative Genetics. Third Ddit. Longman Scientific & Technical; 1989.
5. Bulik-Sullivan B, Finucane HK, Anttila V, et al. An atlas of genetic correlations across human diseases and traits. Nature Genetics 2015 47:11 2015;47:1236–1241. Available at: https://www.nature.com/articles/ng.3406 [Accessed March 14, 2025].
6. Sayers EW, Bolton EE, Brister JR, et al. Database resources of the national center for biotechnology information. Nucleic Acids Res 2022;50:D20–D26. Available at: https://pubmed.ncbi.nlm.nih.gov/34850941/ [Accessed March 14, 2025].

Disclosure

TJ reports consultancy for Ferring and Pfizer. The remaining authors have no disclosures.