Introduction

GLPG3970, a potent and selective salt-inducible kinase (SIK) 2/3 inhibitor, exerts a dual mechanism combining anti-inflammatory and immunoregulatory activity.¹ In chronic inflammatory diseases, such as inflammatory bowel disease (IBD), GLPG3970 has the potential to restore immune balance and homeostasis.^2,3 In a 6-week signal-detection phase 2a study in patients with ulcerative colitis (UC),⁴ GLPG3970 showed positive effects in histology, endoscopy and faecal calprotectin versus placebo, despite no differentiation from placebo on change from baseline on total Mayo Clinic Score at week 6.^4,5

Aims & Methods

We investigated the dual mechanism of GLPG3970 in severely inflamed ex vivo treated IBD tissue biopsies. Inflamed intestinal biopsies (most affected segment; n = 9 per patient) were obtained from patients with UC (n = 10) and Crohn’s disease (CD; n = 10) with active endoscopic disease (UC: Mayo endoscopic subscore ≥ 2; CD: SES-CD of ≥ 4). Patients were biologic-naive (UC: n = 5; CD: n = 5) or biologic-experienced (UC: n = 5; CD: n = 5). Three individual biopsies per condition were exposed ex vivo for 24 hours to vehicle control (DMSO), tofacitinib (10 µM, positive control) or GLPG3970 (60 µM). Protein secretion in supernatant was analysed by V-PLEX Human Biomarker 54-Plex (two-way ANOVA, Dunnett’s multiple comparison). RNA sequencing of biopsies was performed on Illumina NovaSeq 6000. Gene expression was quantified using Salmon (v1.5.2) and differential expression analysis was performed with DESeq2 (v1.28.0; criteria: |log2FC|> 0.58, FDR < 0.05, baseMean > 32).

Results

High levels of inflammatory cytokines and chemokines were observed in the supernatant after ex vivo culturing. Exposure to GLPG3970 resulted in a significant decrease of pro-inflammatory cytokines (e.g. TNFα, GM-CSF, IFN-γ, IL-2) and chemokines (e.g. MCP-1, MIP1α, MIP1β) in both UC and CD biopsies, relative to vehicle control. GLPG3970 activity was statistically stronger than tofacitinib for most evaluated proteins (p value), except for IL-1RA, IL-3, IL-9, IL-22, IL-23, among others. RNAseq analysis showed a clear signature of differentially expressed genes (DEGs) for GLPG3970 versus vehicle control (UC: 549 DEGs, with 288 downregulated, including pro-inflammatory genes CSF2, MMP9 and CCL4; CD: 673 DEGs, with 238 downregulated, including CSF​2, CXCL10 and CXCL11). Tofacitinib versus vehicle resulted in 582 (UC) and 681 (CD) DEGs including JAK/STAT dependent genes, such as MX1, SOCS3 and IFITM1. Direct comparison of GLPG3970 versus tofacitinib highlighted the impact of GLPG3970 on pathways involved in ‘TGF-β signalling’, indicative of enhancing immunoregulatory mechanisms, ‘TNFα signalling via NF-κB’ and ‘glycolysis’, whereas tofacitinib mainly affected ‘IFN-α response’ and ‘IFN-γ response’ in both UC and CD biopsies. In addition, GLPG3970 exposure to ex vivo biopsies resulted in a partial reversion of UC and CD transcriptome signatures (Spearman correlation: -0.25 [UC], -0.22 [CD]).⁶

Conclusion

Acute exposure of GLPG3970 to ex vivo inflamed tissue biopsies from patients with UC and CD showed a strong reduction in the release of pro-inflammatory mediators. Transcriptomic analysis further confirmed GLPG3970’s robust activity in reducing inflammatory NF-κB-mediated pathways while modulating TGF-β-related immunoregulatory pathways versus tofacitinib. Our findings support the dual mechanism of GLPG3970 in relevant pathogenic pathways in IBD and confirm the therapeutic potential of SIK2/SIK3 inhibition in treating patients with either UC or CD.

References

1. Peixoto C et al. J Med Chem 2024;67:5233–58.
2. Pereira-Fernandes A et al. [abstract] United European Gastroenterol J 2021;9:S8.
3. Lavazais S et al. [abstract] United European Gastroenterol J 2021;9:S8.
4. ClinicalTrials.gov. A Study Evaluating the Effects of GLPG3970 Given as an Oral Treatment for 6 Weeks in Adults With Ulcerative Colitis (SEA TURTLE). 2020. Available from: https://clinicaltrials.gov/study/NCT04577794 (Accessed 8 April 2024).
5. Galapagos. Galapagos demonstrates early clinical activity with SIK2/3 inhibition in inflammation. 2021. Available from: https://www.glpg.com/press-releases/galapagos-demonstrates-early-clinical-activity-with-sik2-3-inhibition-in-inflammation/ (Accessed 8 April 2024).
6. Massimo L et al. Nat Comput Sci 2021;1:511–15.

Disclosure

This study was funded by Galapagos NV (Mechelen, Belgium).
Editorial and publications management support was provided by PharmaGenesis London, London, UK, and was funded by Galapagos NV.
LG and KA are joint first authors.
LG, KA and EV report no disclosures.
MC and SDV are employees of Galapagos.
BV reports research support from AbbVie, Biora Therapeutics (formerly Progenity), Landos Biopharma, Pfizer, Sosei Heptares and Takeda; speaker fees from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring Pharmaceuticals, Galapagos, Janssen Pharmaceuticals, Lily, MSD, Pfizer, R-Biopharm, Sandoz, Takeda, Tillots Pharma, Truvion Healthcare and Viatris; consultancy fees from Abbvie, Alfasigma, Alimentiv, Applied Strategic, AstraZeneca, Atheneum, BenevolentAI, Biora Therapeutics (formerly Progenity), Boxer Capital, Bristol Myers Squibb, Galapagos, Guidepont, Landos, Lily, Mylan, Inotrem, Ipsos, Janssen Pharmaceuticals, Pfizer, Sandoz, Sanofi, Santa Ana Bio, Sapphire Therapeutics, Sosei Heptares, Takeda, Tillots Pharma and Viatris; and stock options from Vagustim.
SV reports speaker and/or consultancy fees from AbbVie, Abivax, AbolerIS Pharma, AgomAb Therapeutics, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Biora Therapeutics (formerly Progenity), Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cytoki Pharma, Dr Falk Pharma, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, Gilead Sciences, GSK, Hospira, IMIDomics, Janssen Pharmaceuticals, Johnson & Johnson, Lilly, Materia Prima, Mestag Therapeutics, MiroBio, Morphic Therapeutic, MRM Health, MSD, Mundipharma, Pfizer, ProDigest, Prometheus Biosciences, Robarts Clinical Trials, Surrozen, Takeda, Theravance Biopharma, Tillotts Pharma, VectivBio, Ventyx Biosciences and Zealand Pharma; grants from AbbVie, Galapagos, Johnson & Johnson, Pfizer and Takeda; and participation on a data safety monitoring board for Sanofi.

Introduction

Recent research finds 25%-30% of IBD patients experience chronic post-traumatic stress due to their disease (IBD-PTS) and IBD-PTS is associated with poorer outcomes. Post-traumatic growth (PTG) is defined as “positive psychological changes that occur as a result of one’s struggle to cope with trauma or a major life crisis.” PTG can reduce the negative impacts of IBD-PTS, which may be moderated by disease activity in IBD.

Aims & Methods

We aim to examine the relationship between remission status, patient expectations regarding if they can achieve and sustain remission, and PTG among patients with IBD. Adults (18+) with IBD were recruited via social media IBD support groups, and flyers posted in gastroenterology clinics and community bathrooms with additional snowball sampling methods. Surveys were completed online via Qualtrics and included demographics, Patient Simple Clinical Colitis Activity Index (P-SCCAI), Post-Traumatic Growth Inventory (PTGI), and PTSD Checklist for DSM-5 (PCL-5). Participants reported if they were in remission or experiencing a flare of symptoms, and their expectations of experiencing a flare in the next 2 months on a 4-Point Likert scale.

Results

313 adults with IBD: UC (n=140, 44.7%), CD (n=173, 55.3%). Age 18-70 years (M=33, SD=11), 75.1% female. Scores for PTGI, P-SCCAI, and PCL-5 are in Table 1. Participants tended to have active disease and high levels of IBD-PTS. No significant correlation existed between P-SCCAI score and PTG (r= -.09 p=.127). Those in a current IBD flare (n=133,42.4%) reported lower confidence in the longevity of their remission over the next 2 months compared to participants who were in remission (Χ2=114.01,p<.001), with no difference in PTG levels between groups (p=.310). However, participants who demonstrated optimism about sustained remission had higher levels of PTG (F(3,309)=4.688,p=.003). Participants who endorsed “I am positive I will experience a flare up in the next two months” had much lower levels of PTG (M=65.91,SD=25.33) than participants who endorsed “I am positive I will not experience another flare up in the next two months” (M=81.52,SD=25.58;p=.004). Those who endorsed “I am at least 50% positive I will experience another flare up” had lower rates of PTG (M=69.99, SD=22.95) than those who endorsed “I am positive I will not experience another flare up in the next 2 months” (M=65.91,SD=25.33;p=.026). A linear regression found the extent of the differences in the levels of confidence in maintaining remission influenced levels of PTG (F(3,309)=4.688 p=.003). Participants who were the least confident in their remission scored 15.61 points lower for PTG than for participants who were the most confident. Participants who were at least 50% sure they would experience another flare in the next two months scored 11.53 points lower for PTG than participants who were the most confident in their remission.

Conclusion

Our findings suggest IBD patients who expect to achieve disease remission are more likely to have higher levels of PTG than those who are more pessimistic about their disease course, independent of current symptom activity. However, those in an IBD flare are less likely to believe they can attain remission. Due to the unpredictable nature of IBD, patients are chronically exposed to risks for medically traumatic experiences. Patients with confidence in their remission longevity may conceptualize remission as an “end” to the threat of IBD-PTS, thus allowing PTG to occur. Conversely, if remission is seen as a temporary reprieve before the next inevitable flare, it may limit patients’ abilities to cultivate PTG. Providers can help patients move towards a PTG mindset by assessing patients’ expectations of remission, modeling optimism in a patient’s prognosis, and providing evidence for ongoing hope.

References

Fuss, A., & Lease, S. (2023). Moderating the Relationship Between Ulcerative Colitis and Crohn’s Disease and Symptoms of PTSD: The Role of Remission. Journal of Clinical Gastroenterology, 57(8), 816-823.

Purc-Stephenson, R. J. (2014). The posttraumatic growth inventory: Factor structure andinvariance among persons with chronic diseases. Rehabilitation Psychology, 59, 10–18.https://doi.org/10.1037/a0035353

Disclosure

The authors have no disclosures

Introduction

Etrasimod is an oral, once-daily, selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC).

Aims & Methods

This post hoc analysis of ELEVATE UC 52 and ELEVATE UC 12 describes etrasimod efficacy and safety in patients stratified according to baseline disease activity. In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients aged 16–80 years with moderately to severely active UC were randomised 2:1 to etrasimod 2 mg once daily or placebo.¹ ELEVATE UC 52 had a treat-through design comprising a 12-week (wk) induction period followed by a 40-wk maintenance period. ELEVATE UC 12 comprised a 12-wk induction period. In this analysis, data were pooled from both trials and patients’ baseline UC activity was stratified as moderately or severely active based on a Modified Mayo score (MMS) of 5–7 or 8–9, respectively. Efficacy endpoints were measured at Wk 12 and included mean percentage change from baseline in MMS and clinical response/remission according to MMS category. Efficacy data were analysed descriptively, and 95% confidence intervals (CIs) were calculated for all means or proportions using normal approximation or simultaneous estimation method, respectively. Safety was assessed up to Wk 52 in the pooled safety analysis set.

Results

Of the 743 patients in this analysis, 525 (70.7%) had a baseline MMS 5–7 and 218 (29.3%) had a baseline MMS 8–9. Baseline characteristics were broadly similar between subgroups, with the exception of lower rates of proctitis in patients with MMS 8–9 vs 5–7 (3.3% and 3.0% vs 9.3% and 9.4% in etrasimod and placebo groups, respectively). At Wk 12, patients treated with etrasimod showed larger mean percentage reductions (95% CI) in MMS, vs placebo, regardless of baseline disease activity (48.4% [52.3, 44.4] vs 27.0% [32.2, 21.7] for baseline MMS 5–7, and 46.4% [51.2, 41.5] vs 29.8% [37.2, 22.3] for baseline MMS 8–9). At Wk 12, more patients treated with etrasimod achieved clinical response, vs placebo, regardless of baseline disease activity, with an overall reduction from baseline disease activity as measured by MMS categorisation in both baseline MMS subgroups (Table). Generally, rates of treatment-emergent adverse events (TEAEs) were similar across treatment and baseline disease activity subgroups (proportion of patients with any TEAE: 59.0% vs 50.8% and 65.1% vs 56.1% for etrasimod vs placebo, in baseline MMS 5–7 and 8–9 groups, respectively).

Conclusion

Etrasimod showed greater reductions in disease severity and higher rates of clinical response, vs placebo, regardless of baseline disease activity. The safety profile of etrasimod was consistent with the overall trial population¹ and was not impacted by baseline disease activity.

References

1. Sandborn WJ et al. Lancet 2023; 401: 1159–1171

Disclosure

BES has received consulting fees from AbbVie, Abivax, Alimentiv, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Janssen, Kaleido, Kallyope, Lilly, Merck, Morphic Therapeutics, MRM Health, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Sun Pharma, Surrozen, Takeda, Target RWE, Teva, Theravance Biopharma, TLL Pharmaceutical, Ventyx Biosciences; speaker fees from Abivax, Bristol Myers Squibb, Janssen, Lilly, Pfizer, Takeda; research grants from Bristol Myers Squibb, Janssen, Pfizer, Takeda, Theravance Biopharma; stock options from Ventyx Biopharma; and other support from Bristol Myers Squibb, Lilly, Janssen, Pfizer and Takeda. MCD is a consultant for AbbVie, Abivax, AstraZeneca, Bristol Myers Squibb, Janssen, Lilly, Merck, Pfizer Inc, Prometheus Labs, Spyre and Takeda. PGK has received consulting and speaker fees from AbbVie, Janssen, Pfizer Inc, and Takeda and has received scientific grants from Pfizer Inc and Takeda. SV has received speaker fees from AbbVie, Dr. Falk Pharma, Ferring, Galapagos, Hospira, Janssen, MSD, Takeda, and Tillotts; consultancy/advisory fees from AbbVie, AbolerIS Pharma, Alimentiv, Arena, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, Johnson and Johnson, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillots Pharma AG and Zealand Pharma; and grant/research support from AbbVie, MSD, Pfizer Inc, Galapagos, Janssen and Takeda. RP has received consulting fees 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, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus, Viatris, Ventyx, UCB; speaker fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, Takeda; an advisory board member for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda, Ventyx; and received research support from AbbVie, Janssen, Takeda and Pfizer. MDL is a consultant for AbbVie, Janssen, Pfizer Inc, Takeda, BMS, Target PharmaSolutions, Prometheus, Lilly, Salix, Valeant, Genentech, Roche, Calibr, Theravance; and has received research support from Pfizer Inc and Takeda. JCW, JW and EB are employees and shareholders of Pfizer Inc. AM is an employee of Pfizer Ltd and shareholder of Pfizer Inc. MG is an employee and shareholder of Pfizer AG. AJY has received consultancy fees from AbbVie, Pfizer Inc, Arena, Takeda, Bristol Myers Squibb; and speaker fees from Bristol Myers Squibb.

Introduction

Ileus, a slowing or halting of intestinal motility, develops in trauma, critically ill, and surgical patients, resulting in prolonged hospital and ICU stays, increased infectious complications, and more hospital readmissions. Inflammatory insult to the gastrointestinal smooth muscle is frequently brought on by direct manipulation of the intestines during surgery, but can also be caused by systemic inflammation, which activates mast cells and macrophages and increases the production of inflammatory cytokines. We have demonstrated that the chemokine (C-X-C motif) ligand 1 (CXCL1), which inhibits intestinal motility, is enhanced in rodent ileus models and in the blood of trauma patients who develop ileus. P21-activated kinase (PAK) 1, which is elevated in response to mechanical stretch, has also been connected to the emergence of ileus.

Aims & Methods

In this study, we focused on the relationship between mechanotransduction, CXCL1, and PAK1. We utilized both an organ bath system and cyclical stretch of cell models via a Flex cell apparatus to study the role of mechanotransduction. Both human intestinal smooth muscle cells (hiSMCs) and macrophages were subjected to physiological (control cyclical stretch, CCS) and pathological (edema cyclical stretch, ECS, as experienced during edema development or ileus) stretch. The role of NF-kB, which has been shown to regulate CXCL1 expression, was investigated. Intestinal tissue samples from wildtype and PAK1 knockout mice were also stretched in the presence or absence of IPA-3, a PAK1 inhibitor, and IMD-5304, an NF-kB inhibitor. The expression and secretion of CXCL-1 in intestinal smooth muscle cells and macrophages were determined by ELISA and RT-qPCR.

Results

In response to the induction of ileus (via gut manipulation), CXCL1 expression was increased in wild-type mice but not PAK1 knockout mice. PAK1 inhibition did not attenuate the inhibitory effects of CXCL1 on intestinal motility; however, the inhibitory effects of CXCL1 were partially inhibited in PAK1 knockout mice. Mechanical stretch increased CXCL1 in the media of macrophages and human intestinal smooth muscle cells. PAK1 inhibition did not prevent the increased CXCL1 secretion in human intestinal smooth muscle cells. NF-kB activation was increased in response to increased stretch, and NF-kB inhibition prevented stretch-induced increase in CXCL1 secretion.

Conclusion

We conclude that during the development of edema and/or ileus, pathological strain can stimulate CXCL1 release from both intestinal smooth muscle cells and macrophages. However, inhibition of NF-kB, but not PAK1, prevents stretch-induced CXCL1 secretion.

References

Asgeirsson, T., El-Badawi, K. I., Mahmood, A., Barletta, J., Luchtefeld, M., & Senagore, A. J. (2010). Postoperative Ileus: It Costs More Than You Expect. Journal of the American College of Surgeons, 210(2), 228–231. https://doi.org/10.1016/j.jamcollsurg.2009.09.028
Chu, J., Pham, N. T., Olate, N., Kislitsyna, K., Day, M. C., LeTourneau, P. A., Kotss, A., Stewart, R. H., Laine, G. A., Cox, C. S., & Uray, K. (2013). Biphasic regulation of myosin light chain phosphorylation by p21-activated kinase modulates intestinal smooth muscle contractility. Journal of Biological Chemistry, 288(2), 1200–1213. https://doi.org/10.1074/JBC.M112.370718
Docsa, T., Bhattarai, D., Sipos, A., Wade, C. E., Cox, C. S., & Uray, K. (2020). CXCL1 is upregulated during the development of ileus resulting in decreased intestinal contractile activity. Neurogastroenterology & Motility, 32(3), e13757. https://doi.org/10.1111/NMO.13757
Joshi, V., Strege, P. R., Farrugia, G., & Beyder, A. (2021). Mechanotransduction in gastrointestinal smooth muscle cells: Role of mechanosensitive ion channels. American Journal of Physiology - Gastrointestinal and Liver Physiology, 320(5), G897–G906. https://doi.org/10.1152/AJPGI.00481.2020/ASSET/IMAGES/MEDIUM/GI-00481-2020R01.PNG
Rychter, J., & Clavé, P. (2013). Intestinal inflammation in postoperative ileus: pathogenesis and therapeutic targets. Gut, 62(11), 1534–1535. https://doi.org/10.1136/gutjnl-2012-304176

Introduction

There is an ongoing paradigm shift toward serology-based diagnosis of celiac disease (CeD). It is essential to target potential endoscopies for those most likely to benefit. Anemia is a common symptom of CeD that may warrant further investigations, but the prevalence and clinical relevance of endoscopic findings in anemic CeD patients remain unclear.

Aims & Methods

The aim of this study was to compare the prevalence of upper and lower endoscopic findings between anemic patients and non-CeD controls, and to identify predictors of significant findings in CeD patients. Medical data, including upper and lower endoscopy findings, were collected from 162 CeD patients and 350 controls. Binary logistic regression analysis was used to identify predictors of findings.

Results

CeD patients were younger (median 49 vs 66 years, p<0.001) and had fewer risk factors such as smoking (14% vs 25%, p<0.001), alcohol abuse (4% vs 14%, p<0.001), chronic comorbidities (55% vs 83%, p<0.001), and previous malignancies (1% vs 8%, p=0.002).
In comparison of upper endoscopy findings, CeD patients had fewer significant findings (21% vs 53%, p<0.001), H. Pylori positive gastritis (6% vs 19%, p<0.001), gastric ulcers (0% vs 5%, p=0.006), and atrophic gastritis (3% vs 9%, p=0.005) compared to the controls.
Twenty-four patients and 208 controls had undergone lower endoscopy with celiac patients more frequently demonstrating significant findings (54% vs 28%, p=0.008), non-specific inflammation (21% vs 1%, p<0.001) and colorectal cancer (25% vs 9%, p=0.018).
Predictors of significant upper endoscopy findings in CeD patients were older age (OR 1.03, 95% CI 1.01-1.05), age >50 (2.44, 1.18-5.06), co-existing chronic conditions (3.45, 1.53-7.78), gastrointestinal symptoms (2.31, 1.07-4.98), and use of acetylsalicylic acid (2.38, 1.01-5.06), and of colonoscopy findings older age (1.01, 0.99-1.04), co-existing conditions (3.48, 1.12-10.8), and gastrointestinal symptoms (4.73, 1.34-16.7).

Conclusion

CeD patients had fewer findings on upper endoscopy but, despite being younger and having fewer risk factors, showed more findings on lower endoscopy compared to controls. In older CeD patients presenting with anemia, lower endoscopy should be strongly considered.

Introduction

Inflammatory Bowel Disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition affecting the gastrointestinal tract. Although primarily associated with intestinal symptoms, IBD has also been linked to various extraintestinal complications, including liver fibrosis (LF). Additionally, metabolic-associated steatotic liver disease (MASLD), a common liver condition driven by metabolic risk factors such as obesity and insulin resistance, could intersect with IBD, given its systemic nature.
While both LF and MASLD are prevalent among the general population, their incidence and associated risk factors in IBD patients remain underexplored. Understanding these liver-related complications is crucial for developing effective screening and management strategies for patients with IBD.

Aims & Methods

We aimed to assess the prevalence of LF and MASLD in IBD patients compared to matched controls. In this cross-sectional, case-control study, we enrolled consecutive IBD patients from an IBD referral center and matched controls from the general population based on age, sex, type 2 diabetes (T2D) status, and body mass index (BMI) in a 1:1 ratio. Liver fibrosis and MASLD were confirmed through shear-wave elastography (SWE) measurements of stiffness and attenuation coefficient. Potential risk factors were analyzed using multivariate logistic regression.

Results

We included 378 participants, comprising 200 IBD patients (106 with CD and 94 with UC) and 178 controls. There were no statistically significant differences regarding distribution by gender, age, T2D status and BMI. The prevalence of LF (SWE ≥ 6.78 kPa) and advanced LF (SWE ≥ 9.15 kPa) was 42.5% and 16.0%, respectively, in IBD patients (48.1% in CD vs. 36.2% in UC; p=0.088) and 28.1% and 9.0%, respectively, in the control group (p<0.05). For UC, history of complicated disease (OR 7.5, CI95% 1.2-46.2 p<0.05) and multiple hospitalizations due to acute disease (OR 5.6, CI95% 1.3-24.8; p<0.05) were significant risk factors. As for CD, previous hospitalizations (OR 9.7, CI95% 1.4-65.8; p<0.05) and heavy smoking habits (OR 4.9, CI95% 2.0-12.4; p<0.001) were the main risk factors. Extraintestinal manifestations, higher fecal calprotectin level at the time of liver stiffness measurement and latest endoscopic activity were not associated with presence of LF. MASLD was not significantly different between IBD and control group (42.0% vs. 51.7%, respectively; p>0.05). Higher BMI, higher waist circumference, higher abdominal wall thickness and metabolic syndrome were significant risk factors for MASLD (p<0.001).

Conclusion

Our case-control study demonstrates that patients with IBD have a higher prevalence of liver fibrosis compared to matched controls, with significant risk factors including a history of complicated disease, multiple hospitalizations, and heavy smoking habits. Conversely, the prevalence of MASLD does not significantly differ between IBD patients and controls, suggesting that metabolic factors might play a more substantial role in MASLD risk. Given these findings, it is critical for clinicians to implement routine liver fibrosis surveillance in IBD patients, especially in those with identified risk factors. Proactive management strategies aimed at reducing risk factors, such as smoking cessation and minimizing hospitalizations through effective disease management, could mitigate liver fibrosis risk in this population. These insights emphasize the need for integrated care approaches that address both IBD-related complications and associated liver health.