Introduction

Urotensin II (U-II) is a vasoactive peptide whose interaction with its specific receptor (UTR) plays a key role in promoting several phlogistic pathways in different inflammatory-related diseases, including ulcerative colitis (UC). The incidence of UC is increasing worldwide, becoming a contemporary important health and socio-economic problem due to the burden of optimal medical management, especially in the acute severe UC (ASUC) setting. In the ASUC, in fact, the main goals for the clinicians at the moment of admission are represented by the rapid severity assessment and risk stratification to make the best therapeutic choice.

Aims & Methods

We aimed to assess the relationship between UTR expression and clinical, endoscopic, and biochemical severity of UC, exploring its predictivity predictive role for intravenous (iv) steroid administration therapeutic outcome. One-hundred patients receiving the first diagnosis of UC and 44 healthy subjects receiving a colorectal cancer screening colonoscopy were consecutively enrolled. UTR expression was assessed by quantitative polymerase chain reaction (qPCR), Western Blot (WB), and immunohistochemistry (IHC). Clinical, endoscopic, and histology activity of UC were evaluated by using Truelove and Witts (T&W) severity index, Mayo Endoscopic Score (MES), Truelove and Richards Index (TRI), Partial Mayo score (PMS) and Full Mayo Score (FMS). The “Albumin, C-reactive protein, Endoscopy” (ACE) index was also determined as a well-known score in the prediction of steroid response. Response to treatment was defined by combining bowel movements frequency and PCR levels according to the clinical practice guidelines.

Results

The UTR expression resulted higher in the lesioned mucosa of UC patients in comparison to healthy subjects (p <0.0001 all). A direct relationship between UTR (mRNA and protein) expression and disease severity assessment (T&W, TRI, MES, PMS, and FMS) was highlighted (p<0.0001 all). Of 100 patients, 72 presented ASUC requiring iv steroid administration. UTR expression (mRNA and protein) was higher in these individuals than in those (28/100) who underwent alternative medications (budesonide, 5-aminosalicylic acid, and others) (p<0.0001). Of 72 steroid-treated patients, 40 were considerable responders. The 32 steroid-non-responders showed an increased UTR expression (WB, IHC, and qPCR from lesioned mucosa), compared to the 40 steroid responders (p:0.0002, p:0.0001, p<0.0001 respectively). Logistic regression analysis revealed the UTR expression levels associated with the negative iv. steroids administration therapeutic outcome (p<0.05).
ROC curves for the prediction of negative iv steroid therapeutic outcome were generated for IHC (AUC: 0.93, 95% CI: 0.86-0.99, p<0.0001), WB (AUC: 0.94, 95% CI: 0.87-1.00, p<0.0001), qPCR from lesioned samples (AUC: 0.99, 95% CI: 0.97-1.00, p<0.0001) UTR expression. The diagnostic performance of qPCR-UTR was superior to the ACE index (AUC: 0.94, 95% CI: 0.88-0.99) in the prediction of steroid response.
Finally, all the steroid responder patients (40/100) were undergone a second colonoscopy after one month and were considered “full responders” because of the reduction of at least two points of the continuous FMS in comparison to the baseline value.

Conclusion

UTR represents a promising inflammatory marker related to clinical, endoscopic, and histology disease activity as well as a predictive marker of steroid administration therapeutic outcome in the UC context.

References

1. Brancaccio D, Merlino F, Limatola A, et al. An investigation into the origin of the biased agonism associated with the urotensin II receptor activation. Journal of peptide science: an official publication of the European Peptide Society. 2015;21(5):392-399.
2. Kaplan GG. The global burden of IBD: from 2015 to 2025. Nature reviews Gastroenterology & hepatology. 2015;12(12):720-727.
3. Ho GT, Mowat C, Goddard CJ, et al. Predicting the outcome of severe ulcerative colitis: development of a novel risk score to aid early selection of patients for second-line medical therapy or surgery. Alimentary pharmacology & therapeutics. 2004;19(10):1079-1087.
4. Gravina AG, Dallio M, Tuccillo C, et al. Urotensin II receptor expression in patients with ulcerative colitis: a pilot study. Minerva gastroenterologica e dietologica. 2020;66(1):23-28.

Introduction

The molecular pathways for the development of ulcerative colitis (UC) are unclear. The purpose of the work is to study the molecular interactions of the apoptotic pathway in patients with UC.

Aims & Methods

The study was prospective comparative cohort with parallel design and included 65 patients (range from 22 to 35 years, 24 men and 41 women) with left-sided UC, mild and moderate activity (Truelove - Witts’ criteria, Mayo score). The induction of UC remission assumed the acceptance of mesalazine 3 to 4 g/day p.o. and rectally 1 to 2 g/day, the duration of therapy was 4.6 years. The control group
included 30 healthy individuals. The separation of individual proteins of colon mucosa was based on technologies of IEF, SDS-PAGE, 2DPAGE, by standard sets (MB-HIC C8 Kit, MB-IMAC Cu, MB-Wax Kit, «Bruker», USA). Automated mass spectrometry imaging was performed by matrix-assisted laser desorption-ionization timeof-flight mass spectrometry (MALDI-TOF-MS/MS, Ultraflex II, «Bruker», USA). The partially identified sequences were then submitted to “BLAST protein-protein” and screened against the Homo sapiens Swissprot database to check if this identification matched the MASCOT-identification (Matrix Science, UK). The data of the molecular interactions and functional features of proteins were received with STRING 10.0 database. Based on the data of standard methods of identification of UC and molecular phenotyping of colon mucosa we conducted new prognostic markers, molecular pathways of UC and diagnostic tests in patients with UC. Statistical analysis of the survey data was performed using the software “Statistica 12.0” (Statsoft).

Results

Bioinformatics analysis revealed the presence of molecules that are the participants in the universal pathways of UC in the active stage, and the molecular interactions involved. We identified following functional groups of peptides and proteins in molecular patterns of bioptates of colon mucosa in UC patients: peptides and proteins regulating the barrier function of colon mucosa; proteins-participants of specific metabolism in epitheliocytes and endocrinocytes; proteins of the fibrosis in colon mucosa; proteins regulating cell cycle, oncogenesis, proteolysis in cell, hormones processing, angiogenesis, coagulation factors; proteins of free radical oxidation and antioxidant system; proteins regulating the receptor activity of epitheliocytes and immune cells; structural proteins of colon mucosa; transcription and translation factors regulating the activity of cell nucleus, regulators of protein folding; transport proteins; proteins-enzyms of detoxification. Significant decrease of the PPARγ expression promotes the activation of STAT and AP-1 signaling pathways, which promotes an increase in the synthesis of IL-2,6,8,12, TNFα, matrix metalloproteinases, the activity of immune and inflamation processes in colon mucosa. A significant increase in the NF-kB expression in colon mucosa is associated with the activation of TNFα and IL-1, which promotes the increase of immune processes in colon mucosa. The molecular interactions of β-defensin-1: the reduction of the β-defensin-1 expression in cells of colon mucosa is accompanied by increased expression of CCR6, which promotes the formation of inflammatory infiltrates in colon submucosa in UC.

Conclusion

Identification of potential new molecular markers for UC development may provide opportunities for the development of diagnostic tests to evaluate the disease.

Introduction

Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation affecting the gastrointestinal tract and extraintestinal organs. The etiology of IBD is multifactorial, involving genetic, immunological, and environmental factors, with significant genetic predisposition indicated by over 200 identified loci associated with the disease. Despite advancements in understanding the genetic basis of IBD, clinical management remains challenging due to heterogeneity in disease presentation and variable treatment responses. Current therapies, including 5-aminosalicylates and biologics, are not universally effective, highlighting the urgent need for reliable biomarkers to predict therapeutic responses. This study investigates the potential role of interferon regulatory factor 5 (IRF5) in IBD pathogenesis, particularly in UC.

Aims & Methods

We conducted a systematic analysis of colon biopsies from adult patients diagnosed with UC and non-IBD controls. Immunostaining was performed to assess IRF5 expression in colonic tissues, and statistical analyses were conducted to evaluate the correlation between IRF5-positive cell counts, disease activity, and inflammatory markers such as calprotectin

Results

Our analysis revealed a significant increase in IRF5-positive macrophage-like cells in the inflamed mucosa of IBD patients compared to healthy controls. The number of IRF5-positive cells correlated positively with disease activity and calprotectin levels, indicating that higher IRF5 expression is associated with increased inflammation.

Conclusion

This study establishes a significant correlation between IRF5 expression and disease activity in UC, suggesting that IRF5 may play a crucial role in the inflammatory processes associated with the disease. The findings propose IRF5 as a novel biomarker for therapeutic intervention in IBD. Further research is warranted to elucidate the exact mechanisms by which IRF5 contributes to IBD pathogenesis and to evaluate the therapeutic potential of targeting this pathway in clinical settings.

References

Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M, Taylor KD, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43(3):246-52.
Dideberg V, Kristjansdottir G, Milani L, Libioulle C, Sigurdsson S, Louis E, et al. An insertion-deletion polymorphism in the interferon regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases. Hum Mol Genet. 2007;16(24):3008-16.
Yang Y, Zhang C, Jing D, He H, Li X, Wang Y, et al. IRF5 Acts as a Potential Therapeutic Marker in Inflammatory Bowel Diseases. Inflammatory bowel diseases. 2021;27(3):407-17.
Troncone E, Laudisi F, Di Fusco V, Dinallo V, De Simone E, Monteleone I, et al. Interferon Regulatory Factor 5 Expressing Cells infiltrate Lamina Propria of IBD Patients and produce inflammatory Cytokines. Digestive and Liver Disease. 2017;49(s2):e73-e223.

Disclosure

Lecturing fees from Immndiagnostik, MSD, Janssen, Takeda, Abbvie, consultancy fees from Vifor Pharma and Takeda

Clinical Case Summary

Tofacitinib has recently been introduced into European guidelines for managing moderate-severe Ulcerative Colitis (UC). Among the various extra-intestinal manifestations of UC is Hidradenitis Suppurativa (HS), also called acne inversa. Unfortunately, there is no evidence on the efficacy of tofacitinib in HS, such that recommendations generally suggest anti-tumour necrosis factors, antibiotics, anakinra, ustekinumab or surgery. We report the case of a 26-year-old Caucasian non-smoking, nonalcohol-drinking, and non-obese woman diagnosed with UC E3 (i.e., pancolitis) according to Montreal classification with Mayo endoscopic subscore (ESS) of 2 at the age of 23 years old. At the time, the patient underwent conventional therapy with oral prednisone at the immunosuppressive dosage combined with oral mesalazine. Following this therapy, she achieved clinical-biochemical remission. A year later, she developed a UC relapse associated with steroid dependence, also received another colonoscopy (E3, ESS=2, C-Reactive protein 18.6 mg/L) and received a dermatologic diagnosis of HS (mainly localized to axillary folds, inguinal folds, intermammary groove) and treated employing topical triamcinolone/neomycin cream. In addition, we introduced Adalimumab. She then experienced primary failure. Due to the persistence of moderate-severe symptoms and iron-deficiency anaemia, we introduced tofacitinib therapy in March 2022. At that moment, the patient had an HS relapse which the previous dermatologic treatment failed. Therefore, the patient undertook tofacitinib induction with 20 mg daily for eight weeks. Because of clinical improvement with the halving of discharges and absence of blood, however, complete clinical remission was not achieved. Therefore, it was decided to continue this regimen for another eight weeks. At the end of the 16 weeks, we noted UC clinical and biochemical remission and a marked amelioration of HS. Today, the patient continues a 10 mg daily tofacitinib regimen.

References

- Chen W-T, Chi C-C. Association of Hidradenitis Suppurativa With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. JAMA Dermatol 2019;155:1022–7.
- Goldburg SR, Strober BE, Payette MJ. Hidradenitis suppurativa: Epidemiology, clinical presentation, and pathogenesis. J Am Acad Dermatol 2020;82:1045–58.
- Savage KT, Santillan MR, Flood KS, Charrow A, Porter ML, Kimball AB. Tofacitinib shows benefit in conjunction with other therapies in recalcitrant hidradenitis suppurativa patients. JAAD Case Rep 2020;6:99–102.
- Raine T, Bonovas S, Burisch J, Kucharzik T, Adamina M, Annese V, Bachmann O, Bettenworth D, Chaparro M, Czuber-Dochan W, Eder P, Ellul P, Fidalgo C, Fiorino G, Gionchetti P, Gisbert JP, Gordon H, Hedin C, Holubar S, Iacucci M, Karmiris K, Katsanos K, Kopylov U, Lakatos PL, Lytras T, Lyutakov I, Noor N, Pellino G, Piovani D, Savarino E, Selvaggi F, Verstockt B, Spinelli A, Panis Y, Doherty G. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. J Crohns Colitis. 2022 Jan 28;16(1):2-17.

Introduction

Vedolizumab has demonstrated efficacy in moderate-severe Ulcerative Colitis (UC). To date, few tools are available to predict medium- and long-term response to the drug. The aim of the study is to characterise the profile of circulating cytokines associated with the pathophysiology of inflammatory bowel disease (IBD) to identify markers of immune response to vedolizumab in UC patients. As a secondary objective, we analysed the possible involvement of baseline characteristics such as smoking and disease duration until drug initiation, previous exposure to other biologics, and baseline faecal calprotectin (FCP) and C-reactive protein (CRP) values in the response to the drug.

Aims & Methods

Retrospective single-centre cohort study including 28 patients diagnosed with UC with inflammatory activity objectified by clinical and biochemical data who started treatment with vedolizumab in the period from 2015 to 2022. Participants consented and authorised the collection of biological samples. Plasma samples were collected prior to drug initiation and response to treatment was assessed at the end of follow-up. Response to treatment was based on clinical remission (pMAYO < 3 with no subscore >1) together with a biochemical response (reduction in FCP and/or CRP > 50%) at the end of follow-up. In patients where colonoscopy was available, endoscopic response was defined as an endoscopic Mayo of 0 or 1. Cytokines were determined by Magpix® Luminex using a Milliplex® Human High Sensitivity T Cell Magnetic Bead Panel containing 12 proteins. The cytokines studied were (interferon-gamma, interleukin 10, interleukin 12, interleukin 13, interleukin 17A, interleukin 10, interleukin 2, interleukin 21, interleukin 23, interleukin 7, interleukin 8, TNF-alpha).

Results

Twenty-eight patients with UC (100% pancolitis or left colitis) and S2+S3 94.7% were included in the study. 85.2% were bioexposed (infliximab in 75%). 50% of patients received concomitant corticosteroid therapy at the start of vedolizumab.
Vedolizumab response was seen in 13 patients (46.4%) after a median overall treatment duration in both cohorts of 2.79 years (IQR 7.55). The responder group was on vedolizumab treatment for a median of 5.58 (IQR 6.9) years vs 1.17 (IQR 5.13) years in the non-responder group, p=0.005. There were no baseline differences between responders in pMayo or in FCP and CRP values. Active smoking, disease duration until vedolizumab initiation and previous exposure to other biologics were not associated with response/non-response to vedolizumab treatment.
Vedolizumab responders had significantly lower median interleukin 8 (IL8) levels at baseline than vedolizumab non-responders (median IL8 1.67 pg/mL versus 3.03 pg/mL, p=0.016). No statistically significant differences in baseline concentrations were found in any of the other interleukins analysed.

Conclusion

In our series of UC patients treated with vedolizumab, patients with long-term response to the drug show lower plasma IL8 levels than non-responders at baseline. Therefore, IL8 could serve as a predictive marker of long-term response to vedolizumab in UC patients. These results should be confirmed in prospective studies with larger sample sizes.

Clinical Case Summary

Introduction: Ustekinumab (UST), a human interleukin-12/23 monoclonal antibody, is approved for the treatment of moderate to severe Crohn’s disease (CD) and ulcerative colitis (UC). Some patients may lose response to standard maintenance therapy. Optimization strategies, such as dose escalation and intravenous (IV) re-induction, have been explored in CD, but scarcely studied in UC.
Clinical Case: A 61-year-old woman, with grade III obesity, hypertension, and peripheral venous insufficiency, diagnosed with UC and associated peripheral arthropathy, was initially treated with high-dose corticosteroids (CTS) for a severe exacerbation. She developed CTS dependence and suffered an osteoporotic fracture.
A combined therapy with methotrexate and an accelerated infliximab (IFX) induction regimen was initiated, but a severe exacerbation occurred after the second induction dose. Despite an early third dose, clinical, biochemical and endoscopic (Mayo score 3) activity persisted.
The patient was swapped to UST with maintenance therapy every 4 weeks. After IV infusion, free-CTS clinical and biochemical (fecal calprotectin (FC) <10 ug/g) remission were achieved, but, over time, there was a loss of response, with a FC 4817 ug/g.
Given the initial positive response to IV UST infusion and insights from CD studies, a 520mg IV UST re-induction followed by 4-week maintenance dose was administered. Eight months later, the patient remains in free-CTS clinical remission, with improved arthralgia, biochemical remission (FC 80 ug/g) and endoscopic response.
Conclusions: This case highlights the potential efficacy of IV UST re-induction in recapturing remission in refractory UC. While recognized in CD, UST re-induction may prove beneficial for UC patients with loss of response to standard UST therapy, serving as an alternative before swapping. Further exploration through randomized, multicenter studies is crucial to assess the efficacy and safety of this strategy in UC patients.