Introduction

Acute severe colitis (ASC) is a medical-surgical emergency that can occur at any time during the course of chronic inflammatory bowel disease. It most commonly affects UC.

Aims & Methods

Aims: The aim of our work is to describe the particularities of GCA management during Crohn's disease (CD).
Materials and methods: This is a retrospective descriptive and analytical study spread over a 5-year period from January 2018 to January 2023. All patients who developed GAC during the course of Crohn's disease, whether inaugural or progressive, were included in our study.Data collected included age, sex, Crohn's disease location and phenotype, Lichtiger score before and after coticotherapy, second-line treatment, and use of surgery. SPSS 2.0 software was used for the statistical study. A binary logistic regression model was used for univariate analysis.

Results

Of the 424 IBD cases, 267 were being followed for Crohn's disease, of whom 38 (14.2%) patients presented with GAC. Mean age was 44.21 ±12.7 years (range 19-72 years). The F/H sex ratio was 1.9 (25 women to 13 men).The location of Crohn's disease was pancolic in 28 patients, ileocolic in 9, and ileocolic with high involvement in 1 patient. GCA was inaugural in 10 patients (26.3%), and complicated known Crohn's disease in 28 patients (73.7%). The mean Lichtiger score calculated at D0 was 11.84±1.8. The mean CRP value on admission was 89.8±47. Mean albumin was 27.9±3.6. Emergency abdomino-pelvic CT scans showed no complications such as colectasis, perforation or abscess in our series. All patients received IV methylprednisolone corticosteroids at a dose of 0.8 mg/kg/d, not to exceed 40 mg/d, with close clinico-biological monitoring. 21 patients (55.2%) were corticosensitive. The mean Lichtiger score calculated at D5 in corticosensitive patients was 8.7, with a mean CRP value at D3 of 36.8±12.

In univariate analysis, CRP >45 (on admission) and hypoalbuminemia were predictive factors for failure of IV corticosteroid therapy, with [OR=3.2 [1.3-5.2]; p=0.0005] and [OR = 1.31 [1.015-7,] p=0.002] respectively.Of the 17 (44.8%) cortico-resistant patients, 3 (7.9%) received emergency second-line treatment with Infliximab, and 15 (39.47%) underwent subtotal colectomy with ileostomy. Of these patients, one was scheduled after failure of second-line treatment. Good outcome was noted in 36 patients (94.7%). 2 cases of death (5.3%) were reported postoperatively. On discharge, 23 patients (63.9%) were treated with immunosuppressive agents or 13 (36.1%) with biotherapy.

Conclusion

Acute severe colitis can reveal or complicate Crohn's disease at any stage of its evolution. Management must be urgent, and requires medical-surgical coordination. The first-line medical treatment is intravenous corticosteroid therapy. Colectomy should be discussed at every stage of management.

Introduction

The interleukin 36 (IL-36) family includes the agonists IL-36α, IL-36β, IL-36γ, which activate the NF-κB pathway and the natural antagonist IL-36RA, which inhibits IL-36 signaling. While missense mutations in the gene encoding IL-36RA (IL36RN) are associated with severe skin inflammation, their role in Crohn’s disease (CD) is currently unknown. Therefore, we here investigated if IL36RN mutations contribute to inflammation in CD and whether IL-36 signaling might represent a potential drug target for personalized therapy.

Aims & Methods

Mutations in IL36RN were identified by whole exome sequencing (WES) followed by targeted Sanger sequencing. Peripheral blood mononuclear cells (PBMCs) of affected patients were analyzed by mass cytometry and serum cytokines were measured by ELISA. Identified IL36RN mutations were characterized by overexpression experiments and functional assays. Clinical and molecular responses of one IL-36RN mutant patient to combined treatment with spesolimab and certolizumab pegol was assessed by fecal calprotectin, endoscopy and mass cytometry at week 0 and 12 of treatment.

Results

In a cohort of 86 ulcerative colitis patients, 244 CD patients and 45 healthy controls, we identified 4 CD patients with heterozygous missense mutations in IL36RN (IL-36RA S113L, IL-36RA P76L and IL-36RA L133I). In the patient carrying the IL-36RA S113L variant, we detected elevated serum levels of IL-18 and IL-23, as well as an increased frequency of TH17 cells in PBMCs, suggesting an overactivation of the IL-36 pathway. Overexpression experiments showed that IL-36RA S113L causes decreased expression of IL-36RA, resulting in increased IL-36 signaling. The patient was therefore treated with 1200 mg of the IL-36R blocking antibody spesolimab every 4 weeks and 200 mg of certolizumab pegol biweekly on the basis of an Out Of Scope request. This approach resulted in reduced intestinal inflammation and a reduction in the frequency of pro-inflammatory myeloid cells in PBMCs.

Conclusion

In this study, we show that pathogenic IL36RN mutations are present in a subset of CD patients and that blocking IL-36 signaling may represent a personalized therapeutic approach for this rare subset of patients in whom conventional biologic therapies have failed.
Disclaimer: Boehringer Ingelheim was given the opportunity to review the abstract for medical and scientific accuracy as well as intellectual property considerations in relation to the potential mention of BI substances.
Boehringer Ingelheim had no role in the design, analysis or interpretation of the results in this study.
Spesolimab was made available on the basis of an out of scope request. Boehringer Ingelheim was given the opportunity to review this abstract as a courtesy.

Disclosure

Britta Siegmund has served as consultant for Abbvie, Abivax, Arena, BMS, Boehringer, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, PsiCro; Speaker fees: AbbVie, BMS, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, Pfizer and grant support by Arena/Pfizer (served as representative of the Charité).