Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals.

Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut-specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell-independent or T cell-dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus-embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA-only-coated or uncoated bacteria. Thus, SIgM may emerge from pre-existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities to mucus.

Long-term Outcome of Risankizumab in Crohn's Disease: a Real-world GETAID Study.

BACKGROUND & AIMS: The aim of this study was to assess the long-term effectiveness and safety of risankizumab maintenance treatment in a large real-world cohort of patients with Crohn's Disease (CD). METHODS: From May 2021 to August 2023, all consecutive patients with CD treated with risankizumab in 25 GETAID centers have been retrospectively included. The primary endpoint was steroid-free clinical remission (Harvey Bradshaw Index [HBI] <5) at 52 weeks. RESULTS: Of the 174 patients included, 99%, 93%, and 96% had been previously exposed to anti-TNF, vedolizumab, and ustekinumab, respectively. All patients had received ≥3 biologics, and 108 (62%) had previous intestinal resection. Median follow-up was 13.7 months (interquartile range, 10.0-18.1 months). The rates of steroid-free clinical remission and clinical remission at week 26 were 47% (72/152) and 52% (79/152), and 46% (58/125), and 48% (60/125) at week 52, respectively. Risankizumab persistence rates were 94%, 89%, and 79% at weeks 12, 26, and 52, respectively. At the end of follow-up, 45 (45/174; 26%) patients had discontinued risankizumab (loss of response, 42%; primary failure, 37%; intolerance, 13%). Thirty-six patients (36/174; 20.9%) were hospitalized, and 22 (22/174; 12.6%) required intestinal resection. Fifty-one patients (29%) had an adverse event, including 26 (15%) serious adverse events (CD flare, n = 17). One death (myocardial infarction) and one cancer (papillary thyroid carcinoma) were observed. CONCLUSION: This is the first real-life study to report long-term outcomes in patients with refractory CD treated with risankizumab. One-half of the patients achieved steroid-free clinical remission after 1 year, and the safety profile was consistent with the literature.

Insights into the expanding intestinal phenotypic spectrum of SOCS1 haploinsufficiency and therapeutic options.

PURPOSE: Hyper activation of the JAK-STAT signaling underlies the pathophysiology of many human immune-mediated diseases. Herein, the study of 2 adult patients with SOCS1 haploinsufficiency illustrates the severe and pleomorphic consequences of its impaired regulation in the intestinal tract. METHODS: Two unrelated adult patients presented with gastrointestinal manifestations, one with Crohn's disease-like ileo-colic inflammation refractory to anti-TNF and the other with lymphocytic leiomyositis causing severe chronic intestinal pseudo-occlusion. Next-generation sequencing was used to identify the underlying monogenic defect. One patient received anti-IL-12/IL-23 treatment while the other received the JAK1 inhibitor, ruxolitinib. Peripheral blood, intestinal tissues, and serum samples were analyzed before-and-after JAK1 inhibitor therapy using mass cytometry, histology, transcriptomic, and Olink assay. RESULTS: Novel germline loss-of-function variants in SOCS1 were identified in both patients. The patient with Crohn-like disease achieved clinical remission with anti-IL-12/IL-23 treatment. In the second patient with lymphocytic leiomyositis, ruxolitinib induced rapid resolution of the obstructive symptoms, significant decrease of the CD8+ T lymphocyte muscular infiltrate, and normalization of serum and intestinal cytokines. Decreased frequencies of circulating Treg cells, MAIT cells, and NK cells, with altered CD56bright:CD16lo:CD16hi NK subtype ratios were not modified by ruxolitinib. CONCLUSION: SOCS1 haploinsufficiency can result in a broad spectrum of intestinal manifestations and need to be considered as differential diagnosis in cases of severe treatment-refractory enteropathies, including the rare condition of lymphocytic leiomyositis. This provides the rationale for genetic screening and considering JAK inhibitors in such cases.

Impact of HIV Infection on the Course of Inflammatory Bowel Disease and Drug Safety Profile: A Multicenter GETAID Study.

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), and human immunodeficiency virus (HIV) both impact innate and adaptive immunity in the intestinal mucosa. As it is a rare situation, the intersection between HIV and IBD remains unclear, especially the impact of HIV infection on the course of IBD, and the drug safety profile is unknown. METHODS: We conducted a multicenter retrospective cohort study between January 2019 and August 2020. All adult patients with IBD and concomitant HIV infection were included. Each IBD patient with HIV was matched to two HIV-uninfected IBD patients. RESULTS: Overall, 195 patients with IBD were included, including 65 HIV-infected patients and 130 without HIV infection. Of the 65 infected patients, 22 (33.8%) required immunosuppressants and 31 (47.7%) biologics. In the HIV-infected group, the need for immunosuppressants (p = 0.034 for CD and p = 0.012 for UC) and biologics (p = 0.004 for CD and p = 0.008 for UC) was significantly lower. The disease course, using a severity composite criterion, was not significantly different between the two groups for CD (hazard ration (HR) = 1.3 [0.7; 2.4], p = 0.45) and UC (HR, 1.1 [0.5; 2.7], p = 0.767). The overall drug safety profile was statistically similar between the two groups. CONCLUSION: Although HIV-infected patients receive less treatments, the course of their IBD did not differ than uninfected, suggesting that HIV infection might attenuate IBD. The drug safety profile is reassuring, allowing physician to treat these patients according to current recommendations.

Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice.

BACKGROUND AND AIMS: Prenatal and early life bacterial colonisation is thought to play a major role in shaping the immune system. Furthermore, accumulating evidence links early life exposures to the risk of developing IBD later in life. We aimed to assess the effect of maternal IBD on the composition of the microbiome during pregnancy and on the offspring's microbiome. METHODS: We prospectively examined the diversity and taxonomy of the microbiome of pregnant women with and without IBD and their babies at multiple time points. We evaluated the role of maternal IBD diagnosis, the mode of delivery, antibiotic use and feeding behaviour on the microbiome composition during early life. To assess the effects of IBD-associated maternal and infant microbiota on the enteric immune system, we inoculated germ-free mice (GFM) with the respective stool and profiled adaptive and innate immune cell populations in the murine intestines. RESULTS: Pregnant women with IBD and their offspring presented with lower bacterial diversity and altered bacterial composition compared with control women and their babies. Maternal IBD was the main predictor of the microbiota diversity in the infant gut at 7, 14, 30, 60 and 90 days of life. Babies born to mothers with IBD demonstrated enrichment in Gammaproteobacteria and depletion in Bifidobacteria. Finally, GFM inoculated with third trimester IBD mother and 90-day infant stools showed significantly reduced microbial diversity and fewer class-switched memory B cells and regulatory T cells in the colon. CONCLUSION: Aberrant gut microbiota composition persists during pregnancy with IBD and alters the bacterial diversity and abundance in the infant stool. The dysbiotic microbiota triggered abnormal imprinting of the intestinal immune system in GFM.

Colonic MicroRNA Profiles, Identified by a Deep Learning Algorithm, That Predict Responses to Therapy of Patients With Acute Severe Ulcerative Colitis.

BACKGROUND & AIMS: Acute severe ulcerative colitis (ASUC) is a life-threatening condition managed with intravenous steroids followed by infliximab, cyclosporine, or colectomy (for patients with steroid resistance). There are no biomarkers to identify patients most likely to respond to therapy; ineffective medical treatment can delay colectomy and increase morbidity and mortality. We aimed to identify biomarkers of response to medical therapy for patients with ASUC. METHODS: We performed a retrospective analysis of 47 patients with ASUC, well characterized for their responses to steroids, cyclosporine, or infliximab, therapy at 2 centers in France. Fixed colonic biopsies, collected before or within the first 3 days of treatment, were used for microarray analysis of microRNA expression profiles. Deep neural network-based classifiers were used to derive candidate biomarkers for discriminating responders from non-responders to each treatment and to predict which patients would require colectomy. Levels of identified microRNAs were then measured by quantitative PCR analysis in a validation cohort of 29 independent patients-the effectiveness of the classification algorithm was tested on this cohort. RESULTS: A deep neural network-based classifier identified 9 microRNAs plus 5 clinical factors, routinely recorded at time of hospital admission, that associated with responses of patients to treatment. This panel discriminated responders to steroids from non-responders with 93% accuracy (area under the curve, 0.91). We identified 3 algorithms, based on microRNA levels, that identified responders to infliximab vs non-responders (84% accuracy, AUC = 0.82) and responders to cyclosporine vs non-responders (80% accuracy, AUC = 0.79). CONCLUSION: We developed an algorithm that identifies patients with ASUC who respond vs do not respond to first- and second-line treatments, based on microRNA expression profiles in colon tissues.

A comprehensive analysis of Lymphoma-associated haemophagocytic syndrome in a large French multicentre cohort detects some clues to improve prognosis.

Lymphoma-associated haemophagocytic syndrome (LAHS) accounts for most cases of secondary haemophagocytic syndrome (HS) and has been extensively described in Asian populations. However, little is known about the epidemiology of LAHS in Western countries. We herein report a case series of 71 LAHS patients in which the lymphomas were mainly of the aggressive type. Diagnoses included non-Hodgkin B cell lymphoma (46·5%) including human herpes virus 8-associated non-Hodgkin lymphoma (12·7%), T cell lymphoma (28·2%) and Hodgkin lymphoma (23·9%). An underlying immunodeficiency was described in 30 patients (42·3%). Early mortality within the 30 days following HS diagnosis was observed in 26·8% of cases. The overall survival was estimated at 45·7% [95% confidence interval, CI (35·4-59·0)] at 6 months, and 34·3% [95% CI (24·8-47·4)] at 2 years. Concurrent infection, age over 50 years, ethnicity and etoposide treatment were independently associated with mortality. While it appears that certain types of lymphomas were more prone to trigger HS, LAHS were not restricted to a few types of lymphoma. The overall prognosis was poor, with a particularly high rate of early mortality, highlighting the importance of both early recognition and choice of initial therapeutic management.

Long-term Follow-up After Ileorectal Anastomosis for Ulcerative Colitis: A GETAID/GETAID Chirurgie Multicenter Retrospective Cohort of 343 Patients.

OBJECTIVES: To determine the cumulative incidence and the prognostic factors of ileorectal anastomosis (IRA) failure after colectomy for ulcerative colitis (UC). BACKGROUND: Although ileal pouch-anal anastomosis is recommended after colectomy for UC, IRA is still performed. METHODS: This was a multicenter retrospective cohort study, which included patients with IRA for UC performed between 1960 and 2014. IRA failure was defined as secondary proctectomy and/or rectal cancer occurrence. Uni- and multivariate survival analyses were performed using Cox-proportional hazards models. RESULTS: A total of 343 patients from 13 French centers were included. Median follow up after IRA was 10.6 years. IRA failure rates were estimated at 27.0% (95% confidence interval, CI, 22-32) and 40.0% (95% CI 33-47) at 10 and 20 years, respectively. Median survival time without IRA failure was estimated at 26.8 years. Two thirds of secondary proctectomies were performed for refractory proctitis, and 20% for rectal neoplasia. Univariate analysis identified factors associated with IRA failure: IRA performed after 2005, a longer duration of disease at the time of IRA, indication for colectomy and having received immunomodulative agents before IRA. In multivariate analysis, treatment with both immunosuppressant (IS) and anti-TNF before colectomy was independently associated with IRA failure (HR=2.9, 95% CI 1.2-7.1). Conversely, colectomy for severe acute colitis was associated with decreased risk of IRA failure (HR=0.6, 95% CI 0.4-0.97). DISCUSSION: Patients with UC have a high risk of IRA failure, particularly when colectomy is performed for refractory disease. However, IRA could be discussed after colectomy for severe acute colitis, or in patients naive to IS and anti-TNF.

Gastrointestinal Disorders Associated with Common Variable Immune Deficiency (CVID) and Chronic Granulomatous Disease (CGD).

Common variable immune deficiency (CVID) and chronic granulomatous disease (CGD) are two of the well-characterized primary immune deficiencies with distinct pathologic defects. While CVID is predominantly a disorder of the adaptive immune system, in CGD, innate immunity is impaired. In both syndromes, the clinical manifestations include an increased susceptibility to infections and a number of non-infectious, inflammatory conditions including systemic autoimmunity, as well as organ-specific pathology. Among the organ-associated disorders, gastrointestinal (GI) manifestations are one of the most intractable. As such, non-infectious inflammatory disorders of the GI tract are clinically challenging as they have protean manifestations, often resembling inflammatory bowel disease (IBD) or celiac disease, are notoriously difficult to treat, and hence are associated with significant morbidity and mortality. Therefore, assessing the pathogenesis and defining appropriate therapeutic approaches for GI disease in patients with CVID and CGD is imperative.

B Cell-Activating Factor (BAFF)-Targeted B Cell Therapies in Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBD) involve dysregulated immune responses to gut antigens in genetically predisposed individuals. While a better elucidation of IBD pathophysiology has considerably increased the number of treatment options, the need for more effective therapeutic strategies remains a pressing priority. Defects of both non-hematopoietic (epithelial and stromal) and hematopoietic (lymphoid and myeloid) cells have been described in patients with IBD. Within the lymphoid system, alterations of the T cell compartment are viewed as essential in the pathogenesis of IBD. However, growing evidence points to the additional perturbations of the B cell compartment. Indeed, the intestinal lamina propria from IBD patients shows an increased presence of antibody-secreting plasma cells, which correlates with enhanced pro-inflammatory immunoglobulin G production and changes in the quality of non-inflammatory IgA responses. These B cell abnormalities are compounded by the emergence of systemic antibody responses to various autologous and microbial antigens, which predates the clinical diagnosis of IBD and identifies patients with complicated disease. It is presently unclear whether such antibody responses play a pathogenetic role, as B cell depletion with the CD20-targeting monoclonal antibody rituximab did not ameliorate ulcerative colitis in a clinical trial. However, it must be noted that unresponsiveness to rituximab is also observed also in some patients with autoimmune disorders usually responsive to B cell-depleting therapies. In this review, we discussed mechanistic aspects of B cell-based therapies and their potential role in IBD with a special interest on BAFF and BAFF-targeting therapies buoyed by the success of anti-BAFF treatments in rheumatologic disorders.

Interest of Integrated Whole-Body PET/MR Imaging in Gastroenteropancreatic Neuroendocrine Neoplasms: A Retro-Prospective Study.

INTRODUCTION AND AIM: Simultaneous positron emission tomography/magnetic resonance imaging (PET-MRI) combines the high sensitivity of PET with the high specificity of MRI and is a tool for the assessment of gastroenteropancreatic neuroendocrine neoplasms (G-NENs). However, it remains poorly evaluated with no clear recommendations in current guidelines. Thus, we evaluated the prognostic impact of PET-MRI in G-NEN patients. METHODS: From June 2017 to December 2021, 71 G-NEN patients underwent whole-body PET-MRI for staging and/or follow-up purposes. A whole-body emission scan with 18F-6-fluoro-L-dihydroxyphenylalanine (18FDOPA, n = 30), 18F-fluoro-2-deoxy-D-glucose (18FDG, n = 21), or 68Ga-(DOTA(0)-Phe(1)-Tyr(3))-octreotide (68Ga-DOTATOC, n = 20) with the simultaneous acquisition of a T1-Dixon sequence and diffusion-weighed imaging (DWI), followed by a dedicated step of MRI sequences with a Gadolinium contrast was performed. The patients underwent PET-MRI every 6-12 months during the follow-up period until death. Over this period, 50 patients with two or more PET-MRI were evaluated. RESULTS: The mean age was 61 [extremes, 31-92] years. At the baseline, PET-MRI provided new information in 12 cases (17%) as compared to conventional imaging: there were more metastases in eight, an undescribed location (myocardia) in two, and an unknown primary location in two cases. G grading at the baseline influenced overall survival. During the follow-up (7-381 months, mean 194), clinical and therapy managements were influenced by PET-MRI in three (6%) patients due to new metastases findings when neither overall, nor disease-free survivals in these two subgroups (n = 12 vs. n = 59), were different. CONCLUSION: Our study suggests that using PET/MRI with the appropriate radiotracer improves the diagnostic performance with no benefit on survival. Further studies are warranted to evaluate the cost-effectiveness of this procedure.

Tofacitinib for Patients with Anti-TNF Refractory Ulcerative Proctitis: A Multicentre Cohort Study from the GETAID.

BACKGROUND: Although ulcerative proctitis [UP] can dramatically impair quality of life, treatment efficacy has been poorly investigated in UP as it was historically excluded from phase 2/3 randomised controlled trials in ulcerative colitis. Our aim was to assess the effectiveness and safety of tofacitinib for the treatment of UP. METHODS: We conducted a retrospective, multicentre study in 17 GETAID centres, including consecutive patients with UP treated with tofacitinib. The primary endpoint was steroid-free remission between Week 8 and Week 14, defined as a partial Mayo score of 2 [and no individual subscore above 1]. Secondary outcomes included clinical response and steroid-free remission after induction and at 1 year. RESULTS: All the 35 enrolled patients previously received anti-tumour necrosis factor [TNF] therapy and 88.6% were exposed to at least two lines of biologics. At baseline, the median partial Mayo score was 7 (intequartile range [IQR] [5.5-7]). After induction [W8-W14], 42.9% and 60.0% of patients achieved steroid-free remission and clinical response, respectively. At 1 year, the steroid-free clinical remission and clinical response rates were 39.4% and 45.5%, respectively, and 51.2% [17/33] were still receiving tofacitinib treatment. Survival without tofacitinib withdrawal was estimated at 50.4% (95% confidence interval [CI] [35.5-71.6]) at 1 year. Only a lower partial Mayo at baseline was independently associated with remission at induction (0dds ratio [OR] = 0.56 for an increase of 1, (95% CI [0.33-0.95], p = 0.03). Five [14.3%] adverse events were reported, with one leading to treatment withdrawal [septic shock secondary to cholecystitis]. CONCLUSION: Tofacitinib may offer a therapeutic option for patients with refractory UP.

HIV-1 infection is associated with depletion of germinal center B cells and a decrease in IgA + plasma cells in the GI tract.

Gastrointestinal (GI) B cells and plasma cells (PCs), critical to mucosal homeostasis, play an important role in the host response to HIV-1 infection. Here, high resolution mapping of human B cells and PCs from colon and ileum during both viremic and suppressed HIV-1 infection identified a significant reduction in germinal center (GC) B cells and Follicular Dendritic Cells (FDCs) during HIV-1 viremia. Further, IgA + PCs, the major cellular output of intestinal GCs were significantly reduced during viremic HIV-1 infection. PC-associated transcriptional perturbations, including type I interferon signaling persisted in antiretroviral therapy (ART) treated individuals, suggesting ongoing disruption of the intestinal immune milieu during ART. GI humoral immune perturbations associated with changes in intestinal microbiome composition and systemic inflammation. Herein, we highlight a key immune defect in the GI mucosa due to HIV-1 viremia, with major implications. One Sentence Summary: Major perturbations in intestinal GC dynamics in viremic HIV-1 infection relate to reduced IgA + plasma cells, systemic inflammation and microbiota changes.

Gut-associated lymphoid tissue attrition associates with response to anti-α4ß7 therapy in ulcerative colitis.

Vedolizumab (VDZ) is a first-line treatment in ulcerative colitis (UC) that targets the α4ß7- mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) axis. To determine the mechanisms of action of VDZ, we examined five distinct cohorts of patients with UC. A decrease in naïve B and T cells in the intestines and gut-homing (ß7+) plasmablasts in circulation of VDZ-treated patients suggested that VDZ targets gut-associated lymphoid tissue (GALT). Anti-α4ß7 blockade in wild-type and photoconvertible (KikGR) mice confirmed a loss of GALT size and cellularity because of impaired cellular entry. In VDZ-treated patients with UC, treatment responders demonstrated reduced intestinal lymphoid aggregate size and follicle organization and a reduction of ß7+IgG+ plasmablasts in circulation, as well as IgG+ plasma cells and FcγR-dependent signaling in the intestine. GALT targeting represents a previously unappreciated mechanism of action of α4ß7-targeted therapies, with major implications for this therapeutic paradigm in UC.

Review article: Updated management of acute severe ulcerative colitis: From steroids to novel medical strategies.

Acute severe ulcerative colitis (ASUC) occurs in up to 25% of patients with ulcerative colitis (UC). Therapeutic approaches have evolved during the past years with the increasing bio exposure of admitted patients and the extension of the number of approved drugs for UC. In this review, we aimed to summarize the latest evidence in short-term and long-term medical strategies for ASUC. In addition to general principles such as venous thromboembolism prophylaxis, screening for triggering and worsening factors and close monitoring, first-line therapy for ASUC remains intravenous corticosteroids. In naive patients, the optimum maintenance strategy for steroid-responding patients does not necessarily include biologics. Second-line therapy includes infliximab or calcineurin inhibitors (CNIs) with similar short- and long-term colectomy rates. Despite its pathophysiological relevance, there is insufficient evidence to promote intensified induction with infliximab. Prior treatment exposure is a cornerstone for guiding therapeutic choice of short- and long-term therapies in the context of ASUC: in anti-TNF exposed patients, CNIs may be favored as a bridge therapy to vedolizumab or ustekinumab. Third-line salvage therapy could be a therapeutic option in selected patients referred to expert centers. Additionally, evidence is accumulating regarding the use of tofacitinib in ASUC.

Focal loss of mural stratification as a radiological predictor for small bowel adenocarcinoma in Crohn's disease.

AIM: Patients with Crohn's disease (CD) are at higher risk of small bowel adenocarcinoma (SBA). We aimed to identify radiological predictors of SBA in CD. METHODS: We conducted a retrospective case-control study at two tertiary inflammatory bowel disease centers and identified CD patients diagnosed with SBA between 2003 and 2019. Patients were matched with up to four controls. Pre-operative imaging (magnetic resonance imaging (MRI) or computed tomography (CT)) were reviewed by three gastrointestinal radiologists. RESULTS: Nineteen patients with CD-associated SBA with a mean age of 54.9 and 32 matched controls were included. Mean length of small bowel involvement was 216 (± 188) mm in the SBA group versus 156 (± 167) mm in the control group (p = 0.76). Only 11.8 % of cases had a diagnosis of SBA made preoperatively. In univariate analysis, focal loss of mural stratification (odds ratio [OR], 11; 95%CI, 2.43-49.5, p = 0.002), and wall thickening (OR, 1.32; 95%CI, 1.05-1.66, p = 0.02) were significantly associated with SBA. After adjustment, focal loss of mural stratification was the only independent risk factor (OR, 11; 95 % CI, 2.43-49.5, p = 0.002). CONCLUSIONS: Focal loss of mural stratification was identified as a predictor of CD-associated SBA, which should be described in imaging reports and further validated.

Crohn-like Disease Affecting Small Bowel Due to Monogenic SLCO2A1 Mutations: First Cases of Chronic Enteropathy Associated with SLCO2A1 Gene [CEAS] in France.

INTRODUCTION: Multiple chronic ulcers of small intestine are mainly ascribed to Crohn's disease. Among possible differential diagnoses are chronic ulcers of small bowel caused by abnormal activation of the prostaglandin pathway either in the archetypal but uncommon non-steroidal anti-inflammatory drug [NSAID]-induced enteropathy, or in rare monogenic disorders due to PLA2G4A and SLCO2A1 mutations. SLCO2A1 variants are responsible for CEAS [chronic enteropathy associated with SLCO2A1], a syndrome which was exclusively reported in patients of Asian origin. Herein, we report the case of two French female siblings, P1 and P2, with CEAS. CASE REPORT: P1 underwent iterative bowel resections [removing 1 m of small bowel in total] for recurrent strictures and perforations. Her sister P2 had a tight duodenal stricture which required partial duodenectomy. Next-generation sequencing was performed on P1's DNA and identified two compound heterozygous variants in exon 12 in SLCO2A1, which were also present in P2. CONCLUSION: CEAS can be detected within the European population and raises the question of its incidence and recognition outside Asia. Presence of intractable recurrent ulcerations of the small intestine, mimicking Crohn's disease with concentric strictures, should motivate a genetic search for SLCO2A1 mutations, particularly in the context of family history or consanguinity.