RARE DISEASE
Refractory celiac disease
Refractory celiac disease
Refractory celiac disease
Synonyms: Refractory CD, Refractory sprue
Synonyms: Refractory CD, Refractory sprue
Synonyms: Refractory CD, Refractory sprue
Drug discovery
1
drug
With orphan designation
Overview
Refractory celiac disease (RCD) is a rare complication of celiac disease characterized by persistent villous atrophy, malabsorptive symptoms, and immune dysregulation despite ≥12 months of strict gluten-free diet. Classified into Type I (normal intraepithelial lymphocytes) and Type II (aberrant clonal lymphocytes), RCD-II carries higher lymphoma risk. Diagnosis requires exclusion of gluten exposure and secondary causes of non-responsiveness [1][5][10].
Categories: rare gastroenterological diseases
Research Papers
336 drug discovery papers about Refractory celiac disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
336 drug discovery papers about Refractory celiac disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-08 | Celiac crisis as an initial presentation of adult celiac disease: A case report and brief literature review
Celiac crisis is a rare, life-threatening manifestation of celiac disease characterized by acute, profuse diarrhea, severe dehydration, and profound metabolic disturbances. Although traditionally considered a pediatric complication, it is increasingly recognized in adults, often heralding the onset of the disease. We present the case of a 32-year-old previously healthy female who developed a celiac crisis. Extensive evaluations, including serology and duodenal biopsy, confirmed the diagnosis of celiac disease with marked villous atrophy, while effectively excluding enteropathy-associated T-cell lymphoma (EATL). The patient required intensive resuscitation, parenteral nutrition, and a short course of systemic corticosteroids alongside a strict gluten-free diet to achieve clinical and metabolic stabilization. This case underscores the critical importance of considering celiac crisis in the differential diagnosis of severe acute malabsorptive syndromes in adults. Early recognition and prompt initiation of dietary and supportive therapies are paramount to prevent serious complications, such as refeeding syndrome or cardiovascular collapse. Furthermore, the successful integration of corticosteroids underscores their utility in refractory or critically ill presentations when dietary withdrawal alone is insufficient to reverse mucosal inflammation rapidly.
2026-06-01 | A rare case of overlap between autoimmune enteropathy and ARBII enteropathy
Text A 75-year-old woman was admitted to our department for weight loss (25 kg in 10 months) and chronicdiarrhea (>6 months). In history: hypertension in Olmesartan 20 mg/day, multinodular goiter. The patient was already tested for anti-transglutaminase antibodies (negative, IgA in normal range) but EGDS showed severe duodenal villous atrophy. On suspicion of ARBsII-associated enteropathy, olmesartan was suspended with partial but not complete benefit on clinical. During hospitalization, the patient presented asthenic, occasionally soporific, severely malnourished (Table 1) and with a picture of pan-cytopenia (Table1). We excluded neurological (brain CT scan), infectious (blood cultures and co-cultures) and hematologic (bone marrow biopsy) causes. Ultrasound of the intestinal loops and ileo-colonoscopy were normal. Video capsule endoscopy showed marked scalloping of DII and jejunum with extensive ulcers (Figure1). Later, she performed at referral center anterograde double-balloon enteroscopy (DBE). DBE confirmed marked atrophy and map ulcers primarily suggestive of refractory celiac disease type II/EATL with ulcerative jejunum-ileitis. Histologic examination described findings referable to chronic exacerbated, erosive enteritis, not diagnostic for celiac disease. HLA search for celiac disease was negative therefore celiac disease was excluded. Hemotransfusions and nutritional supplementation were administered in consideration of anemia and nutritional deficiency. Empiric/ex juvantibus therapy with steroid was also set up with marked improvement in symptomatology. Following hospitalization, she was re-evaluated on an outpatient basis at enteropathy referral center. Here she was first imposed high-dose steroid therapy with marked improvement and weight gain, then Azathioprine in maintenance. She was therefore discharged with a diagnosis of autoimmune enteropathy with likely previous overlap with sartane enteropathy [ 1 ] [ 2 ]. Publication History Article published online: 05 June 2026 © 2026. European Society of Gastrointestinal Endoscopy. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-05-14 | A novel clustering of down syndrome and coeliac disease complicated by enteritis and small intestinal strictures: a case series.
Down syndrome (DS) increases risk for autoimmune conditions, including coeliac disease (CeD). Here, we report five adults with DS and biopsy-proven CeD who developed enteritis and symptomatic small bowel stricturing, a clustering not previously described in this population. All five patients had confirmed DS and CeD, and despite apparent adherence to a gluten-free diet, all developed small bowel strictures requiring endoscopic intervention, most commonly at the duodenal D1/D2 junction. Stricture histology demonstrated active CeD with varying degrees of inflammation and fibrosis. Three patients had elevated faecal calprotectin without consistent colonic pathology, suggesting enteritis as an important inflammatory driver. Two patients responded well to open capsule budesonide with symptom resolution and histological improvement. One patient showed no sustained benefit from multiple immunosuppressive agents, including corticosteroids, azathioprine, and infliximab, requiring repeated endoscopic dilatations. Differential diagnoses, including Crohn's disease, tuberculosis, nonsteroidal anti-inflammatory drug (NSAID) enteropathy, refractory CeD, and cryptogenic multifocal ulcerating stenosing enteritis were excluded based on clinical history, imaging, and histological findings. No granulomas or aberrant T-cell populations were identified. We propose this clustering may reflect a shared pathogenic mechanism linked to the interferonopathy of DS. Trisomy 21 causes overexpression of interferon receptors, creating heightened interferon signalling. Combined with CeD-triggered interferon production from gluten exposure, this may drive amplified immune activation, chronic enteritis, and fibrotic stricture formation. This hypothesis warrants further investigation through transcriptomic and immunohistochemical studies. Clinicians should consider this clustering in DS patients with CeD who present with persistent gastrointestinal symptoms. Given the underlying biology, JAK inhibitors may represent a promising therapeutic option for this phenotype and merit future study.
2026-04-27 | Celiac Disease with Systemic Extraintestinal Manifestations: Pathophysiological Mechanisms, Comprehensive Diagnostic Approach, and Integrated Therapeutic Management
Celiac disease is a chronic immune-mediated disorder triggered by gluten ingestion in genetically predisposed individuals, particularly those carrying HLA-DQ2 or HLA-DQ8 haplotypes. Although traditionally considered a gastrointestinal condition, it is now recognized as a systemic disease with a broad spectrum of extraintestinal manifestations. Gluten exposure induces deamidation of gliadin peptides by tissue transglutaminase, facilitating antigen presentation to CD4-positive T lymphocytes and initiating a proinflammatory cascade. This immune activation leads to villous atrophy, autoantibody production, and increased intestinal permeability, allowing inflammatory mediators to enter the systemic circulation and contribute to distant organ involvement. Extraintestinal manifestations are diverse and may include iron deficiency anemia, osteoporosis, dermatitis herpetiformis, neurological disorders such as ataxia and neuropathy, hepatic abnormalities, endocrine diseases including type 1 diabetes and autoimmune thyroiditis, and reproductive complications. These systemic features may occur in the absence of gastrointestinal symptoms, contributing to underdiagnosis and delayed treatment. Diagnosis relies on a structured approach that includes serologic testing with immunoglobulin A anti–tissue transglutaminase antibodies, confirmation by duodenal biopsy, and selective genetic testing in equivocal cases. A strict gluten-free diet remains the cornerstone of therapy, preventing ongoing immune activation and promoting mucosal healing. Comprehensive management also requires correction of nutritional deficiencies, monitoring of adherence, and multidisciplinary follow-up. Refractory disease and the risk of enteropathy-associated T-cell lymphoma underscore the importance of vigilant surveillance. Emerging therapies targeting gluten degradation, intestinal permeability, and immune modulation offer promising future directions in personalized management.
2026-03-15 | European Society for the Study of Coeliac Disease (ESsCD) 2025 Updated Guidelines on the Diagnosis and Management of Coeliac Disease in Adults. Part 2: Management, Follow-Up, and Complex Disease Courses.
Since the publication of the first European Society for the Study of Coeliac Disease (ESsCD) guidelines in 2019, substantial advances have been made in understanding the management and complex disease courses of coeliac disease (CeD) in adults. These 2025 updated guidelines aim to integrate new evidence, refine management strategies, and promote a personalised and multidisciplinary approach to care. The ESsCD convened a multidisciplinary panel of experts to revise the 2019 guidelines using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) framework. Evidence was appraised and graded according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Statements and recommendations were draughted within working groups and finalised through a structured Delphi consensus process. The updated guidelines are presented in two parts. Part 1, which has already been published, addresses the diagnostic approach to CeD in adults, whereas Part 2 focuses on disease management, structured follow-up, and the evaluation and treatment of persistent symptoms despite a gluten-free diet or refractory disease. New or expanded sections include guidance on the safe inclusion of oats, use of low-FODMAP diets in patients with persistent symptoms, management of exocrine pancreatic insufficiency, recognition of functional asplenia and related vaccination recommendations, and stratified bone-health screening. The guidelines also discuss nutritional and psychosocial support, digital models of care, and structured transition from paediatric to adult services. Updated therapeutic strategies for refractory CeD are provided, including immunosuppressive and novel pharmacologic options. These updated guidelines offer a comprehensive, evidence-based framework for the management and follow-up of adults with CeD. By integrating recent scientific advances with pragmatic, patient-centred recommendations, they seek to optimise clinical outcomes, quality of life, and long-term health in individuals with CeD.
proteins
2023-07-24 | Transcriptome profile and immune infiltrated landscape revealed a novel role of γδT cells in mediating pyroptosis in celiac disease
Celiac disease (CeD) is a primary malabsorption syndrome with no specific therapy, which greatly affects the quality of life. Since the pathogenesis of CeD remains riddled, based on multiple transcriptome profiles, this study aimed to establish an immune interaction network and elucidated new mechanisms involved in the pathogenesis of CeD, providing potentially new evidence for the diagnosis and treatment of CeD.Three microarray and three RNA sequencing datasets of human duodenal tissue with or without CeD were included in Gene Expression Omnibus and respectively merged into derivation and validation cohorts. Differential expression gene and functional enrichment analysis were developed, then pyroptosis enrichment score (PES) model was established to quantify pyroptosis levels. Immune infiltration and co-expression network were constructed based on Xcell database. Protein-protein interaction and weighted gene co-expression network analysis were determined to identify pyroptosis relative hub genes, whose predictive efficiency were tested using a least absolute shrinkage and selection operator (LASSO) regression model. CeD animal and in vitro cell line models were established to verify the occurrence of pyroptosis and molecules expression employing immunofluorescence, western blotting, cell counting kit-8 assay and enzyme-linked immunosorbent assay. Analysis of single-cell RNAseq (scRNAseq) was performed using "Seurat" R package.Differentially expressed genes (DEGs) (137) were identified in derivation cohort whose function was mainly enriched in interferon response and suppression of metabolism. Since an enrichment of pyroptosis pathway in CeD was unexpectedly discovered, a PES model with high efficiency was constructed and verified with two external databases, which confirmed that pyroptosis was significantly upregulated in CeD epithelia. γδT cells exhibited high expression of IFN-γ were the most relevant cells associated with pyroptosis and occupied a greater weight in the LASSO predictive model of CeD. An accumulation of GSDMD expressed in epithelia was identified using scRNAseq, while animal model and in vitro experiments confirmed that epithelium cells were induced to become "pre-pyroptotic" status via IFN-γ/IRF1/GSDMD axis. Furthermore, gluten intake triggered pyroptosis via caspase-1/GSDMD/IL-1β pathway.Our study demonstrated that pyroptosis was involved in the pathogenesis of CeD, and elucidated the novel role of γδT cells in mediating epithelial cell pyroptosis.
2021-10-07 | The costs of celiac disease: a contingent valuation in Switzerland
This paper proposes a first monetary measure of the private costs of celiac disease, including intangible costs (physical symptoms, logistical constraints, etc.) in Switzerland. This auto-immune disease damages the intestine when patients ingest gluten. The only treatment currently available is a gluten-free diet, which implies great nutritional constraints. To get a monetary equivalent of the costs borne by celiac patients, we used a contingent valuation. The scenario suggested to celiac patients a treatment in form of a daily pill, which would allow them to eat normally and avoid any physical pain from celiac disease. Mean Willingness To Pay (WTP) for the treatment is found to be around CHF 87 (approx. USD 87) per month. WTP is positively influenced by direct and indirect costs of the disease. Oppositely, individuals, who find the gluten-free diet healthier are willing to pay less. Finally, unlike symptoms before diagnostic, the current presence or intensity of physical symptoms are found to be insignificant. The latter result can be explained by the fact that, individuals facing stronger symptoms are more likely to adhere strictly to the GFD and hence to reduce their frequency.
2021-04-12 | In vivo assessment of a delayed release formulation of larazotide acetate indicated for celiac disease using a porcine model
There is no FDA approved therapy for the treatment of celiac disease (CeD), aside from avoidance of dietary gluten. Larazotide acetate (LA) is a first in class oral peptide developed as a tight junction regulator, which is a lead candidate for management of CeD. A delayed release formulation was tested in vitro and predicted release in the mid duodenum and jejunum, the target site of CeD. The aim of this study was to follow the concentration versus time profile of orally administered LA in the small intestine using a porcine model. A sensitive liquid chromatography/tandem mass spectrometry method was developed to quantify LA concentrations in porcine intestinal fluid samples. Oral dosing of LA (1 mg total) in overnight fasted pigs resulted in time dependent appearance of LA in the distal duodenum and proximal jejunum. Peak LA concentrations (0.32-1.76 μM) occurred at 1 hour in the duodenum and in proximal jejunum following oral dosing, with the continued presence of LA (0.02-0.47 μM) in the distal duodenum and in proximal jejunum (0.00-0.43 μM) from 2 to 4 hours following oral dosing. The data shows that LA is available in detectable concentrations at the site of CeD.
2019-07-16 | Challenges to drug discovery for celiac disease and approaches to overcome them
Introduction: The only available effective treatment for celiac disease (CD) is strict and long-term compliance with a gluten-free diet. Dietary gluten restriction must be strict and long term, but is difficult to achieve in many cases and alternative dietary strategies have been investigated in the past few years.Areas covered: This review highlights the progress that has been made in the development of new therapeutics for CD. Detailed information is provided on the targets of drugs for CD as their related mechanisms of action. The therapies are classified in five mechanisms: modification of gluten, intraluminal therapies, immunomodulation, intestinal permeability and modulation of adaptative response. The actual development phase and future approach are also described and discussed.Expert opinion: There are several limitations in each of the treatment targets related either through complications or the lack of complete response to a normal gluten containing diet. It is clear that the most desired therapy for celiac patients would induce gluten tolerance and progress has been made as per the treatments described herein. Therefore, it is shortly expected that curative or complimentary tools to a gluten free diet will be available that will improve the quality of life of CD sufferers.
2019-06-01 | OWE-18 Non-responsive and refractory coeliac disease: the largest UK experience from the NHS england national centre
Non-responsive coeliac disease (NRCD) is defined by persisting symptoms or laboratory abnormalities in patients with coeliac disease (CD) despite a gluten-free diet (GFD). Causes of NRCD are heterogeneous, with refractory CD (RCD) being associated with poor prognosis. The aims of this study are to identify the aetiologies for persisting symptoms in patients with NRCD referred to a national UK centre for CD, and to assess mortality rates in each group. Data on all CD patients, including those with persisting symptoms and tertiary referrals, was collected prospectively from 1998–2018. Patients were systematically investigated to establish the aetiology of their continued symptoms. They were also referred to a specialist coeliac dietitian to identify any lapses in GFD adherence or gluten cross-contamination. A repeat duodenal biopsy was performed and compared to previous biopsies where possible to check for histological remission. Colonoscopy, lactose hydrogen breath test, glucose hydrogen breath test, SeHCAT scan, CLO testing, faecal elastase, immunohistochemistry and γ-TCR clonality were performed. 2,356 patients with suspected CD were seen in this time period (121 were tertiary referrals). 157 were excluded from analysis due to unconfirmed diagnosis. Of the remaining 2,199 patients with confirmed CD, 2,123 had both villous atrophy and positive IgA-EMA/TTG, and 76 had seronegative CD. Of the 2,199 patients with CD (67% female, mean age at diagnosis 42.8 ± 18.5), 292 (13%) had persisting symptoms. The leading causes for persisting symptoms in patients without RCD (73% female, mean age at diagnosis 35.7 ± 19.2) were: gluten contamination (22%), functional/irritable bowel syndrome (20%), pancreatic exocrine insufficiency (7%), reflux dysmotility (5%), and microscopic colitis (5%). Of a total of 74 patients who were identified with RCD, 56 had RCD I (71% female, mean age at CD diagnosis 41.8 ± 19.0) and 18 had RCD II (33% female, mean age at CD diagnosis 55.4 ± 13.3). After a median follow up of 40.5 months (IQR 21.8–73.3), mortality was 7% in the RCD I group, compared to 39% in the RCD II group (p=0.019). Higher age at diagnosis of CD is a predictor for having RCD in patients with persisting symptoms (p<0.001). This is the largest UK study of NRCD and RCD. The contemporary mortality data in RCD II remains poor. Patients with suspected RCD should be referred to the National Centre for consideration of novel therapies such as IL-15 and Stem Cell Transplant.
cell therapies
2025-03-21 | Can autoimmune disease be cured by deep CD19+ cell depletion?
Therapeutic B cell depletion with monoclonal antibodies targeting CD20 forced a rethink about the pathogenic role of B cells and plasma cells in autoimmune diseases; however, it was tempered by frequent clinical relapses or nonresponse to CD20-directed therapy. Here, we re-evaluate B cell depletion strategies in autoimmunity prompted by 4 recent advances. The first is analysis of clonal accumulations of CD20- CD19+ plasma cells making autoantibodies in patients with anti-CD20 refractory autoimmune disease. The second is the remarkable clinical remissions induced by anti-CD19 chimeric antigen receptor T cells in cases of anti-CD20 refractory autoimmunity. The third is evidence that CD19+ plasma cells comprise the majority of plasma cells in humans, are not terminally differentiated, are long-lived, and if self-reactive have potent capacity to capture autoantigens via their surface immunoglobulin and present major histocompatibility complex class II-bound peptides. The fourth is the role of autoantigen-binding B cells and CD19+ plasma cells as key antigen-presenting cells in "T cell-mediated" autoimmune disorders, type 1 diabetes and celiac disease. Viewing human memory B cells and plasma cells from this alternative perspective offers an explanation for why deep CD19 compartmental depletion may be effective at achieving complete and durable remissions in the autoantibody-positive autoimmune diseases as a group, irrespective of whether the autoantibody is pathogenic.
2025-02-14 | Refractory Coeliac Disease: Diagnosis, Treatment, and Emerging Therapies
Coeliac disease (CD) is a chronic immune-mediated disorder triggered by gluten ingestion in genetically predisposed individuals, leading to intestinal damage, malabsorption, and systemic complications. Although traditionally considered a gastrointestinal disorder, CD is now recognized as a multisystem condition with neurological, musculoskeletal, endocrine, and cardiovascular manifestations. Despite advancements in diagnostic tools, the disease remains underdiagnosed due to its diverse clinical presentations. The global prevalence of CD is approximately 1%, with increasing incidence linked to improved screening and environmental factors. Diagnosis involves serological testing, histological examination, and, in select cases, genetic screening. While strict adherence to a gluten-free diet (GFD) is currently the only effective treatment, many patients face dietary compliance challenges, nutritional deficiencies, and persistent symptoms, necessitating further investigation for refractory CD. Findings highlight that while GFD remains the cornerstone of treatment, adherence difficulties and ongoing symptoms in some patients require alternative interventions. Research into immune modulation, gut microbiota therapies, and intestinal permeability regulation is ongoing, with promising developments for non-dietary treatment options.
2023-05-19 | Celiac Disease and the Potential of Stems Cells as Treatment
Celiac disease is characterized by having a broad spectrum of clinical presentations ranging from asymptomatic cases to classical gastrointestinal manifestations of disease and cases of severe progression in refractory celiac disease and the development of certain types of cancers. The age of onset of disease also varies greatly, with genetics, environmental and immunological factors. While this autoimmune disease currently affects 1% of Western populations, cases have been increasing globally due to presence of gluten in westernized diets and improved diagnostic testing and awareness. The only current treatment for celiac disease is a strict lifelong adherence to a gluten free diet; however, patient reports suggest they are not satisfied with quality of life and clinical improvement involving only dietary treatment and future routes of treatment should be explored. The overall lack of understanding of a complex model of this disease has led to notable obstacles when conducting clinical trials investigating future treatments. Stem cells play a crucial role in the human body as they could help regulate inflammation that is often associated with autoimmune disorders by regenerating and differentiating into several different cell types. Mesenchymal stem cells and hematopoietic stem cells are highly proliferating, while mesenchymal stem cells can cross the HLAQ barrier and prevent an adverse immunological response in patients. For this reason, stem cells, especially mesenchymal stem cells, are prime candidates for investigation of future treatments designed with a goal of restoring the epithelial barrier and preventing villous atrophy while reducing inflammation.
2023-04-25 | Enhancing Regulatory T Cells to Treat Inflammatory and Autoimmune Diseases
Regulatory T cells (Tregs) control immune responses and are essential to maintain immune homeostasis and self-tolerance. Hence, it is no coincidence that autoimmune and chronic inflammatory disorders are associated with defects in Tregs. These diseases have currently no cure and are treated with palliative drugs such as immunosuppressant and immunomodulatory agents. Thereby, there is a great interest in developing medical interventions against these diseases based on enhancing Treg cell function and numbers. Here, we give an overview of Treg cell ontogeny and function, paying particular attention to mucosal Tregs. We review some notable approaches to enhance immunomodulation by Tregs with therapeutic purposes including adoptive Treg cell transfer therapy and discuss relevant clinical trials for inflammatory bowel disease. We next introduce ways to expand mucosal Tregs in vivo using microbiota and dietary products that have been the focus of clinical trials in various autoimmune and chronic-inflammatory diseases.
2023-01-12 | Potential Of Stem Cell Based Therapy To Treat Celiac Disease And Its Complications
Celiac Disease affects 1% of the population in the Western world, however, the number of affected people is rising due to high gluten diets.Celiac disease is caused by a number of things involving interactions between genetic, environmental, and immunological factors.Lack of a comprehensive model to conduct trials on makes treating celiac disease a difficult feat.In terms of clinical trials, low incidence and variability in patients are significant obstacles in the establishment of treatments.Stem cells play a pivotal role in chronic inflammatory pathologies due to their ability to regenerate and differentiate into numerous cell types as well as their essential role in homeostasis.Mesenchymal stem cells are highly proliferating, multipotent stromal cells that can cross the HLAQ barrier and lack immunogenicity.Based on these properties, mesenchymal stem cells are able to maintain the epithelial barrier, prevent villous atrophy, and subdue inflammation in CD patients and have proven to be successful in multiple clinical trials.For this reason, stem cells, primarily mesenchymal, possess the potential to be an effective therapy and should be further researched.
antibodies
2026-05-18 | Aberrant intra-epithelial lymphocytes cause enterocyte cell death in refractory celiac disease by CD103-β7-receptor-mediated granzyme-B degranulation which can be restored by etrolizumab.
Refractory celiac disease type II (RCDII) is an intestinal tumor of aberrant intra-epithelial T-lymphocytes (IEL). The severe enteropathy found in RCDII is caused by aberrant IEL that exert cytotoxicity against enterocytes. In this study, we investigated the cell death mechanism responsible for villous atrophy in RCDII. Aberrant IEL were isolated from duodenal biopsies of RCDII patients. Enterocyte and RCDII patient-derived cell lines and human small intestinal organoids were used. mRNA expression was determined with reverse transcriptase-multiplex ligation-dependent probe amplification. Protein expression, degranulation and enterocyte killing were measured using flow cytometry, immunofluorescence or bright field microscopy. Secretion of granzyme-B was detected by enzyme immunoassay. Levels of granzyme-B expression were significantly upregulated in aberrant IEL of RCDII patients compared to patients with celiac disease (CD) on gluten-free diet (P = 0.0001) and correlated with severity of villous atrophy and clinical response to therapy. Killing of intestinal epithelial cells was caused by granzyme-B. For granzyme-B degranulation and subsequent cytotoxicity, cell-cell binding via the CD103-receptor, which was upregulated on aberrant IEL, was essential. In a preclinical model, aberrant IEL migrated to the intestinal organoids and induced organoid disintegration and CD103-dependent cell death. Targeting CD103-heterodimeric partner β7 with therapeutic monoclonal antibody etrolizumab prevented enterocyte cell killing and resulted in survival of organoids. Killing of enterocytes in RCDII patients depends on degranulation of granzyme-B by aberrant IEL through CD103-β7 binding. By blocking this interaction, etrolizumab restores the intestinal epithelium and therefore should be considered as potential therapy for RCDII patients.
2026-01-04 | A Clinical Review of Collagenous Sprue, Refractory Celiac Disease, Ulcerative Jejunitis, and Enteropathy-Associated T-cell Lymphoma
Celiac disease is a chronic immune-mediated enteropathy caused by gluten exposure. It affects approximately 1% of the world"s population and can present at any age with a wide range of signs and symptoms including malabsorption. Adherence to a gluten-free diet is the basis of treatment; however, a small subset of patients can develop worsening and life-threatening gastrointestinal symptoms despite gluten avoidance. Clinical worsening despite a gluten-free diet should raise concern for other conditions such as collagenous sprue or other more severe forms of celiac disease. Collagenous sprue is characterized by a subepithelial collagen band and celiac-like histologic features in the small bowel mucosa. It is unclear whether collagenous sprue falls within the celiac disease spectrum or represents a distinct entity. Refractory celiac disease is a rare form of celiac disease unresponsive to a gluten-free diet and can be subdivided into types I and II. The latter is defined by a clonal aberrant population of intraepithelial lymphocytes that accumulate lymphomagenic mutations. Refractory celiac disease type II is a premalignant condition that may exhibit ulcerative jejunitis or progress to the very aggressive enteropathy-associated T-cell lymphoma. Immunohistochemistry, flow cytometry, and T-cell receptor clonality testing aid in the diagnosis of refractory celiac disease. Treatment options include immunosuppressants, chemotherapy, and stem cell transplantation. The objective of this paper is to provide an overview of collagenous sprue, refractory celiac disease, ulcerative jejunitis, and enteropathy-associated T-cell lymphoma with a focus on presentation, pathogenesis, diagnosis, and treatment.
2025-12-22 | Persistent symptoms and enteropathy in coeliac disease: clinical considerations and therapeutic opportunities.
Coeliac disease is an immune-mediated enteropathy triggered by gluten ingestion. While a strict gluten-free diet remains the basis of treatment, a sizeable proportion of patients continue to experience symptoms or histological abnormalities despite adherence. This clinical entity of non-responsive coeliac disease imposes diagnostic and therapeutic challenges. Inadvertent gluten intake is a leading cause and can be difficult to detect, but measuring gluten immunogenic peptides in the urine or stool can provide objective evidence of exposure. Persistent symptoms or enteropathy can also originate from coexisting gastrointestinal disorders or the rare complication of refractory coeliac disease, which requires specialized treatment. Several novel therapies, including intestinal gluten neutralization, intestinal permeability modulation, HLA-gluten or cytokine blockade, transglutaminase inhibition and induction of gluten tolerance have reached Phase 1b/2 clinical trials. While coeliac drug development still faces several hurdles, these advances offer hope for more personalized, effective management beyond the gluten-free diet.
2025-12-18 | [Intestinal T-cell lymphomas and NK/T-cell lymphoproliferations-an overview].
We describe the defined entities of intestinal T‑cell lymphomas and NK-/T-cell lymphoproliferations that occur in the gastrointestinal tract. The spectrum encompasses aggressive T‑cell lymphomas such as enteropathy-associated T‑cell lymphoma as well as in situ lymphomas like refractory celiac disease type II and essentially benign lesions like indolent NK-cell lymphoproliferation of the gastrointestinal tract.
2025-10-01 | Autoimmune Autonomic Ganglionopathy in a Patient with Celiac Disease on Dialysis: A Rare Case of Refractory Orthostatic Hypotension
Introduction: Orthostatic hypotension (OH) is a frequent yet complex complication in hemodialysis patients. While commonly linked to ultrafiltration, volume depletion, or medications, persistent symptoms in autoimmune patients may signal an underlying autonomic dysfunction. I present a case of post-dialysis OH in a celiac patient diagnosed with Autoimmune Autonomic Ganglionopathy, managed through pharmacologic, immunologic, and lifestyle interventions. Case Description: A 56-year-old male with a history of celiac disease and hypertension was admitted with respiratory distress. Workup revealed ESRD secondary to chronic hypertension, and he was initiated on peritoneal dialysis. However, after a few sessions, he developed severe orthostatic symptoms, including dizziness and syncope, significantly impairing mobility. Due to intolerance, he was switched to in-center hemodialysis, where he exhibited resting hypertension with marked orthostatic hypotension and paradoxical bradycardia, suggesting autonomic dysfunction. Cardiac, endocrine, and medication-related causes were excluded. Despite monitored midodrine therapy, symptoms persisted. A strong clinical suspicion for autonomic dysfuntion was considered. Further evaluation revealed positive ganglionic (α3-AChR) autoantibodies, confirming the diagnosis of Autoimmune Autonomic Ganglionopathy. After the diagnosis was confired, the patient was treated with lifestyle modifications, including the use of an abdominal binder and postural precautions. Additionally, intravenous immunoglobulin (IVIG) therapy was initiated 3 times a week. Over time, his functional status and hemodynamic stability improved, allowing successful transition back to peritoneal dialysis. Discussion: This case highlights the diagnostic challenge of OH in dialysis patients. While OH is often attributed to volume shifts, autoimmune autonomic dysfunction should be considered in patients with severe symptoms, particularly those with autoimmune conditions. Treatment with IVIG or Plasma Exchange has been reported to be effective. There are also strong evidences that novel immunosuppressant agents such as Mycophenolate mofetil and Rituximab may be effective in certain patients who are unresponsive to IVIG or PE. Autoimmune Autonomic Ganglionopathy (AAG) is a rare but potentially treatable cause of OH, requiring a high index of clinical suspicion.
other
2024-02-19 | Impaired IgM Memory B Cell Function Is Common in Coeliac Disease but Conjugate Pneumococcal Vaccination Induces Robust Protective Immunity
Coeliac disease (CD) is associated with hyposplenism, an acquired impairment of spleen function associated with reduced IgM memory B cells and increased susceptibility to serious pneumococcal infection. Little is known about the immune implications of hyposplenism in CD or the optimal pneumococcal vaccination strategy. In this study, the immune effects of hyposplenism in CD, and the accuracy of screening approaches and protective responses induced by two different pneumococcal vaccines were examined. Active and treated CD cohorts, and healthy and surgically splenectomised controls underwent testing for the presence of Howell-Jolly bodies and pitted red cells, spleen ultrasound, and immune assessment of IgM memory B cell frequency and IgM memory B cell responses to T cell-dependent (TD) or T cell-independent (TI) stimulation. Responses following conjugate (TD) and polysaccharide (TI) pneumococcal vaccination were compared using ELISA and opsonophagocytic assays. Although hyposplenism is rare in treated CD (5.1%), functional B cell defects are common (28-61%) and are not detected by current clinical tests. Conjugate pneumococcal vaccination induced superior and sustained protection against clinically relevant serotypes. Clinical practice guidelines in CD should recommend routine pneumococcal vaccination, ideally with a conjugate vaccine, of all patients in lieu of hyposplenism screening.
2013-03-07 | Hyposplenism as a cause of pneumococcal meningoencephalitis in an adult patient with coeliac disease
Introduction: Coeliac disease can be associated with hyposplenism and splenic atrophy, which may increase the patient’s risk for fatal infections caused by Streptococcus pneumoniae or Pneumococcus. It is general opinion that many more patients with coeliac disease have died from hyposplenism-related infections than those reported in literature. Case report: A 62-year-old woman with recently diagnosed coeliac disease was hospitalized with high fever, disorientation, and nuchal rigidity. Cerebral computed tomography was negative. Laboratory tests showed an elevated leukocyte count and very high levels of C reactive protein. The cerebrospinal fluid (CSF) contained an increased number of mononuclear cells associated with a low glucose level and high protein concentrations. The CSF culture was positive for Streptococcus pneumoniae. Neurological conditions rapidly deteriorated with the onset of coma, and magnetic resonance imaging of the brain revealed initial signs of encephalitis extending above and below the tentorium. Abdominal ultrasonography disclosed splenic hypotrophy that raised the suspicion of hyposplenism. The diagnosis of hyposplenism was confirmed by demonstration of Howell-Jolly bodies in a peripheral blood smear. Discussion: This is the first reported case of pneumococcal meningoencephalitis caused by splenic hypofunction in a patient with coeliac disease. When coeliac disease is diagnosed with a marked delay in an elderly patient, spleen function should always be assessed. If impaired, the patient should undergo vaccination with pneumococcal conjugate vaccine to prevent pneumococcal infections.
small molecules
2026-07-08 | Celiac crisis as an initial presentation of adult celiac disease: A case report and brief literature review
Celiac crisis is a rare, life-threatening manifestation of celiac disease characterized by acute, profuse diarrhea, severe dehydration, and profound metabolic disturbances. Although traditionally considered a pediatric complication, it is increasingly recognized in adults, often heralding the onset of the disease. We present the case of a 32-year-old previously healthy female who developed a celiac crisis. Extensive evaluations, including serology and duodenal biopsy, confirmed the diagnosis of celiac disease with marked villous atrophy, while effectively excluding enteropathy-associated T-cell lymphoma (EATL). The patient required intensive resuscitation, parenteral nutrition, and a short course of systemic corticosteroids alongside a strict gluten-free diet to achieve clinical and metabolic stabilization. This case underscores the critical importance of considering celiac crisis in the differential diagnosis of severe acute malabsorptive syndromes in adults. Early recognition and prompt initiation of dietary and supportive therapies are paramount to prevent serious complications, such as refeeding syndrome or cardiovascular collapse. Furthermore, the successful integration of corticosteroids underscores their utility in refractory or critically ill presentations when dietary withdrawal alone is insufficient to reverse mucosal inflammation rapidly.
2026-06-01 | A rare case of overlap between autoimmune enteropathy and ARBII enteropathy
Text A 75-year-old woman was admitted to our department for weight loss (25 kg in 10 months) and chronicdiarrhea (>6 months). In history: hypertension in Olmesartan 20 mg/day, multinodular goiter. The patient was already tested for anti-transglutaminase antibodies (negative, IgA in normal range) but EGDS showed severe duodenal villous atrophy. On suspicion of ARBsII-associated enteropathy, olmesartan was suspended with partial but not complete benefit on clinical. During hospitalization, the patient presented asthenic, occasionally soporific, severely malnourished (Table 1) and with a picture of pan-cytopenia (Table1). We excluded neurological (brain CT scan), infectious (blood cultures and co-cultures) and hematologic (bone marrow biopsy) causes. Ultrasound of the intestinal loops and ileo-colonoscopy were normal. Video capsule endoscopy showed marked scalloping of DII and jejunum with extensive ulcers (Figure1). Later, she performed at referral center anterograde double-balloon enteroscopy (DBE). DBE confirmed marked atrophy and map ulcers primarily suggestive of refractory celiac disease type II/EATL with ulcerative jejunum-ileitis. Histologic examination described findings referable to chronic exacerbated, erosive enteritis, not diagnostic for celiac disease. HLA search for celiac disease was negative therefore celiac disease was excluded. Hemotransfusions and nutritional supplementation were administered in consideration of anemia and nutritional deficiency. Empiric/ex juvantibus therapy with steroid was also set up with marked improvement in symptomatology. Following hospitalization, she was re-evaluated on an outpatient basis at enteropathy referral center. Here she was first imposed high-dose steroid therapy with marked improvement and weight gain, then Azathioprine in maintenance. She was therefore discharged with a diagnosis of autoimmune enteropathy with likely previous overlap with sartane enteropathy [ 1 ] [ 2 ]. Publication History Article published online: 05 June 2026 © 2026. European Society of Gastrointestinal Endoscopy. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-05-14 | A novel clustering of down syndrome and coeliac disease complicated by enteritis and small intestinal strictures: a case series.
Down syndrome (DS) increases risk for autoimmune conditions, including coeliac disease (CeD). Here, we report five adults with DS and biopsy-proven CeD who developed enteritis and symptomatic small bowel stricturing, a clustering not previously described in this population. All five patients had confirmed DS and CeD, and despite apparent adherence to a gluten-free diet, all developed small bowel strictures requiring endoscopic intervention, most commonly at the duodenal D1/D2 junction. Stricture histology demonstrated active CeD with varying degrees of inflammation and fibrosis. Three patients had elevated faecal calprotectin without consistent colonic pathology, suggesting enteritis as an important inflammatory driver. Two patients responded well to open capsule budesonide with symptom resolution and histological improvement. One patient showed no sustained benefit from multiple immunosuppressive agents, including corticosteroids, azathioprine, and infliximab, requiring repeated endoscopic dilatations. Differential diagnoses, including Crohn's disease, tuberculosis, nonsteroidal anti-inflammatory drug (NSAID) enteropathy, refractory CeD, and cryptogenic multifocal ulcerating stenosing enteritis were excluded based on clinical history, imaging, and histological findings. No granulomas or aberrant T-cell populations were identified. We propose this clustering may reflect a shared pathogenic mechanism linked to the interferonopathy of DS. Trisomy 21 causes overexpression of interferon receptors, creating heightened interferon signalling. Combined with CeD-triggered interferon production from gluten exposure, this may drive amplified immune activation, chronic enteritis, and fibrotic stricture formation. This hypothesis warrants further investigation through transcriptomic and immunohistochemical studies. Clinicians should consider this clustering in DS patients with CeD who present with persistent gastrointestinal symptoms. Given the underlying biology, JAK inhibitors may represent a promising therapeutic option for this phenotype and merit future study.
2026-04-27 | Celiac Disease with Systemic Extraintestinal Manifestations: Pathophysiological Mechanisms, Comprehensive Diagnostic Approach, and Integrated Therapeutic Management
Celiac disease is a chronic immune-mediated disorder triggered by gluten ingestion in genetically predisposed individuals, particularly those carrying HLA-DQ2 or HLA-DQ8 haplotypes. Although traditionally considered a gastrointestinal condition, it is now recognized as a systemic disease with a broad spectrum of extraintestinal manifestations. Gluten exposure induces deamidation of gliadin peptides by tissue transglutaminase, facilitating antigen presentation to CD4-positive T lymphocytes and initiating a proinflammatory cascade. This immune activation leads to villous atrophy, autoantibody production, and increased intestinal permeability, allowing inflammatory mediators to enter the systemic circulation and contribute to distant organ involvement. Extraintestinal manifestations are diverse and may include iron deficiency anemia, osteoporosis, dermatitis herpetiformis, neurological disorders such as ataxia and neuropathy, hepatic abnormalities, endocrine diseases including type 1 diabetes and autoimmune thyroiditis, and reproductive complications. These systemic features may occur in the absence of gastrointestinal symptoms, contributing to underdiagnosis and delayed treatment. Diagnosis relies on a structured approach that includes serologic testing with immunoglobulin A anti–tissue transglutaminase antibodies, confirmation by duodenal biopsy, and selective genetic testing in equivocal cases. A strict gluten-free diet remains the cornerstone of therapy, preventing ongoing immune activation and promoting mucosal healing. Comprehensive management also requires correction of nutritional deficiencies, monitoring of adherence, and multidisciplinary follow-up. Refractory disease and the risk of enteropathy-associated T-cell lymphoma underscore the importance of vigilant surveillance. Emerging therapies targeting gluten degradation, intestinal permeability, and immune modulation offer promising future directions in personalized management.
2026-03-15 | European Society for the Study of Coeliac Disease (ESsCD) 2025 Updated Guidelines on the Diagnosis and Management of Coeliac Disease in Adults. Part 2: Management, Follow-Up, and Complex Disease Courses.
Since the publication of the first European Society for the Study of Coeliac Disease (ESsCD) guidelines in 2019, substantial advances have been made in understanding the management and complex disease courses of coeliac disease (CeD) in adults. These 2025 updated guidelines aim to integrate new evidence, refine management strategies, and promote a personalised and multidisciplinary approach to care. The ESsCD convened a multidisciplinary panel of experts to revise the 2019 guidelines using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) framework. Evidence was appraised and graded according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Statements and recommendations were draughted within working groups and finalised through a structured Delphi consensus process. The updated guidelines are presented in two parts. Part 1, which has already been published, addresses the diagnostic approach to CeD in adults, whereas Part 2 focuses on disease management, structured follow-up, and the evaluation and treatment of persistent symptoms despite a gluten-free diet or refractory disease. New or expanded sections include guidance on the safe inclusion of oats, use of low-FODMAP diets in patients with persistent symptoms, management of exocrine pancreatic insufficiency, recognition of functional asplenia and related vaccination recommendations, and stratified bone-health screening. The guidelines also discuss nutritional and psychosocial support, digital models of care, and structured transition from paediatric to adult services. Updated therapeutic strategies for refractory CeD are provided, including immunosuppressive and novel pharmacologic options. These updated guidelines offer a comprehensive, evidence-based framework for the management and follow-up of adults with CeD. By integrating recent scientific advances with pragmatic, patient-centred recommendations, they seek to optimise clinical outcomes, quality of life, and long-term health in individuals with CeD.
proteins
2023-07-24 | Transcriptome profile and immune infiltrated landscape revealed a novel role of γδT cells in mediating pyroptosis in celiac disease
Celiac disease (CeD) is a primary malabsorption syndrome with no specific therapy, which greatly affects the quality of life. Since the pathogenesis of CeD remains riddled, based on multiple transcriptome profiles, this study aimed to establish an immune interaction network and elucidated new mechanisms involved in the pathogenesis of CeD, providing potentially new evidence for the diagnosis and treatment of CeD.Three microarray and three RNA sequencing datasets of human duodenal tissue with or without CeD were included in Gene Expression Omnibus and respectively merged into derivation and validation cohorts. Differential expression gene and functional enrichment analysis were developed, then pyroptosis enrichment score (PES) model was established to quantify pyroptosis levels. Immune infiltration and co-expression network were constructed based on Xcell database. Protein-protein interaction and weighted gene co-expression network analysis were determined to identify pyroptosis relative hub genes, whose predictive efficiency were tested using a least absolute shrinkage and selection operator (LASSO) regression model. CeD animal and in vitro cell line models were established to verify the occurrence of pyroptosis and molecules expression employing immunofluorescence, western blotting, cell counting kit-8 assay and enzyme-linked immunosorbent assay. Analysis of single-cell RNAseq (scRNAseq) was performed using "Seurat" R package.Differentially expressed genes (DEGs) (137) were identified in derivation cohort whose function was mainly enriched in interferon response and suppression of metabolism. Since an enrichment of pyroptosis pathway in CeD was unexpectedly discovered, a PES model with high efficiency was constructed and verified with two external databases, which confirmed that pyroptosis was significantly upregulated in CeD epithelia. γδT cells exhibited high expression of IFN-γ were the most relevant cells associated with pyroptosis and occupied a greater weight in the LASSO predictive model of CeD. An accumulation of GSDMD expressed in epithelia was identified using scRNAseq, while animal model and in vitro experiments confirmed that epithelium cells were induced to become "pre-pyroptotic" status via IFN-γ/IRF1/GSDMD axis. Furthermore, gluten intake triggered pyroptosis via caspase-1/GSDMD/IL-1β pathway.Our study demonstrated that pyroptosis was involved in the pathogenesis of CeD, and elucidated the novel role of γδT cells in mediating epithelial cell pyroptosis.
2021-10-07 | The costs of celiac disease: a contingent valuation in Switzerland
This paper proposes a first monetary measure of the private costs of celiac disease, including intangible costs (physical symptoms, logistical constraints, etc.) in Switzerland. This auto-immune disease damages the intestine when patients ingest gluten. The only treatment currently available is a gluten-free diet, which implies great nutritional constraints. To get a monetary equivalent of the costs borne by celiac patients, we used a contingent valuation. The scenario suggested to celiac patients a treatment in form of a daily pill, which would allow them to eat normally and avoid any physical pain from celiac disease. Mean Willingness To Pay (WTP) for the treatment is found to be around CHF 87 (approx. USD 87) per month. WTP is positively influenced by direct and indirect costs of the disease. Oppositely, individuals, who find the gluten-free diet healthier are willing to pay less. Finally, unlike symptoms before diagnostic, the current presence or intensity of physical symptoms are found to be insignificant. The latter result can be explained by the fact that, individuals facing stronger symptoms are more likely to adhere strictly to the GFD and hence to reduce their frequency.
2021-04-12 | In vivo assessment of a delayed release formulation of larazotide acetate indicated for celiac disease using a porcine model
There is no FDA approved therapy for the treatment of celiac disease (CeD), aside from avoidance of dietary gluten. Larazotide acetate (LA) is a first in class oral peptide developed as a tight junction regulator, which is a lead candidate for management of CeD. A delayed release formulation was tested in vitro and predicted release in the mid duodenum and jejunum, the target site of CeD. The aim of this study was to follow the concentration versus time profile of orally administered LA in the small intestine using a porcine model. A sensitive liquid chromatography/tandem mass spectrometry method was developed to quantify LA concentrations in porcine intestinal fluid samples. Oral dosing of LA (1 mg total) in overnight fasted pigs resulted in time dependent appearance of LA in the distal duodenum and proximal jejunum. Peak LA concentrations (0.32-1.76 μM) occurred at 1 hour in the duodenum and in proximal jejunum following oral dosing, with the continued presence of LA (0.02-0.47 μM) in the distal duodenum and in proximal jejunum (0.00-0.43 μM) from 2 to 4 hours following oral dosing. The data shows that LA is available in detectable concentrations at the site of CeD.
2019-07-16 | Challenges to drug discovery for celiac disease and approaches to overcome them
Introduction: The only available effective treatment for celiac disease (CD) is strict and long-term compliance with a gluten-free diet. Dietary gluten restriction must be strict and long term, but is difficult to achieve in many cases and alternative dietary strategies have been investigated in the past few years.Areas covered: This review highlights the progress that has been made in the development of new therapeutics for CD. Detailed information is provided on the targets of drugs for CD as their related mechanisms of action. The therapies are classified in five mechanisms: modification of gluten, intraluminal therapies, immunomodulation, intestinal permeability and modulation of adaptative response. The actual development phase and future approach are also described and discussed.Expert opinion: There are several limitations in each of the treatment targets related either through complications or the lack of complete response to a normal gluten containing diet. It is clear that the most desired therapy for celiac patients would induce gluten tolerance and progress has been made as per the treatments described herein. Therefore, it is shortly expected that curative or complimentary tools to a gluten free diet will be available that will improve the quality of life of CD sufferers.
2019-06-01 | OWE-18 Non-responsive and refractory coeliac disease: the largest UK experience from the NHS england national centre
Non-responsive coeliac disease (NRCD) is defined by persisting symptoms or laboratory abnormalities in patients with coeliac disease (CD) despite a gluten-free diet (GFD). Causes of NRCD are heterogeneous, with refractory CD (RCD) being associated with poor prognosis. The aims of this study are to identify the aetiologies for persisting symptoms in patients with NRCD referred to a national UK centre for CD, and to assess mortality rates in each group. Data on all CD patients, including those with persisting symptoms and tertiary referrals, was collected prospectively from 1998–2018. Patients were systematically investigated to establish the aetiology of their continued symptoms. They were also referred to a specialist coeliac dietitian to identify any lapses in GFD adherence or gluten cross-contamination. A repeat duodenal biopsy was performed and compared to previous biopsies where possible to check for histological remission. Colonoscopy, lactose hydrogen breath test, glucose hydrogen breath test, SeHCAT scan, CLO testing, faecal elastase, immunohistochemistry and γ-TCR clonality were performed. 2,356 patients with suspected CD were seen in this time period (121 were tertiary referrals). 157 were excluded from analysis due to unconfirmed diagnosis. Of the remaining 2,199 patients with confirmed CD, 2,123 had both villous atrophy and positive IgA-EMA/TTG, and 76 had seronegative CD. Of the 2,199 patients with CD (67% female, mean age at diagnosis 42.8 ± 18.5), 292 (13%) had persisting symptoms. The leading causes for persisting symptoms in patients without RCD (73% female, mean age at diagnosis 35.7 ± 19.2) were: gluten contamination (22%), functional/irritable bowel syndrome (20%), pancreatic exocrine insufficiency (7%), reflux dysmotility (5%), and microscopic colitis (5%). Of a total of 74 patients who were identified with RCD, 56 had RCD I (71% female, mean age at CD diagnosis 41.8 ± 19.0) and 18 had RCD II (33% female, mean age at CD diagnosis 55.4 ± 13.3). After a median follow up of 40.5 months (IQR 21.8–73.3), mortality was 7% in the RCD I group, compared to 39% in the RCD II group (p=0.019). Higher age at diagnosis of CD is a predictor for having RCD in patients with persisting symptoms (p<0.001). This is the largest UK study of NRCD and RCD. The contemporary mortality data in RCD II remains poor. Patients with suspected RCD should be referred to the National Centre for consideration of novel therapies such as IL-15 and Stem Cell Transplant.
cell therapies
2025-03-21 | Can autoimmune disease be cured by deep CD19+ cell depletion?
Therapeutic B cell depletion with monoclonal antibodies targeting CD20 forced a rethink about the pathogenic role of B cells and plasma cells in autoimmune diseases; however, it was tempered by frequent clinical relapses or nonresponse to CD20-directed therapy. Here, we re-evaluate B cell depletion strategies in autoimmunity prompted by 4 recent advances. The first is analysis of clonal accumulations of CD20- CD19+ plasma cells making autoantibodies in patients with anti-CD20 refractory autoimmune disease. The second is the remarkable clinical remissions induced by anti-CD19 chimeric antigen receptor T cells in cases of anti-CD20 refractory autoimmunity. The third is evidence that CD19+ plasma cells comprise the majority of plasma cells in humans, are not terminally differentiated, are long-lived, and if self-reactive have potent capacity to capture autoantigens via their surface immunoglobulin and present major histocompatibility complex class II-bound peptides. The fourth is the role of autoantigen-binding B cells and CD19+ plasma cells as key antigen-presenting cells in "T cell-mediated" autoimmune disorders, type 1 diabetes and celiac disease. Viewing human memory B cells and plasma cells from this alternative perspective offers an explanation for why deep CD19 compartmental depletion may be effective at achieving complete and durable remissions in the autoantibody-positive autoimmune diseases as a group, irrespective of whether the autoantibody is pathogenic.
2025-02-14 | Refractory Coeliac Disease: Diagnosis, Treatment, and Emerging Therapies
Coeliac disease (CD) is a chronic immune-mediated disorder triggered by gluten ingestion in genetically predisposed individuals, leading to intestinal damage, malabsorption, and systemic complications. Although traditionally considered a gastrointestinal disorder, CD is now recognized as a multisystem condition with neurological, musculoskeletal, endocrine, and cardiovascular manifestations. Despite advancements in diagnostic tools, the disease remains underdiagnosed due to its diverse clinical presentations. The global prevalence of CD is approximately 1%, with increasing incidence linked to improved screening and environmental factors. Diagnosis involves serological testing, histological examination, and, in select cases, genetic screening. While strict adherence to a gluten-free diet (GFD) is currently the only effective treatment, many patients face dietary compliance challenges, nutritional deficiencies, and persistent symptoms, necessitating further investigation for refractory CD. Findings highlight that while GFD remains the cornerstone of treatment, adherence difficulties and ongoing symptoms in some patients require alternative interventions. Research into immune modulation, gut microbiota therapies, and intestinal permeability regulation is ongoing, with promising developments for non-dietary treatment options.
2023-05-19 | Celiac Disease and the Potential of Stems Cells as Treatment
Celiac disease is characterized by having a broad spectrum of clinical presentations ranging from asymptomatic cases to classical gastrointestinal manifestations of disease and cases of severe progression in refractory celiac disease and the development of certain types of cancers. The age of onset of disease also varies greatly, with genetics, environmental and immunological factors. While this autoimmune disease currently affects 1% of Western populations, cases have been increasing globally due to presence of gluten in westernized diets and improved diagnostic testing and awareness. The only current treatment for celiac disease is a strict lifelong adherence to a gluten free diet; however, patient reports suggest they are not satisfied with quality of life and clinical improvement involving only dietary treatment and future routes of treatment should be explored. The overall lack of understanding of a complex model of this disease has led to notable obstacles when conducting clinical trials investigating future treatments. Stem cells play a crucial role in the human body as they could help regulate inflammation that is often associated with autoimmune disorders by regenerating and differentiating into several different cell types. Mesenchymal stem cells and hematopoietic stem cells are highly proliferating, while mesenchymal stem cells can cross the HLAQ barrier and prevent an adverse immunological response in patients. For this reason, stem cells, especially mesenchymal stem cells, are prime candidates for investigation of future treatments designed with a goal of restoring the epithelial barrier and preventing villous atrophy while reducing inflammation.
2023-04-25 | Enhancing Regulatory T Cells to Treat Inflammatory and Autoimmune Diseases
Regulatory T cells (Tregs) control immune responses and are essential to maintain immune homeostasis and self-tolerance. Hence, it is no coincidence that autoimmune and chronic inflammatory disorders are associated with defects in Tregs. These diseases have currently no cure and are treated with palliative drugs such as immunosuppressant and immunomodulatory agents. Thereby, there is a great interest in developing medical interventions against these diseases based on enhancing Treg cell function and numbers. Here, we give an overview of Treg cell ontogeny and function, paying particular attention to mucosal Tregs. We review some notable approaches to enhance immunomodulation by Tregs with therapeutic purposes including adoptive Treg cell transfer therapy and discuss relevant clinical trials for inflammatory bowel disease. We next introduce ways to expand mucosal Tregs in vivo using microbiota and dietary products that have been the focus of clinical trials in various autoimmune and chronic-inflammatory diseases.
2023-01-12 | Potential Of Stem Cell Based Therapy To Treat Celiac Disease And Its Complications
Celiac Disease affects 1% of the population in the Western world, however, the number of affected people is rising due to high gluten diets.Celiac disease is caused by a number of things involving interactions between genetic, environmental, and immunological factors.Lack of a comprehensive model to conduct trials on makes treating celiac disease a difficult feat.In terms of clinical trials, low incidence and variability in patients are significant obstacles in the establishment of treatments.Stem cells play a pivotal role in chronic inflammatory pathologies due to their ability to regenerate and differentiate into numerous cell types as well as their essential role in homeostasis.Mesenchymal stem cells are highly proliferating, multipotent stromal cells that can cross the HLAQ barrier and lack immunogenicity.Based on these properties, mesenchymal stem cells are able to maintain the epithelial barrier, prevent villous atrophy, and subdue inflammation in CD patients and have proven to be successful in multiple clinical trials.For this reason, stem cells, primarily mesenchymal, possess the potential to be an effective therapy and should be further researched.
antibodies
2026-05-18 | Aberrant intra-epithelial lymphocytes cause enterocyte cell death in refractory celiac disease by CD103-β7-receptor-mediated granzyme-B degranulation which can be restored by etrolizumab.
Refractory celiac disease type II (RCDII) is an intestinal tumor of aberrant intra-epithelial T-lymphocytes (IEL). The severe enteropathy found in RCDII is caused by aberrant IEL that exert cytotoxicity against enterocytes. In this study, we investigated the cell death mechanism responsible for villous atrophy in RCDII. Aberrant IEL were isolated from duodenal biopsies of RCDII patients. Enterocyte and RCDII patient-derived cell lines and human small intestinal organoids were used. mRNA expression was determined with reverse transcriptase-multiplex ligation-dependent probe amplification. Protein expression, degranulation and enterocyte killing were measured using flow cytometry, immunofluorescence or bright field microscopy. Secretion of granzyme-B was detected by enzyme immunoassay. Levels of granzyme-B expression were significantly upregulated in aberrant IEL of RCDII patients compared to patients with celiac disease (CD) on gluten-free diet (P = 0.0001) and correlated with severity of villous atrophy and clinical response to therapy. Killing of intestinal epithelial cells was caused by granzyme-B. For granzyme-B degranulation and subsequent cytotoxicity, cell-cell binding via the CD103-receptor, which was upregulated on aberrant IEL, was essential. In a preclinical model, aberrant IEL migrated to the intestinal organoids and induced organoid disintegration and CD103-dependent cell death. Targeting CD103-heterodimeric partner β7 with therapeutic monoclonal antibody etrolizumab prevented enterocyte cell killing and resulted in survival of organoids. Killing of enterocytes in RCDII patients depends on degranulation of granzyme-B by aberrant IEL through CD103-β7 binding. By blocking this interaction, etrolizumab restores the intestinal epithelium and therefore should be considered as potential therapy for RCDII patients.
2026-01-04 | A Clinical Review of Collagenous Sprue, Refractory Celiac Disease, Ulcerative Jejunitis, and Enteropathy-Associated T-cell Lymphoma
Celiac disease is a chronic immune-mediated enteropathy caused by gluten exposure. It affects approximately 1% of the world"s population and can present at any age with a wide range of signs and symptoms including malabsorption. Adherence to a gluten-free diet is the basis of treatment; however, a small subset of patients can develop worsening and life-threatening gastrointestinal symptoms despite gluten avoidance. Clinical worsening despite a gluten-free diet should raise concern for other conditions such as collagenous sprue or other more severe forms of celiac disease. Collagenous sprue is characterized by a subepithelial collagen band and celiac-like histologic features in the small bowel mucosa. It is unclear whether collagenous sprue falls within the celiac disease spectrum or represents a distinct entity. Refractory celiac disease is a rare form of celiac disease unresponsive to a gluten-free diet and can be subdivided into types I and II. The latter is defined by a clonal aberrant population of intraepithelial lymphocytes that accumulate lymphomagenic mutations. Refractory celiac disease type II is a premalignant condition that may exhibit ulcerative jejunitis or progress to the very aggressive enteropathy-associated T-cell lymphoma. Immunohistochemistry, flow cytometry, and T-cell receptor clonality testing aid in the diagnosis of refractory celiac disease. Treatment options include immunosuppressants, chemotherapy, and stem cell transplantation. The objective of this paper is to provide an overview of collagenous sprue, refractory celiac disease, ulcerative jejunitis, and enteropathy-associated T-cell lymphoma with a focus on presentation, pathogenesis, diagnosis, and treatment.
2025-12-22 | Persistent symptoms and enteropathy in coeliac disease: clinical considerations and therapeutic opportunities.
Coeliac disease is an immune-mediated enteropathy triggered by gluten ingestion. While a strict gluten-free diet remains the basis of treatment, a sizeable proportion of patients continue to experience symptoms or histological abnormalities despite adherence. This clinical entity of non-responsive coeliac disease imposes diagnostic and therapeutic challenges. Inadvertent gluten intake is a leading cause and can be difficult to detect, but measuring gluten immunogenic peptides in the urine or stool can provide objective evidence of exposure. Persistent symptoms or enteropathy can also originate from coexisting gastrointestinal disorders or the rare complication of refractory coeliac disease, which requires specialized treatment. Several novel therapies, including intestinal gluten neutralization, intestinal permeability modulation, HLA-gluten or cytokine blockade, transglutaminase inhibition and induction of gluten tolerance have reached Phase 1b/2 clinical trials. While coeliac drug development still faces several hurdles, these advances offer hope for more personalized, effective management beyond the gluten-free diet.
2025-12-18 | [Intestinal T-cell lymphomas and NK/T-cell lymphoproliferations-an overview].
We describe the defined entities of intestinal T‑cell lymphomas and NK-/T-cell lymphoproliferations that occur in the gastrointestinal tract. The spectrum encompasses aggressive T‑cell lymphomas such as enteropathy-associated T‑cell lymphoma as well as in situ lymphomas like refractory celiac disease type II and essentially benign lesions like indolent NK-cell lymphoproliferation of the gastrointestinal tract.
2025-10-01 | Autoimmune Autonomic Ganglionopathy in a Patient with Celiac Disease on Dialysis: A Rare Case of Refractory Orthostatic Hypotension
Introduction: Orthostatic hypotension (OH) is a frequent yet complex complication in hemodialysis patients. While commonly linked to ultrafiltration, volume depletion, or medications, persistent symptoms in autoimmune patients may signal an underlying autonomic dysfunction. I present a case of post-dialysis OH in a celiac patient diagnosed with Autoimmune Autonomic Ganglionopathy, managed through pharmacologic, immunologic, and lifestyle interventions. Case Description: A 56-year-old male with a history of celiac disease and hypertension was admitted with respiratory distress. Workup revealed ESRD secondary to chronic hypertension, and he was initiated on peritoneal dialysis. However, after a few sessions, he developed severe orthostatic symptoms, including dizziness and syncope, significantly impairing mobility. Due to intolerance, he was switched to in-center hemodialysis, where he exhibited resting hypertension with marked orthostatic hypotension and paradoxical bradycardia, suggesting autonomic dysfunction. Cardiac, endocrine, and medication-related causes were excluded. Despite monitored midodrine therapy, symptoms persisted. A strong clinical suspicion for autonomic dysfuntion was considered. Further evaluation revealed positive ganglionic (α3-AChR) autoantibodies, confirming the diagnosis of Autoimmune Autonomic Ganglionopathy. After the diagnosis was confired, the patient was treated with lifestyle modifications, including the use of an abdominal binder and postural precautions. Additionally, intravenous immunoglobulin (IVIG) therapy was initiated 3 times a week. Over time, his functional status and hemodynamic stability improved, allowing successful transition back to peritoneal dialysis. Discussion: This case highlights the diagnostic challenge of OH in dialysis patients. While OH is often attributed to volume shifts, autoimmune autonomic dysfunction should be considered in patients with severe symptoms, particularly those with autoimmune conditions. Treatment with IVIG or Plasma Exchange has been reported to be effective. There are also strong evidences that novel immunosuppressant agents such as Mycophenolate mofetil and Rituximab may be effective in certain patients who are unresponsive to IVIG or PE. Autoimmune Autonomic Ganglionopathy (AAG) is a rare but potentially treatable cause of OH, requiring a high index of clinical suspicion.
other
2024-02-19 | Impaired IgM Memory B Cell Function Is Common in Coeliac Disease but Conjugate Pneumococcal Vaccination Induces Robust Protective Immunity
Coeliac disease (CD) is associated with hyposplenism, an acquired impairment of spleen function associated with reduced IgM memory B cells and increased susceptibility to serious pneumococcal infection. Little is known about the immune implications of hyposplenism in CD or the optimal pneumococcal vaccination strategy. In this study, the immune effects of hyposplenism in CD, and the accuracy of screening approaches and protective responses induced by two different pneumococcal vaccines were examined. Active and treated CD cohorts, and healthy and surgically splenectomised controls underwent testing for the presence of Howell-Jolly bodies and pitted red cells, spleen ultrasound, and immune assessment of IgM memory B cell frequency and IgM memory B cell responses to T cell-dependent (TD) or T cell-independent (TI) stimulation. Responses following conjugate (TD) and polysaccharide (TI) pneumococcal vaccination were compared using ELISA and opsonophagocytic assays. Although hyposplenism is rare in treated CD (5.1%), functional B cell defects are common (28-61%) and are not detected by current clinical tests. Conjugate pneumococcal vaccination induced superior and sustained protection against clinically relevant serotypes. Clinical practice guidelines in CD should recommend routine pneumococcal vaccination, ideally with a conjugate vaccine, of all patients in lieu of hyposplenism screening.
2013-03-07 | Hyposplenism as a cause of pneumococcal meningoencephalitis in an adult patient with coeliac disease
Introduction: Coeliac disease can be associated with hyposplenism and splenic atrophy, which may increase the patient’s risk for fatal infections caused by Streptococcus pneumoniae or Pneumococcus. It is general opinion that many more patients with coeliac disease have died from hyposplenism-related infections than those reported in literature. Case report: A 62-year-old woman with recently diagnosed coeliac disease was hospitalized with high fever, disorientation, and nuchal rigidity. Cerebral computed tomography was negative. Laboratory tests showed an elevated leukocyte count and very high levels of C reactive protein. The cerebrospinal fluid (CSF) contained an increased number of mononuclear cells associated with a low glucose level and high protein concentrations. The CSF culture was positive for Streptococcus pneumoniae. Neurological conditions rapidly deteriorated with the onset of coma, and magnetic resonance imaging of the brain revealed initial signs of encephalitis extending above and below the tentorium. Abdominal ultrasonography disclosed splenic hypotrophy that raised the suspicion of hyposplenism. The diagnosis of hyposplenism was confirmed by demonstration of Howell-Jolly bodies in a peripheral blood smear. Discussion: This is the first reported case of pneumococcal meningoencephalitis caused by splenic hypofunction in a patient with coeliac disease. When coeliac disease is diagnosed with a marked delay in an elderly patient, spleen function should always be assessed. If impaired, the patient should undergo vaccination with pneumococcal conjugate vaccine to prevent pneumococcal infections.
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Drug Discovery Landscape
1 orphan drug designation for Refractory celiac disease.
1 orphan drug designation for Refractory celiac disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
human immunoglobulin (IgG1K) monoclonal antibody that binds to interleukin 15 | antibodies | FDA | 2018-04-10 | — | Amgen Inc. |
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