Celiac.com 06/27/2025 - Most people diagnosed with celiac disease begin to feel better once they stop eating gluten, a protein found in wheat, barley, and rye. A gluten-free diet typically allows the small intestine to heal and symptoms such as diarrhea, fatigue, and abdominal pain to go away. However, for a small percentage of people, these symptoms continue even when they strictly follow the diet. This condition is known as refractory celiac disease.

There are two types:

• Type 1 is a mystery because there’s no clear reason why the symptoms continue.
• Type 2 is more dangerous and involves unusual immune cells that can turn into a type of intestinal cancer called lymphoma.

Until now, scientists didn’t fully understand what causes these persistent forms of celiac disease, especially type 1. But a new study has begun to uncover answers.

A High-Tech Look Inside the Gut

In this study, researchers used a powerful tool called single-cell sequencing. This technology allows scientists to look at the behavior and genetic makeup of thousands of individual cells taken from tissue samples. By using this technique on small intestine biopsies from patients with refractory celiac disease, the team was able to see things that older methods had missed.

They found something surprising: a group of immune cells, specifically T cells, were behaving in unusual ways. These cells had genetic changes—called mutations—that are usually found in cancer cells, especially in lymphomas. This was true not only in patients with the more dangerous type 2 refractory celiac disease, but also in many patients with the mysterious type 1 form.

Rogue Immune Cells with Cancer-Like Mutations

The study revealed that many of the immune cells found in the guts of people with refractory celiac disease carried specific mutations. These mutations affect how cells grow, divide, and avoid death. The mutations found were the same ones that drive the development of certain blood cancers, especially those in the lymphatic system.

In type 2 refractory celiac disease, researchers confirmed that the abnormal cells were immature immune cells, stuck somewhere between an early development stage and fully functioning immune cells. These immature cells also lacked some of the surface markers that normal T cells have. In other words, they were "stalled" in their development, but still causing trouble in the gut by promoting inflammation and possibly turning into cancer later on.

Even more importantly, in type 1 refractory celiac disease—which until now had no clear explanation—they found that six out of ten patients had mature T cells that carried cancer-like mutations. These cells had grown into large clones, meaning they had copied themselves many times and were now dominating the immune environment in the small intestine. These rogue clones were highly inflammatory and capable of damaging tissue, likely contributing to ongoing symptoms.

Clues for Earlier Diagnosis and More Precise Treatment

Because these abnormal immune cells were only detectable through advanced techniques like single-cell sequencing, they had previously gone unnoticed. This study is the first to connect refractory celiac disease, especially type 1, to these hidden populations of mutated T cells.

By identifying these mutations, scientists are now opening the door to new ways of diagnosing the disease. For example, if a biopsy from a patient shows the presence of these rogue immune cells, it might help doctors understand whether the patient is at risk for refractory disease and what kind of treatment might work best.

Possibility of New Treatments Using Existing Medications

Right now, the only treatment for refractory celiac disease is immunosuppressive therapy, which dampens the overall immune response. Unfortunately, this approach is not very targeted and can come with significant side effects.

However, this study found that many of the rogue immune cells carried mutations in a specific pathway known as JAK-STAT, which helps control how cells grow and respond to inflammation. Drugs that target this pathway—called JAK inhibitors—are already approved for use in other diseases, including some types of cancer and autoimmune conditions.

This discovery suggests that some patients with refractory celiac disease might benefit from these existing drugs, offering a more personalized and effective treatment approach that directly targets the problem cells rather than the entire immune system.

Why This Research Matters for People With Celiac Disease

This study is a major step forward in understanding why some people with celiac disease do not get better on a gluten-free diet. By identifying specific immune cells that carry dangerous mutations, scientists have not only explained the cause of many cases of refractory disease but also pointed to new, more precise ways to treat it.

For patients and their families, this research provides hope. It means that persistent symptoms may not just be due to "hidden gluten" or dietary mistakes—but could actually be driven by an underlying immune issue that can be tested for and treated. It also emphasizes the need for further research to develop safer and more effective therapies for those affected.

Finally, this study shows how far science has come in using advanced genetic tools to uncover hidden causes of disease. What was once invisible is now within reach, and that could change the lives of people living with the most challenging forms of celiac disease.

In summary, the discovery of mutated immune cells in refractory celiac disease opens up new paths for diagnosis, treatment, and understanding. For those with stubborn symptoms that won’t go away despite a gluten-free diet, this could offer not just answers, but real hope for the future.

Read more at: science.org

Celiac.com 01/09/2025 - Celiac disease is a chronic autoimmune condition triggered by consuming gluten, a protein found in wheat, barley, and rye. For most individuals with this condition, following a strict gluten-free diet is the key to managing symptoms and promoting intestinal healing. However, not all patients experience relief, even after adhering to this diet for six to twelve months. This condition, termed non-responsive celiac disease, has now been the subject of a comprehensive study analyzing its prevalence and causes.

What Is Non-Responsive Celiac Disease?

Non-responsive celiac disease refers to the persistence of symptoms such as diarrhea, abdominal pain, and malnutrition despite maintaining a gluten-free diet for an extended period. This phenomenon can arise either due to ongoing gluten consumption—knowingly or unknowingly—or because of other underlying medical conditions.

According to the study, approximately 20 percent of individuals with celiac disease do not respond to a gluten-free diet as expected. This alarming proportion highlights the complexity of managing celiac disease and the need for further understanding of why some patients continue to suffer.

The Most Common Cause: Hidden Gluten Exposure

For one-third of patients with non-responsive celiac disease, the main culprit is inadvertent gluten exposure. Gluten is ubiquitous, often hiding in processed foods, sauces, and even medications. Even trace amounts can provoke an immune reaction in sensitive individuals.

Many patients are unaware that they may still be consuming gluten, either due to poor food labeling or a lack of education about gluten-containing products. This underscores the need for better awareness, improved labeling regulations, and ongoing dietary counseling for individuals newly diagnosed with celiac disease.

Other Causes of Persistent Symptoms

Functional Gastrointestinal Disorders

The study found that 16 percent of cases of non-responsive celiac disease were linked to functional gastrointestinal conditions, such as irritable bowel syndrome. These disorders, which are not caused by structural abnormalities or ongoing gluten exposure, often mimic celiac disease symptoms, making diagnosis and treatment challenging.

Refractory Celiac Disease

In rare but serious cases, symptoms persist due to a condition called refractory celiac disease. This occurs when the immune system continues to attack the small intestine despite strict adherence to a gluten-free diet. Refractory celiac disease is further divided into two types:

• Type I: Generally responds well to treatment and follows a milder course.
• Type II: Associated with a higher risk of progression to lymphoma, a form of cancer.

Refractory celiac disease, while less common, represents a significant concern because of its potential for severe complications.

Misdiagnosis or Other Conditions

In some cases, a misdiagnosis of celiac disease could explain ongoing symptoms. Alternatively, other conditions such as small intestinal bacterial overgrowth, lactose intolerance, or inflammatory bowel disease may be the true cause of persistent issues. A thorough medical evaluation is crucial for ruling out these possibilities.

Implications for Healthcare

The findings of this study highlight several critical areas for improving care for individuals with celiac disease:

Enhanced Dietary Education

Patients need comprehensive guidance on identifying and avoiding hidden gluten sources. This includes recognizing potential cross-contamination in kitchens, understanding food labels, and staying vigilant about gluten-free certification.

Better Food Labeling Standards

Gluten labeling varies widely across countries, with some regions lacking clear regulations. Standardized global practices could help reduce inadvertent gluten exposure and improve quality of life for celiac patients.

Targeted Medical Interventions

For those with non-responsive celiac disease, a personalized approach is essential. This may include testing for other conditions, functional disorders, or refractory celiac disease. Additionally, new therapies targeting persistent symptoms are being developed, offering hope for those who do not respond to dietary changes alone.

Why This Study Matters

For individuals living with celiac disease, non-responsive cases can be particularly distressing. The persistence of symptoms can lead to ongoing health issues such as malnutrition, anemia, and decreased bone density, not to mention the emotional toll of chronic illness.

This study emphasizes the importance of addressing all potential causes of persistent symptoms and tailoring care to individual needs. By identifying the main drivers of non-responsive celiac disease—such as hidden gluten and functional gastrointestinal disorders—it provides a roadmap for improving diagnosis, treatment, and overall patient outcomes.

Ultimately, these findings remind us that while a gluten-free diet remains the cornerstone of celiac disease management, it is not always a cure-all. Continued research, enhanced education, and more effective treatments are essential to supporting the one in five patients who do not find relief from dietary changes alone.

Read more at: onlinelibrary.wiley.com

Celiac.com 08/14/2024 - Refractory celiac disease type II, commonly referred to as RCDII, is a rare and severe form of celiac disease. Unlike typical celiac disease, RCDII does not respond to a gluten-free diet. This condition is marked by the clonal expansion of abnormal intraepithelial lymphocytes, which can lead to high mortality rates due to the lack of effective treatment options. One promising treatment involves the use of tofacitinib, a small-molecule inhibitor targeting specific enzymes known as JAK1 and JAK3. This study explores the potential of tofacitinib to induce clinical remission in patients with RCDII.

Study Overview and Methodology

This open-label clinical study involved six patients diagnosed with RCDII, who had not responded to previous treatments, including the drug cladribine. Four patients were treated according to the study protocol in the Netherlands, while two patients in Germany received similar treatment outside the protocol. The patients were given 10 mg of tofacitinib twice daily for 12 weeks. The study aimed to assess both the clinical and immunologic responses to the treatment.

Baseline Characteristics of Patients

At the beginning of the study, all patients exhibited significant symptoms of malabsorption, such as weight loss, diarrhea, abdominal pain, and low levels of albumin in the blood. Small intestine biopsies showed a high percentage of abnormal intraepithelial lymphocytes, ranging from 70% to 90%. Two patients also had ulcerative jejunitis, a severe condition causing ulcers in the small intestine. Histological examinations revealed varying degrees of villous atrophy, a condition where the finger-like projections in the small intestine are damaged, affecting nutrient absorption.

Clinical Response to Tofacitinib Treatment

All patients completed the 12-week treatment course with tofacitinib. Within a span of two to fourteen days, patients experienced a noticeable resolution of diarrhea and abdominal pain. Additionally, they showed significant weight gain, with a median increase of over 12% by the end of the 12 weeks. One patient with severe ulcerative jejunitis was even able to discontinue total parenteral nutrition by week nine. However, upon discontinuation of tofacitinib, all patients quickly relapsed, experiencing weight loss and a return of symptoms. When tofacitinib treatment was resumed, patients again showed rapid and complete clinical improvement.

Immunologic and Histologic Findings

The primary immunologic endpoint was to achieve a reduction of at least 20% in the number of abnormal intraepithelial lymphocytes. This goal was not met by any patient. The median percentage of abnormal cells remained relatively unchanged from baseline to the end of the 12-week treatment period. Despite this, four out of six patients showed significant improvement in the histology of their small intestine, indicating mucosal healing. This improvement was particularly evident in patients with ulcerative jejunitis.

Adverse Events and Safety

Throughout the study, all patients experienced adverse events. The most common was lymphopenia, a condition characterized by low levels of lymphocytes in the blood. One patient suffered a serious adverse event, developing a pulmonary embolism associated with a line sepsis caused by a bacterial infection. This patient continued to receive tofacitinib at a reduced dose of 5 mg twice daily, with continued clinical improvement. No other serious infections were reported, and there was no progression to enteropathy-associated T-cell lymphoma in any patient.

Extended Follow-Up and Long-Term Outcomes

During an extended follow-up period of up to two years, the patients continued to show persistent clinical remission while on a reduced dose of tofacitinib. The median weight gain further increased, and duodenal biopsies indicated ongoing histologic improvement. Capsule endoscopy revealed complete or near-complete resolution of intestinal ulcerations in patients with ulcerative jejunitis. These findings suggest that tofacitinib not only provides short-term relief but also contributes to long-term clinical remission in patients with RCDII.

Implications for Future Treatment of Celiac Disease

This study is significant for several reasons. First, it demonstrates that tofacitinib can induce rapid and sustained clinical remission in patients with refractory celiac disease type II, a condition that has been notoriously difficult to treat. Second, the study's findings suggest that while tofacitinib may not reduce the number of abnormal intraepithelial lymphocytes, it effectively mitigates their harmful activity. This functional impact is crucial for improving patient outcomes.

For those with celiac disease, particularly the rare and severe RCDII, this study offers hope for a viable treatment option where none previously existed. It also underscores the importance of continued research and clinical trials to explore and refine new therapies. The potential for tofacitinib to change the treatment landscape for RCDII patients is substantial, offering a path to better management and improved quality of life.

Read more at: cghjournal.org

Celiac.com 01/06/2023 - Non-responsive celiac disease (NRCD) affects up to 15% of children with celiac disease. A Gluten Contamination Elimination Diet (GCED) is a more stringent diet consisting of fresh, whole, and unprocessed naturally gluten-free foods. A team of researchers recently set out to assess their approach to identifying and treating NRCD with budesonide and the Gluten Contamination Elimination Diet (GCED). Their results were encouraging. Here's what they found.

The research team included Awab Ali Ibrahim, Victoria Kenyon, Alessio Fasano, and Maureen M Leonard. They are variously affiliated withthe Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA; the Department of Pediatrics, Harvard Medical School, Harvard University, Boston, MA; the Center for Celiac Research and Treatment, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA; the Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Boston, MA; the Celiac Research Program, Harvard Medical School, Boston, MA.

NRCD Defined

Non-responsive celiac disease is defined as patients having persistent symptoms and enteropathy, with at least Marsh 3 histology, after following a gluten-free diet for at least 12 months. 

Researchers think that NRCD affects up to 15% of children with celiac disease, but there is limited data, and no research to date, describing treatment of children with this NRCD. 

Retrospective, Single Center Analysis

The team performed a retrospective, single center analysis over a 5-year period of patients with celiac disease  18 years of age and under, who received treatment for persistent symptoms and enteropathy despite following a gluten-free diet.

NRCD Patients Respond to GCED and Budesonide

The team found a total of 22 patients with NRCD. Of the thirteen patients treated with the GCED for 3 months, nearly half experienced both histological and symptomatic resolution of celiac disease. 

Of the nine patients were treated with budesonide (6-9 mg), nearly ninety percent experienced both symptomatic and histologic resolution after treatment averaging three months. 

Further, more than two-thirds of patients who responded to the GCED, and 100% of patients who responded to budesonide, experienced remission of at least 6 months following treatment transition back to a gluten-free diet.

Treatment of NRCD with the GCED and budesonide can provide benefit most NRCD patients. Most patients with NRCD can return to a standard gluten-free diet after about three months of treatment.

This is some of the most promising treatment information we've seen with regard to NRCD. The article shows that many celiac patients not responding to a gluten-free diet can respond to a more stringent approach. The high response rate to this treatment offers exciting news for patients with NRCD and their physicians. Stay tuned for more on this and related stories.

Read more at J Pediatr Gastroenterol Nutr. 2022 Nov 1;75(5):616-622.
 

Celiac.com 05/18/2020 - Most people with celiac disease see a major improvement in the weeks and months after they begin a gluten-free diet. Most celiac patients on a gluten-free diet experience full gut healing within the first few months, and nearly all of them within 12-18 months. However, nearly one in three celiac patients may show adverse signs, symptoms or persistent small intestinal damage after one year on a gluten-free diet. To properly diagnose and treat these patients, they must be assessed for other common GI problems, and for their celiac disease status. 

A team of researchers recently set out to develop guidelines for the indications and use of the gluten contamination elimination diet for patients with non-responsive celiac disease. The research team included Maureen M. Leonard, Pamela Cureton, and Alessio Fasano, who are variously affiliated with the Center for Celiac Research, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children, Boston, MA, USA, and the Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA.

In their paper titled, Indications and Use of the Gluten Contamination Elimination Diet for Patients with Non-Responsive Celiac Disease, they offer a method for assessing patients with celiac disease with ongoing symptoms, elevated serology, and or villous atrophy, even on a gluten-free diet. 

The team details methods for diagnosing, and distinguishing between, non-responsive and refractory celiac disease. Lastly, the team describes the range of conditions for employing the gluten contamination elimination diet, and offers guidance for clinicians to use the diet as needed for their non-responsive celiac patients who meet the criteria.

Since a significant number of people with celiac disease fail to improve on a gluten-free diet, these guidelines will be helpful in spotting and treating these patients. Do you or a loved one suffer from non-responsive celiac disease? Share your story in the comments below.

Read more in Nutrients, Volume 9  Issue 10

Celiac.com 04/22/2020 - Collagenous sprue, aka enteritis, is a rare mucosal small intestinal disorder marked by a clear histopathological lesion containing collagen. People who suffer from collagenous sprue frequently experience severe diarrhea, progressive nutrient malabsorption, protein depletion and weight loss.

Closely linked to celiac disease, collagenous sprue is notoriously difficult to treat, and medical literature records only a few claims of successful therapy. Clinical studies suggest myriad causes for collagenous sprue, with prognoses often depending on the cause. 

Recently, collagenous sprue has been found in numerous diverse settings, including as a paraneoplastic feature of early malignancies, and as a result of the toxic medications including non-steroidal anti-inflammatory drugs (NSAIDs) and the angiotensin II receptor antagonist, olmesartan. 

In a paper published in the International Journal of Celiac Disease, Hugh James Freeman, of the Department of Medicine (Gastroenterology), University of British Columbia, Vancouver, BC, Canada, writes about the return to normal of such clinical and pathological changes, and notes that knowing the medication history of such patients is crucial to treating patients with sprue-like intestinal disease.

Knowing the patient medication history can provide a crucial roadmap for treating such patients.

Read more in the International Journal of Celiac Disease. 2019, 7(1), 13-15. DOI: 10.12691/ijcd-7-1-2

Celiac.com 02/19/2020 - What role, if any, do nutrients play in non-responsive celiac disease?

A team of researchers recently set out to compile an overview of the causes of non-responsive celiac disease (NRCD) in adults, highlight a systematic approach to investigate these patients, and assess the latest approaches to managing this subset of celiac disease. 

The team included Hugo A. Penny, Elisabeth M. R. Baggus, Anupam Rej, John A. Snowden, and David S. Sanders. They are variously associated with the Academic Unit of Gastroenterology, University of Sheffield, Sheffield, UK; the Lydia Becker Institute of Inflammation and Immunology, University of Manchester in Manchester, UK; and the Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.  

Celiac disease is a common autoimmune condition of the gut which results from gluten consumption by genetically susceptible individuals. A lifelong gluten-free diet is still the only currently recognized treatment for celiac disease. 

While most people with celiac disease see a major improvement in symptoms once eating a gluten-free diet, nearly one-in-three continue to show symptoms, including ongoing gut inflammation. 

Patients who continue to suffer symptoms on a gluten-free diet are said to have "non-responsive celiac disease". This may be due to ongoing gluten ingestion, witting or unwitting, slow healing, refractory celiac disease, and/or some other condition. 

The team recently published their review of the causes of non-responsive celiac disease in adults. In their paper, they also delineate a process for investigating these patients, and gauge the latest approaches to managing this type of celiac disease.

The main causes of non-responsive celiac disease:

• An Alternative Primary Diagnosis
• An Associated Condition
• Dietary Indiscretion
• Gluten Super-Sensitivity
• Refractory Celiac Disease

The researchers conclude:

Quote

Up to a third of individuals with CD develop NRCD. Dietary indiscretion is the commonest cause of NRCD, yet currently there is no reliable objective assessment of ongoing gluten ingestion in these patients. The diagnosis and management of RCD is challenging, and patients should be referred to a specialist center with multi-disciplinary experience in RCD for assessment, diagnostics, treatment, and follow-up. Novel therapeutic strategies are required to provide realistic treatment options in RCD2 to impact the dismal mortality in this condition.

Read their full report in Nutrients

Celiac.com 09/05/2018 - About one out of every twenty celiac patients fails to respond to a gluten-free diet, and goes on to develop refractory celiac disease (RCD). RCD is a serious condition marked by appearance of intraepithelial T lymphocytes. Depending on the phenotype of the lymphocytes, people develop either RCD I or RCD II. Patients with RCD type II (RCDII) show clonal expansions of intraepithelial T lymphocytes, and face an especially poor prognosis. Just over half of these patients will die within five years of onset due to aggressive enteropathy-associated T-cell lymphoma. 

At this time, researchers don’t know whether genetic variations might play a role in the severe progression from celiac disease to RCDII. A team of researchers recently set out to try to get some answers.  The team began by conducting the first genome-wide association study to identify the causal genes for RCDII, along with the molecular pathways at play in cases of RCDII. 

For their genome-wide association study, the team used 38 Dutch patients with RCDII, and replicated the 15 independent top-associated single nucleotide polymorphism (SNP) variants (P<5×10) in 56 independent French and Dutch patients with RCDII.

The team found that, after replication, SNP rs2041570 on chromosome 7 was significantly associated with progression to RCDII (P=2.37×10, odds ratio=2.36), but not to celiac disease susceptibility. They also found that SNP rs2041570 risk allele A was associated with lower levels of FAM188B expression in blood and small intestinal biopsies. Stratifying RCDII biopsies by rs2041570 genotype revealed differential expression of innate immune and antibacterial genes that are expressed in Paneth cells.

The team’s efforts resulted in the identification of a new SNP associated with the severe progression of celiac disease to RCDII.  Their data suggest that genetic susceptibility to celiac disease might be unrelated to celiac progression to RCDII, and suggests that Paneth cells might play a role in RCDII progression.

Source:

• Eur J Gastroenterol Hepatol. 2018 Aug;30(8):828-837.

The research team included B Hrdlickova, CJ Mulder, G Malamut, B Meresse, M Platteel, Y Kamatani, I Ricaño-Ponce, RLJ van Wanrooij, MM Zorro, M Jan Bonder, J Gutierrez-Achury, C Cellier, A Zhernakova, P Nijeboer, P Galan, S Withoff, M Lathrop, G Bouma, RJ Xavier, B Jabri, NC Bensussan, C Wijmenga, and V Kumar. They are variously affiliated with the Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Department of Gastroenterology, VUMC, Amsterdam, The Netherlands, INSERM U1163, Imagine Institute and Paris Descartes University, the Department of Gastroeneterology, Georges Pompidou European Hospital, the Paris 13 University Sorbonne Paris Cité, UREN, Inserm (U557), Inra (U1125), Cnam, Bobigny, France, the scientific director of McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada, the Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, the Department of Medicine, University of Chicago, Chicago, Illinois, USA., and the K.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Norway.

Celiac.com 06/14/2018 - Refractory celiac disease type II (RCDII) is a rare complication of celiac disease that has high death rates. To diagnose RCDII, doctors identify a clonal population of phenotypically aberrant intraepithelial lymphocytes (IELs). 

However, researchers really don’t have much data regarding the frequency and significance of clonal T cell receptor (TCR) gene rearrangements (TCR-GRs) in small bowel (SB) biopsies of patients without RCDII. Such data could provide useful comparison information for patients with RCDII, among other things.

To that end, a research team recently set out to try to get some information about the frequency and importance of clonal T cell receptor (TCR) gene rearrangements (TCR-GRs) in small bowel (SB) biopsies of patients without RCDII. The research team included Shafinaz Hussein, Tatyana Gindin, Stephen M Lagana, Carolina Arguelles-Grande, Suneeta Krishnareddy, Bachir Alobeid, Suzanne K Lewis, Mahesh M Mansukhani, Peter H R Green, and Govind Bhagat.

They are variously affiliated with the Department of Pathology and Cell Biology, and the Department of Medicine at the Celiac Disease Center, New York Presbyterian Hospital/Columbia University Medical Center, New York, USA. Their team analyzed results of TCR-GR analyses performed on SB biopsies at our institution over a 3-year period, which were obtained from eight active celiac disease, 172 celiac disease on gluten-free diet, 33 RCDI, and three RCDII patients and 14 patients without celiac disease. 

Clonal TCR-GRs are not infrequent in cases lacking features of RCDII, while PCPs are frequent in all disease phases. TCR-GR results should be assessed in conjunction with immunophenotypic, histological and clinical findings for appropriate diagnosis and classification of RCD.

The team divided the TCR-GR patterns into clonal, polyclonal and prominent clonal peaks (PCPs), and correlated these patterns with clinical and pathological features. In all, they detected clonal TCR-GR products in biopsies from 67% of patients with RCDII, 17% of patients with RCDI and 6% of patients with gluten-free diet. They found PCPs in all disease phases, but saw no significant difference in the TCR-GR patterns between the non-RCDII disease categories (p=0.39). 

They also noted a higher frequency of surface CD3(−) IELs in cases with clonal TCR-GR, but the PCP pattern showed no associations with any clinical or pathological feature. 

Repeat biopsy showed that the clonal or PCP pattern persisted for up to 2 years with no evidence of RCDII. The study indicates that better understanding of clonal T cell receptor gene rearrangements may help researchers improve refractory celiac diagnosis. 

Source:

• Journal of Clinical Pathologyhttp://dx.doi.org/10.1136/jclinpath-2018-205023

Celiac.com 07/03/2017 - Refractory celiac disease (RCD) is a serious complication of celiac disease. There are two types, RCD I, and RCD II. Unlike RCD type I, RCD type II often leads to enteropathy-associated T-cell lymphoma (EATL), which is associated with clonally expanding T-cells that are also found in the sequentially developing EATL.

Using high-throughput sequencing (HTS), a team of researchers recently set out to establish the small-intestinal T-cell repertoire (TCR) in celiac disease and RCD to unravel the role of distinct T-cell clonotypes in RCD pathogenesis.

The research team included J Ritter, K Zimmermann, K Jöhrens, S Mende, A Seegebarth, B Siegmund, S Hennig, K Todorova, A Rosenwald, S Daum, M Hummel, and M Schumann.

They are variously affiliated with the Institute of Pathology, Charité-University Medicine, Berlin, Germany, the Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-University Medicine, Berlin, Germany, HS Diagnomics GmbH, Berlin, Germany, the Center for Tumor Medicine, Charité-University Medicine, Berlin, Germany, the Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken (CCCMF), Würzburg, Germany, the Berlin Institute of Health, Berlin, Germany, the Berlin-Brandenburg School for Regenerative Therapies, Berlin, Germany.

Their team examined DNA extracted from duodenal mucosa specimens of 9 control subjects, 10 active celiacs, 9 celiacs on a gluten-free diet, 8 RCD type I patients, 8 RCD type II patients, and 3 unclassified Marsh I cases collected from 2002 to 2013. To make their examination, they used TCRβ-complementarity-determining regions 3 (CDR3) multiplex PCR, followed by HTS of the amplicons.

They generated an average of 106 sequence reads per sample, consisting of up to 900 individual TCRβ rearrangements.

In RCD type II, the most frequent clonotypes (sequence reads with identical CDR3) represent about 43% of all TCRβ rearrangements. This was substantially higher than in control subjects (6.8%; p

Repeat endoscopies in individual patients showed that the clonotypes remain stable for up to a few years without clinical symptoms of EATL. Individual patients with RCD type II showed unique dominant clonotypes that were un-related among patients. Celiac-associated, gliadin-dependent CDR3 motifs were only detectable at low frequencies.

TCRβ-HTS analysis unravels the TCR in celiac disease, and allows for detailed analysis of individual TCRβ changes.

Patients with RCD type II have unique, dominant TCRβ sequences that are critically different from known gliadin-specific TCR sequences, which indicates that these clonal T-cells expand on their own, with no influence from gluten stimulation.

Source:

• Gut. 2017 Feb 10. pii: gutjnl-2016-311816. doi: 10.1136/gutjnl-2016-311816.

Celiac.com 06/15/2017 - Enteropathy-associated T cell lymphoma (EATL) subtypes are characterized by loss of function of SETD2. Although EATL is rare condition, it is deadly. It is also the most common neoplastic complication of celiac disease.

A team of researchers recently conducted whole-exome sequencing of 69 EATL tumors, which helped them to define the genetic landscape of EATL. They found that SETD2 was silenced in 32% of EATL patients, making it the most frequently silenced gene in EATL.

The research team included AB Moffitt, SL Ondrejka, M McKinney, RE Rempel, JR Goodlad, CH Teh, S Leppa, S Mannisto, PE Kovanen, E Tse, RKH Au-Yeung, YL Kwong, G Srivastava, J Iqbal, J Yu, K Naresh, D Villa, RD Gascoyne, J Said, MB Czader, A Chadburn, KL Richards, D Rajagopalan, NS Davis, EC Smith, BC Palus, TJ Tzeng, JA Healy, PL Lugar, J Datta, C Love, S Levy, DB Dunson, Y Zhuang, ED Hsi, and SS Dave.

The team also noted that the JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1, and that the condition causes highly overlapping genetic alterations among the mutations in KRAS, TP53, and TERT Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma), which indicates shared mechanisms underlying their causes.

To model the effects of SETD2 loss in vivo, the team developed a T cell-specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis.

The team's data provides the most comprehensive genetic portrait to date of this rare, but deadly disease, and will likely play a key role in future classifications of EATL.

Source:

• J Exp Med. 2017 May 1;214(5):1371-1386. doi: 10.1084/jem.20160894. Epub 2017 Apr 19.

The researchers are variously affiliated with the Duke Center for Genomics and Computational Biology, Duke University, Durham, NC, the Duke Cancer Institute, Duke University School of Medicine, Durham, NC, the Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, the Haematological Malignancy Diagnostic Service, St. James's University Hospital, Leeds LS9 7TF, England, UK, the Haematology Department, Western General Hospital, Edinburgh, Scotland, UK, the Department of Oncology and Research Program Unit, Faculty of Medicine, Helsinki University Hospital Cancer Center and University of Helsinki in Helsinki, Finland, HUSLAB and Medicum, Helsinki University Hospital Cancer Center and University of Helsinki, Helsinki, Finland, the University of Hong Kong, Queen Mary Hospital, Hong Kong, China, the University of Nebraska Medical Center, Omaha, NE, Imperial College London, London, England, UK, the British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada, the University of California, Los Angeles, Los Angeles, CA, Indiana University, Indianapolis, IN, the Presbyterian Hospital, Pathology and Cell Biology, Cornell University, New York, NY, the University of North Carolina at Chapel Hill, Chapel Hill, NC, the Department of Medicine, Duke University School of Medicine, Durham, NC, the Department of Statistical Science, Duke University, Durham, NC, the Hudson Alpha Institute for Biotechnology, Huntsville, AL 35806, and the Department of Immunology, Duke University School of Medicine, Durham, NC.

Celiac.com 05/24/2017 - Refractory celiac disease (RCD) is a rare manifestation of celiac disease that is difficult to treat, and often results in death from enteropathy-associated T-cell lymphoma.

Doctors looking to treat RCD have found very limited success with a number of immunosuppressive medications (IMs), including azathioprine, systemic corticosteroids, or regular budesonide. A team of researchers at the Mayo Clinic recently set out to assess open-capsule budesonide (OB) treatment on RCD patients, including those who saw no improvement with previous IM treatments. The research team included Saurabh S Mukewar, Ayush Sharma, Alberto Rubio-Tapia, Tsung-Teh Wu, Bana Jabri and Joseph A Murray.

The team first looked for RCD patients treated with OB at Mayo Clinic, Rochester, Minnesota from 2003 to 2015. They then reviewed demographic, serologic, and clinical variables in these patients. The team found a total of 57 patients who received OB as treatment for suspected RCD.

Based on clonal T-cell receptor gamma gene rearrangement or aberrant phenotype of intraepithelial lymphocytes (IELs), the team classified 13 patients (23%) as having RCD-2 and 43 (75%) as RCD-1.

The team was unable to determine TCR gene rearrangement status for one patient (2%). Most patients were women (69%), with an average age of 60.5 (+/- 3.5) years, while average body mass index was 28.4 kg/m2.

Nearly 75% of patients suffered from diarrhea, with an average of 6 bowel movements per day (range, 4–25). Nearly half of these patients failed to improve with IM treatment. Twenty-four patients (42%) were anemic, while 12 patients (21%) had hypoalbuminemia. Biopsies showed Marsh 3 lesions in all patients, broken down as follows: 19% were Marsh 3a, 46% were Marsh 3b, and 35% were Marsh 3c.

After OB therapy, 92% showed clinical improvement, while 89% showed histologic improvement. Subsequent biopsies showed that 7 out of 13 patients with RCD-2 (53%) displayed an absence of the previously observed clonal TCR gamma gene rearrangement/aberrant IEL phenotype. During the follow-up period, two patients died of enteropathy-associated T-cell lymphoma.

Most RCD patients show clinical and histopathologic improvement with OB treatment, including those who previously failed to respond to other IMs.

These results show that treatment with open-capsule budesonide is a promising option for patients looking to manage RCD.

Source:

• The American Journal of Gastroenterology, (21 March 2017). doi:10.1038/ajg.2017.71