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Celiac.com 02/06/2023 - Typically, doctors diagnose celiac disease using serological markers, like anti-tissue transglutaminase antibodies (t-TGA), along with a biopsy of the small bowel (SBB) to spot mucosal damage in the gut. To get a better understanding of the connection between serological markers and changes to gut mucosa in children with celiac disease, a team of researchers recently examined the connection between serological markers, and changes of the intestinal mucosa in children with celiac disease. To do so, they used data from a national Spanish registry, called REPAC-2, that included children under 15 years old. The wanted to determine the potential connection between t-TGA levels and other factors, such as mucosal damage and clinical findings, based on gender, age, symptoms. The study included nearly 5,000 patients with celiac disease, nearly 3,000 of whom underwent both t-TGA and a SBB for diagnosis. The results showed that more than two-thirds of the patients with normal IgA values had a Marsh 3b-c lesion, which is a severe form of mucosal damage, and nearly as many had t-TGA IgA levels at or above 10 times the upper limit of normal (ULN). The study found a statistically significant association between t-TGA IgA levels and the degree of mucosal damage. The higher the t-TGA IgA levels, the more severe the mucosal damage. Among other things, the study found that patients who reported symptoms had more severe mucosal damage compared to those who did not. They also found a negative association between age and changes of the intestinal mucosa, which suggests that younger patients are more likely to suffer severe mucosal damage. But, the team found no connection between gender and changes to gut mucosa. The study included a subgroup of 18 IgA-deficient patients. The results showed that nearly half of these patients had t-TGA IgA levels at or above 10 times ULN, while nearly seventy percent had Marsh 3b-c lesions. The team found no significant connection between t-TGA IgG levels and changes to gut mucosa, including for factors like age, gender, or symptom type. The results of this study suggest a positive association between t-TGA IgA levels and the degree of gut mucosal changes in children with celiac disease. However, they found no association in IgA-deficient patients with positive t-TGA IgG results. These findings echo the recommendations of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN), which advises SBB in IgA-deficient patients, even with high t-TGA IgG readings. The study reinforces the practice of factoring in both t-TGA IgA and IgG levels, as well as conducting a small bowel biopsy, when diagnosing celiac disease in children, especially in those with IgA deficiency, regardless of t-TGA IgG levels. Studies like this are helpful for getting clinicians and primary care physicians on the same page about best practices for celiac diagnosis in children. However, there is still much to be discovered about the relationship between serological markers and changes to gut mucosa in celiac patients. Stay tuned for more on this and related topics. Read more in the Journal of Pediatric Gastroenterology & Nutrition

Celiac.com 07/05/2021 - One of the many approaches to alternative treatments for celiac disease includes the inhibition of various bio-chemical or bio-mechanical factors that promote mucous damage in the guts of untreated celiacs. One focus has been on inhibiting small intestinal transglutaminase 2. In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which increases T cell stimulation and triggers mucosal damage. Inhibition of transglutaminase 2 is a potential treatment for celiac disease. A team of researchers recently set out to determine whether ZED1227, a selective oral transglutaminase 2 inhibitor, can successfully inhibit transglutaminase 2, and reduce duodenal mucosal damage, as a potential treatment for celiac disease. The team recently conducted a small proof-of-concept trial, to gauge the efficacy and safety of ZED1227 over a 6-week treatment at three dosage levels, compared against placebo, in adults with well-controlled celiac disease who received a daily gluten challenge. The main end point was the level of reduction in gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Other end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score, which is used to assess a patient's health-related quality of life. The team's results showed that, of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dosage levels reduced gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 in the 10-mg group, in the 50-mg group (P<0.001), and 0.48 in the 100-mg group. The estimated differences from placebo in the change in intraepithelial lymphocyte density were −2.7 cells per 100 epithelial cells in the 10-mg group, −4.2 cells per 100 epithelial cells in the 50-mg group, and −9.6 cells per 100 epithelial cells in the 100-mg group. Use of the 100-mg dose may have improved both symptom and quality-of-life scores. The most common side effects included headache, nausea, diarrhea, vomiting, and abdominal pain. Three of 40 patients in the 100-mg group developed a rash. In this small proof-of-concept trial, celiac patients treated with ZED1227 showed a reduction in gluten-induced duodenal mucosal damage. A proof of concept trial, however successful, leaves a long way to go before this treatment proves itself useful and desirable. Many prior efforts have shown early, and even late, promise, only to fail spectacularly at the end of the day. Stay tuned for more on this and similar stories regarding alternative treatment approaches currently under development for celiac disease. Read more in the New England Journal of Medicine The research team included Detlef Schuppan, M.D., Ph.D., Markku Mäki, M.D., Ph.D., Knut E.A. Lundin, M.D., Ph.D., Jorma Isola, M.D., Ph.D., Tina Friesing-Sosnik, M.D., Juha Taavela, M.D., Ph.D., Alina Popp, M.D., Ph.D., Jari Koskenpato, M.D., Jost Langhorst, M.D., Øistein Hovde, M.D., Ph.D., Marja-Leena Lähdeaho, M.D., Ph.D., Stefano Fusco, M.D., Michael Schumann, M.D., Helga P. Török, M.D., Juozas Kupcinskas, M.D., Yurdagül Zopf, M.D., Ansgar W. Lohse, M.D., Mika Scheinin, M.D., Ph.D., Karin Kull, M.D., Luc Biedermann, M.D., Valerie Byrnes, M.D., Andreas Stallmach, M.D., Jørgen Jahnsen, M.D., Jonas Zeitz, M.D., Ralf Mohrbacher, M.Sc., and Roland Greinwald, Ph.D., for the CEC-3 Trial Group.

Celiac.com 06/27/2017 - What can gene cells tell us about potential gut damage in people with celiac disease? Can they be harnessed to paint an accurate picture of what's going on in the gut? A team of researchers recently set out to study autoimmunity and the transition in immune cells as dietary gluten induces small intestinal lesions. Specifically, they wanted to know if a B-cell gene signature correlates with the extent of gluten-induced gut damage in celiac disease. The research team included Mitchell E. Garber, Alok Saldanha, Joel S. Parker, Wendell D. Jones, Katri Kaukinen, Kaija Laurila, Marja-Leena Lähdeaho, Purvesh Khatri, Chaitan Khosla, Daniel C. Adelman, and Markku Mäki. They are variously affiliated with the Alvine Pharmaceuticals, Inc, San Carlos, California, the Department of Chemistry, Stanford, California, the Institute for Immunity, Transplantation and Infection, Stanford, California, the Division of Biomedical Informatics, Department of Medicine, Stanford, California, the Department of Chemical Engineering, Stanford, California, the Stanford ChEM-H, Stanford University, Stanford, California, the InterSystems Corporation, Cambridge, Massachusetts, the Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, the Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, the EA Genomics, Division of Q2 Solutions, Morrisville, North Carolina, the Tampere Center for Child Health Research, Tampere, Finland, the University of Tampere Faculty of Medicine and Life Sciences, Tampere, Finland, the Department of Pediatrics, Tampere, Finland, the Department of Internal Medicine, Tampere, Finland, Tampere University Hospital, Tampere, Finland, and with the Division of Allergy/Immunology, Department of Medicine, University of California San Francisco, San Francisco, California. The team looked at seventy-three celiac disease patients who followed a long-term, gluten-free diet. Those patients ingested a known amount of gluten daily for 6 weeks. Prior to the study, the team took a peripheral blood sample and intestinal biopsy specimens, then did the same after 6 weeks of gluten challenge. To accurately quantify gluten-induced intestinal injury, they reported biopsy results on a continuous numeric scale that measured the villus-height–to–crypt-depth ratio. As patient gut mucosa remained either relatively healthy or else deteriorated under the gluten challenge, the team isolated pooled B and T cells from whole blood, and used DNA microarray to analyze RNA for changes in peripheral B- and T-cell gene expression that correlated with changes in villus height to crypt depth. As is often the case with celiac disease, intestinal damage from the gluten challenge varied considerably among the patients, ranging from no visible damage to extensive damage. Genes differentially expressed in B cells correlated strongly with the extent of gut damage. Increased B-cell gene expression correlated with a lack of sensitivity to gluten, whereas their decrease correlated with gluten-caused mucosal damage. The the correlation with gut damage was tied to a core B-cell gene module, representing a subset of B-cell genes analyzed. In patients with little to no intestinal damage, genes comprising the core B-cell module showed an overall increase in expression over the 6 week period. This suggests that B-cell immune response in these patients may be a reaction to promote mucosal homeostasis and circumvent inflammation. The idea that B-cell gene signature can reveal the extent of gut damage in celiac patients is intriguing. Clearly more research is needed to determine how this revelation might be harnessed to improve the evaluation and treatment of celiac disease. Source: Cell Mol Gastroenterol Hepatol. 2017 Jul; 4(1): 1–17. Published online 2017 Jan 28. doi: 10.1016/j.jcmgh.2017.01.011. PMCID: PMC5413199