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Coeliac disease

Abstract

Coeliac disease is an immune-mediated enteropathy against dietary gluten present in wheat, rye and barley and is one of the most common lifelong food-related disorders worldwide. Coeliac disease is also considered to be a systemic disorder characterized by a variable combination of gluten-related signs and symptoms and disease-specific antibodies in addition to enteropathy. The ingestion of gluten leads to the generation of harmful gluten peptides, which, in predisposed individuals, can induce adaptive and innate immune responses. The clinical presentation is extremely variable; patients may have severe gastrointestinal symptoms and malabsorption, extraintestinal symptoms or have no symptoms at all. Owing to the multifaceted clinical presentation, diagnosis remains a challenge and coeliac disease is heavily underdiagnosed. The diagnosis of coeliac disease is achieved by combining coeliac disease serology and small intestinal mucosal histology during a gluten-containing diet. Currently, the only effective treatment for coeliac disease is a lifelong strict gluten-free diet; however, the diet is restrictive and gluten is difficult to avoid. Optimizing diagnosis and care in coeliac disease requires continuous research and education of both patients and health-care professionals.

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Fig. 1: The global seroprevalence of coeliac disease.
Fig. 2: Cereals harmful for patients with coeliac disease.
Fig. 3: Gluten peptide presentation by HLA-DQ2.
Fig. 4: Adaptive immune responses involved in coeliac disease.
Fig. 5: Innate immune responses involved in coeliac disease.
Fig. 6: The clinical manifestations of coeliac disease.
Fig. 7: The continuum of small intestinal mucosal damage in coeliac disease.

References

  1. 1.

    Abadie, V., Sollid, L. M., Barreiro, L. B. & Jabri, B. Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Ann. Rev. Immunol. 29, 493–525 (2011).

    CAS  Article  Google Scholar 

  2. 2.

    Karell, K. et al. HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on celiac disease. Hum. Immunol. 64, 469–477 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Singh, P. et al. Global prevalence of celiac disease: systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 16, 823–836 (2018). This paper presents a recent meta-analysis of the worldwide prevalence of coeliac disease.

    PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Volta, U., Caio, G., Stanghellini, V. & De Giorgio, R. The changing clinical profile of celiac disease: a 15-year experience (1998–2012) in an Italian referral center. BMC Gastroenterol. 14, 194 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Kivelä, L. et al. Presentation of celiac disease in Finnish children is no longer changing: a 50-year perspective. J. Pediatr. 167, 1109–1115 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Fuchs, V. et al. Delayed celiac disease diagnosis predisposes to reduced quality of life and incremental use of health care services and medicines: a prospective nationwide study. United Eur. Gastroenterol. J. 6, 567–575 (2018).

    Article  Google Scholar 

  7. 7.

    Tio, M., Cox, M. R. & Eslick, G. D. Meta-analysis: coeliac disease and the risk of all-cause mortality, any malignancy and lymphoid malignancy. Aliment. Pharmacol. Ther. 35, 540–551 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Han, Y., Chen, W., Li, P. & Ye, J. Association between coeliac disease and risk of any malignancy and gastrointestinal malignancy: a meta-analysis. Medicine (Baltimore) 94, e1612 (2015).

    Article  Google Scholar 

  9. 9.

    Tuire, I. et al. Persistent duodenal intraepithelial lymphocytosis despite a long-term strict gluten-free diet in celiac disease. Am. J. Gastroenterol. 107, 1563–1569 (2012).

    PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Vilppula, A. et al. Clinical benefit of gluten-free diet in screen-detected older celiac disease patients. BMC Gastroenterol. 11, 136 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Catassi, C. et al. Coeliac disease in the year 2000: exploring the iceberg. Lancet 343, 200–203 (1994).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Mäki, M. et al. Prevalence of celiac disease among children in Finland. N. Engl. J. Med. 348, 2517–2524 (2003). This article presents a milestone study applying coeliac-specific serology to uncover the true prevalence of coeliac disease in the general population.

    PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    McMillan, S. A. et al. Factors associated with serum antibodies to reticulin, endomysium, and gliadin in an adult population. Gut 39, 43–47 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Mustalahti, K. et al. The prevalence of celiac disease in Europe: results of a centralized, international mass screening project. Ann. Med. 42, 587–595 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    West, J. et al. Seroprevalence, correlates, and characteristics of undetected coeliac disease in England. Gut 52, 960–965 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Korponay-Szabó, I. R. et al. Population screening for coeliac disease in primary care by district nurses using a rapid antibody test: diagnostic accuracy and feasibility study. BMJ 335, 1244–1247 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Rubio-Tapia, A., Ludvigsson, J. F., Brantner, T. L., Murray, J. A. & Everhart, J. E. The prevalence of celiac disease in the United States. Am. J. Gastroenterol. 107, 1538–1544 (2012).

    PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Parra-Medina, R. et al. Prevalence of celiac disease in Latin America: a systematic review and meta-regression. PLOS ONE 10, e0124040 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19.

    Hovell, C. J. et al. High prevalence of coeliac disease in a population-based study from Western Australia: a case for screening? Med. J. Aust. 175, 247–250 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Ramakrishna, B. S. et al. Prevalence of adult celiac disease in India: regional variations and associations. Am. J. Gastroenterol. 111, 115–123 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Shamir, R. et al. The use of a single serological marker underestimates the prevalence of celiac disease in Israel: a study of blood donors. Am. J. Gastroenterol. 97, 2589–2594 (2002).

    PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Yuan, J. et al. Prevalence of celiac disease autoimmunity among adolescents and young adults in China. Clin. Gastroenterol. Hepatol. 15, 1572–1579 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Makharia, G. K. et al. World Gastroenterology Organization-Asia Pacific Association of Gastroenterology Working Party on Celiac Disease. Issues associated with the emergence of coeliac disease in the Asia–Pacific region: a working party report of the World Gastroenterology Organization and the Asian Pacific Association of Gastroenterology. J. Gastroenterol. Hepatol. 29, 666–677 (2014).

    PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Lohi, S. et al. Increasing prevalence of coeliac disease over time. Aliment. Pharmacol. Ther. 26, 1217–1225 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Catassi, C. et al. Natural history of celiac disease autoimmunity in a USA cohort followed since 1974. Ann. Med. 42, 530–538 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Rubio-Tapia, A. et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology 137, 88–93 (2009). This comprehensive paper shows an increase in the true prevalence of coeliac disease over time and suggests increased mortality in individuals with unrecognized coeliac disease.

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Ilus, T. et al. Refractory coeliac disease in a country with a high prevalence of clinically-diagnosed coeliac disease. Aliment. Pharmacol. Ther. 39, 418–425 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Vilppula, A. et al. Increasing prevalence and high incidence of celiac disease in elderly people: a population-based study. BMC Gastroenterol. 9, 49 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Kondrashova, A. et al. Lower economic status and inferior hygienic environment may protect against celiac disease. Ann. Med. 40, 223–231 (2008).

    PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    Kemppainen, K. et al. Factors that increase risk of celiac disease autoimmunity after a gastrointestinal infection in early life. Clin. Gastroenterol. Hepatol. 15, 694–702 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Andrén Aronsson, C. et al. Effects of gluten intake on risk of celiac disease: a case–control study on a Swedish birth cohort. Clin. Gastroenterol. Hepatol. 14, 403–409 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  32. 32.

    Mariné, M. et al. The prevalence of coeliac disease is significantly higher in children compared with adults. Aliment. Pharmacol. Ther. 33, 477–486 (2011).

    PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Singh, P., Arora, S., Lal, S., Strand, T. A. & Makharia, G. K. Risk of celiac disease in the first- and second-degree relatives of patients with celiac disease: a systematic review and meta-analysis. Am. J. Gastroenterol. 110, 1539–1548 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Husby, S. et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J. Pediatr. Gastroenterol. Nutr. 54, 136–160 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Shewry, P. R., Halford, N. G., Belton, P. S. & Tatham, A. S. The structure and properties of gluten: an elastic protein from wheat grain. Phil. Trans. R. Soc. 357, 133–142 (2002).

    CAS  Article  Google Scholar 

  36. 36.

    Kasarda, D. D. in Celiac Disease — Proceedings of the Seventh International Symposiumon Coeliac Disease (eds Mäki, M., Collin, P. & Visakorpi, J. K.) 195–212 (Coeliac Disease Study Group, 1996).

  37. 37.

    Shan, L. et al. Structural basis for gluten intolerance in celiac sprue. Science 297, 2275–2279 (2002). This excellent study demonstrates the proteolytic resistance of gliadin and is the first to suggest a new treatment modality based on proteolytic breakdown of gluten peptides.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    Sollid, L. M. Coeliac disease: dissecting a complex inflammatory disorder. Nat. Rev. Immunol. 2, 647–655 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Caminero, A. et al. Duodenal bacteria from patients with celiac disease and healthy subjects distinctly affect gluten breakdown and immunogenicity. Gastroenterology 151, 670–683 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Pinto-Sánchez, M. I. et al. Safety of adding oats to a gluten-free diet for patients with celiac disease: systematic review and meta-analysis of clinical and observational studies. Gastroenterology 153, 395–409 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  41. 41.

    van Heel, D. A. et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat. Genet. 39, 827–829 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. 42.

    Trynka, G. et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat. Genet. 43, 1193–1201 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Gutierrez-Achury, J. et al. Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease. Nat. Genet. 47, 577–578 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Sollid, L. M. The roles of MHC class II genes and post-translational modification in celiac disease. Immunogenetics 69, 605–616 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Pietzak, M. M., Schofield, T. C., McGinniss, M. J. & Nakamura, R. M. Stratifying risk for celiac disease in a large at-risk United States population by using HLA alleles. Clin. Gastroenterol. Hepatol. 7, 966–971 (2009).

    PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Hunt, K. A. et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat. Genet. 40, 395–402 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Dubois, P. C. et al. Multiple common variants for celiac disease influencing immune gene expression. Nat. Genet. 42, 295–302 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Lundin, K. E. et al. Gliadin-specific, HLA-DQ(alpha 1*0501, beta 1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients. J. Exp. Med. 178, 187–196 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  49. 49.

    van de Wal, Y. et al. Small intestinal T cells of celiac disease patients recognize a natural pepsin fragment of gliadin. Proc. Natl Acad. Sci. USA 95, 10050–10054 (1998).

    PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Dieterich, W. et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat. Med. 3, 797–801 (1997). This landmark study identifies TG2 as the target of coeliac-disease-specific autoantibodies and is the first study to suggest that gliadin is a preferred substrate for this enzyme.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Molberg, O. et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat. Med. 4, 713–717 (1998). This outstanding article shows that TG2-mediated deamidation of gliadin peptides creates epitopes that bind efficiently to coeliac-type HLA-DQ2, which are capable of inducing strong T cell activation, which is a hallmark of adaptive immune response in coeliac disease.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Tollefsen, S. et al. HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease. J. Clin. Invest. 116, 2226–2236 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Rossjohn, J. & Koning, F. A biased view toward celiac disease. Mucosal Immunol. 9, 583–586 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Bodd, M. et al. HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22. Mucosal Immunol. 3, 594–601 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55.

    Stamnaes, J. & Sollid, L. M. Celiac disease: autoimmunity in response to food antigen. Semin. Immunol. 27, 343–352 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Korponay-Szabó, I. R. et al. In vivo targeting of intestinal and extraintestinal transglutaminase 2 by coeliac autoantibodies. Gut 53, 641–648 (2004).

    PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Di Niro, R. et al. Responsive population dynamics and wide seeding into the duodenal lamina propria of transglutaminase-2-specific plasma cells in celiac disease. Mucosal Immunol. 9, 254–264 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  58. 58.

    Iversen, R. et al. Strong clonal relatedness between serum and gut IgA despite different plasma cell origins. Cell Rep. 20, 2357–2367 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Rauhavirta, T., Hietikko, M., Salmi, T. & Lindfors, K. Transglutaminase 2 and transglutaminase 2 autoantibodies in celiac disease: a review. Clin. Rev. Allergy Immunol. https://doi.org/10.1007/s12016-016-8557-4 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Sarra, M. et al. IL-15 positively regulates IL-21 production in celiac disease mucosa. Mucosal Immunol. 6, 244–255 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Malamut, G. et al. IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J. Clin. Invest. 120, 2131–2143 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Salvati, V. M. et al. Interleukin 18 and associated markers of T helper cell type 1 activity in coeliac disease. Gut 50, 186–190 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Mention, J. J. et al. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 125, 730–745 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64.

    Kutlu, T. et al. Numbers of T cell receptor (TCR) alpha beta+ but not of TcR gamma delta+ intraepithelial lymphocytes correlate with the grade of villous atrophy in coeliac patients on a long term normal diet. Gut 34, 208–214 (1993).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Maiuri, L. et al. FAS engagement drives apoptosis of enterocytes of coeliac patients. Gut 48, 418–424 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Oberhuber, G. et al. Evidence that intestinal intraepithelial lymphocytes are activated cytotoxic T cells in celiac disease but not in giardiasis. Am. J. Pathol. 148, 1351–1357 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Meresse, B. et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21, 357–366 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Hüe, S. et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 21, 367–377 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    Luciani, A. et al. Lysosomal accumulation of gliadin p31-43 peptide induces oxidative stress and tissue transglutaminase-mediated PPARgamma downregulation in intestinal epithelial cells and coeliac mucosa. Gut 59, 311–319 (2010).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  70. 70.

    Araya, R. E. et al. Mechanisms of innate immune activation by gluten peptide p31-43 in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G40–G49 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  71. 71.

    Riddle, M. S., Murray, J. A., Cash, B. D., Pimentel, M. & Porter, C. K. Pathogen-specific risk of celiac disease following bacterial causes of foodborne illness: a retrospective cohort study. Dig. Dis. Sci. 58, 3242–3245 (2013).

    PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Setty, M. et al. Distinct and synergistic contributions of epithelial stress and adaptive immunity to functions of intraepithelial killer cells and active celiac disease. Gastroenterology 149, 681–691 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Bouziat, R. et al. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science 356, 44–50 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Zevallos, V. F. et al. Nutritional wheat amylase-trypsin inhibitors promote intestinal inflammation via activation of myeloid cells. Gastroenterology 152, 1100–1113 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Forsberg, G. et al. Presence of bacteria and innate immunity of intestinal epithelium in childhood celiac disease. Am. J. Gastroenterol. 99, 894–904 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  76. 76.

    Ou, G. et al. Proximal small intestinal microbiota and identification of rod-shaped bacteria associated with childhood celiac disease. Am. J. Gastroenterol. 104, 3058–3067 (2009).

    PubMed  Article  PubMed Central  Google Scholar 

  77. 77.

    Wacklin, P. et al. Altered duodenal microbiota composition in celiac disease patients suffering from persistent symptoms on a long-term gluten-free diet. Am. J. Gastroenterol. 109, 1933–1941 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Sánchez, E., Donat, E., Ribes-Koninckx, C., Fernández-Murga, M. L. & Sanz, Y. Duodenal-mucosal bacteria associated with celiac disease in children. Appl. Environ. Microbiol. 79, 5472–5479 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    D’Argenio, V. et al. Metagenomics reveals dysbiosis and a potentially pathogenic N. flavescens strain in duodenum of adult celiac patients. Am. J. Gastroenterol. 111, 879–890 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Verdu, E. & Caminero, A. How infection can incite sensitivity to food. Science 556, 29–30 (2017).

    Article  Google Scholar 

  81. 81.

    Lerner, A., Arleevskaya, M., Schmiedl, A. & Mathiass, T. Microbes and viruses are bugging the gut in celiac disease. Are they friends or foes? Front. Microbiol. 8, 1392 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Vriezinga, S. L. et al. Randomized feeding intervention in infants at high risk for celiac disease. N. Engl. J. Med. 371, 1304–1315 (2014). This multicentre, randomized, double-blind, placebo-controlled dietary intervention study in at-risk children addresses whether the early introduction of gluten is able to prevent the onset of coeliac disease.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. 83.

    Decker, E. et al. Cesarean delivery is associated with celiac disease but not inflammatory bowel disease in children. Pediatrics 125, e1433–e1440 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  84. 84.

    Koletzko, S. et al. Cesarean section on the risk of celiac disease in the offspring: the Teddy study. J. Pediatr. Gastroenterol. Nutr. 66, 417–424 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  85. 85.

    Mårild, K. et al. Antibiotic exposure and the development of coeliac disease: a nationwide case-control study. BMC Gastroenterol. 13, 109 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Kemppainen, K. et al. Association between early-life antibiotic use and the risk of islet or celiac disease autoimmunity. JAMA Pediatr. 171, 1217–1225 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Lebwohl, B., Spechler, S. J., Wang, T. C., Green, P. H. & Ludvigsson, J. F. Use of proton pump inhibitors and subsequent risk of celiac disease. Dig. Liver Dis. 46, 36–40 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  88. 88.

    Ivarsson, A. et al. Epidemic of coeliac disease in Swedish children. Acta Paediatr. 89, 165–171 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  89. 89.

    Szajewska, H. et al. Systematic review with meta-analysis: early infant feeding and coeliac disease — update 2015. Aliment. Pharmacol. Ther. 41, 1038–1054 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    Lionetti, E. et al. Introduction of gluten, HLA status, and the risk of celiac disease in children. N. Engl. J. Med. 371, 1295–1303 (2014).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  91. 91.

    Crespo-Escobar, P. et al. The role of gluten consumption at an early age in celiac disease development: a further analysis of the prospective PreventCD cohort study. Am. J. Clin. Nutr. 105, 890–896 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92.

    Snook, J. A. et al. Adult coeliac disease and cigarette smoking. Gut 39, 60–62 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Steens, R. F. et al. A national prospective study on childhood celiac disease in the Netherlands 1993–2000: an increasing recognition and a changing clinical picture. J. Pediatr. 147, 239–243 (2005).

    PubMed  Article  PubMed Central  Google Scholar 

  94. 94.

    Collin, P., Salmi, T. T., Hervonen, K., Kaukinen, K. & Reunala, T. Dermatitis herpetiformis: a cutaneous manifestation of coeliac disease. Ann. Med. 49, 23–31 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. 95.

    Jericho, H., Sansotta, N. & Guandalini, S. Extraintestinal manifestations of celiac disease: effectiveness of the gluten-free diet. J. Pediatr. Gastroenterol. Nutr. 65, 75–79 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  96. 96.

    Rampertab, S. D., Pooran, N., Brar, P., Singh, P. & Green, P. H. Trends in the presentation of celiac disease. Am. J. Med. 119, 355 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  97. 97.

    Giersiepen, K. et al. Accuracy of diagnostic antibody tests for coeliac disease in children: summary of an evidence report. J. Pediatr. Gastroenterol. Nutr. 54, 229–241 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  98. 98.

    Lewis, N. R. & Scott, B. B. Systemic review: the use of serology to exclude or diagnose coeliac disease (a comparison of the endomysial and tissue transglutaminase antibody tests). Aliment. Pharmacol. Ther. 24, 47–54 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  99. 99.

    Chou, R. et al. Screening for celiac disease. Evidence report and systemic review for the US preventive services task force. JAMA 217, 1258–1268 (2017).

    Article  Google Scholar 

  100. 100.

    Ferrara, F. et al. Anti-transglutaminase antibodies in non-coeliac children suffering from infectious diseases. Clin. Exp. Immunol. 159, 217–223 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Lewis, N. R. & Scott, B. B. Meta-analysis: deamidated gliadin peptide antibody and tissue transglutaminase antibody compared as screening tests for coeliac disease. Aliment. Pharmacol. Ther. 31, 73–81 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  102. 102.

    Hoerter, N. A. et al. Diagnostic yield of isolated deamidated gliadin peptide antibody elevation for celiac disease. Dig. Dis. Sci. 62, 1272–1276 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  103. 103.

    Korponay-Szabó, I. R. et al. Elevation of IgG antibodies against tissue transglutaminase as a diagnostic tool for coeliac disease in selective IgA deficiency. Gut 52, 1567–1571 (2003).

    PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Aziz, I. et al. The clinical and phenotypical assessment of seronegative villous atrophy; a prospective UK centre experience evaluating 200 adult cases over a 15-year period (2000–2015). Gut 66, 1563–1572 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. 105.

    Singh, P. et al. Diagnostic accuracy of point of care tests for diagnosing celiac disease: a systematic review and meta-analysis. J. Clin. Gastroenterol. https://doi.org/10.1097/MCG.0000000000001081 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Kurppa, K. et al. Diagnosing mild enteropathy celiac disease: a randomized, controlled clinical study. Gastroenterology 136, 816–823 (2009).

    PubMed  Article  PubMed Central  Google Scholar 

  107. 107.

    Zanini, B. et al. Celiac disease with mild enteropathy is not mild disease. Clin. Gastroenterol. Hepatol. 11, 253–258 (2013).

    PubMed  Article  PubMed Central  Google Scholar 

  108. 108.

    Taavela, J. et al. A prospective study on the usefulness of duodenal bulb biopsies in celiac disease diagnosis in children: urging caution. Am. J. Gastroenterol. 111, 124–133 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. 109.

    Taavela, J. et al. Validation of morphometric analyses of small-intestinal biopsy readouts in celiac disease. PLOS ONE 8, e76163 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Villanacci, V. et al. Histopathological evaluation of duodenal biopsy in the PreventCD project. An observational interobserver agreement study. APMIS 126, 208–214 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  111. 111.

    Kaukinen, K., Partanen, J., Mäki, M. & Collin, P. HLA-DQ typing in the diagnosis of celiac disease. Am. J. Gastroenterol. 97, 695–699 (2002).

    PubMed  Article  PubMed Central  Google Scholar 

  112. 112.

    Salmi, T. T., Collin, P., Reunala, T., Mäki, M. & Kaukinen, K. Diagnostic methods beyond conventional histology in coeliac disease diagnosis. Dig. Liver Dis. 42, 28–32 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  113. 113.

    Anderson, R. P., Degano, P., Godkin, A. J., Jewell, D. P. & Hill, A. V. In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T cell epitope. Nat. Med. 6, 337–342 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  114. 114.

    Raki, M. et al. Tetramer visualization of gut-homing gluten-specific T cells in the peripheral blood of celiac disease patients. Proc. Natl Acad. Sci. USA 104, 2831–2836 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  115. 115.

    Sarna, V. K. et al. HLA-DQ-gluten tetramer blood test accurately identifies patients with and without celiac disease in absence of gluten consumption. Gastroenterology 54, 886–896 (2018).

    Article  Google Scholar 

  116. 116.

    Biesiekierski, J. R. et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am. J. Gastroenterol. 106, 508–514 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  117. 117.

    Carroccio, A. et al. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am. J. Gastroenterol. 107, 1898–1906 (2012).

    PubMed  Article  PubMed Central  Google Scholar 

  118. 118.

    Carraccio, A. et al. Persistence of nonceliac wheat sensitivity, based on long-term follow-up. Gastroenterology 153, 56–58 (2017).

    Article  Google Scholar 

  119. 119.

    Uhde, M. et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut 65, 1930–1937 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Francavilla, R. et al. Randomized double-blind placebo-controlled crossover trial for the diagnosis of non-celiac gluten sensitivity in children. Am. J. Gastroenterol. 113, 421–430 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  121. 121.

    Sapone, A. et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 10, 13 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Skodje, G. I. et al. Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiac gluten sensitivity. Gastroenterology 154, 529–539 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  123. 123.

    Biagi, F. & Corazza, G. R. Mortality in celiac disease. Nat. Rev. Gastroenterol. Hepatol. 7, 158–162 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  124. 124.

    Van Doorn, R. K. et al. CDDUX: a disease-specific health-related quality-of-life questionnaire for children with celiac disease. J. Pediatr. Gastroenterol. Nutr. 47, 147–152 (2008).

    PubMed  Article  PubMed Central  Google Scholar 

  125. 125.

    Nachman, F. et al. Quality of life in celiac disease patients: prospective analysis on the importance of clinical severity at diagnosis and the impact of treatment. Dig. Liver Dis. 41, 15–25 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  126. 126.

    Shamir, R., Hernell, O. & Leshno, M. Cost-effectiveness analysis of screening for celiac disease in the adult population. Med. Decis. Making 26, 282–293 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  127. 127.

    Mearin, M. L. The prevention of coeliac disease. Best Pract. Res. Clin. Gastroenterol. 29, 493–501 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  128. 128.

    Ivarsson, A. et al. Prevalence of childhood celiac disease and changes in infant feeding. Pediatrics 131, 687–694 (2013).

    Article  Google Scholar 

  129. 129.

    Stordal, K., White, R. A. & Eggesbo, M. Early feeding and risk of celiac disease in a prospective birth cohort. Pediatrics 132, 1202–1209 (2013).

    Article  Google Scholar 

  130. 130.

    Jansen, M. A. et al. Infant feeding and anti-tissue transglutaminase antibody concentrations in the Generation R Study. Am. J. Clin. Nutr. 100, 1095–1101 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  131. 131.

    Aronsson, C. A. et al. Age at gluten introduction and risk of celiac disease. Pediatrics 135, 239–245 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Silano, M., Agostoni, C., Sanz, Y. & Guandalini, S. Infant feeding and risk of developing celiac disease: a systematic review. BMJ Open 6, e009163 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Mårild, K. et al. Infections and risk of celiac disease in childhood: a prospective nationwide cohort study. Am. J. Gastroenterol. 110, 1475–1484 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  134. 134.

    Lionetti, E. et al. Mode of delivery and risk of celiac disease: risk of celiac disease and age at gluten introduction cohort study. J. Pediatr. 184, 81–86 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  135. 135.

    Downey, L., Houten, R., Murch, S. & Longson, D. Recognition, assessment, and management of coeliac disease: summary of updated NICE guidance. BMJ 351, h4513 (2015).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  136. 136.

    Catassi, C. et al. Detection of celiac disease in primary care: a multicentre case-finding study in North America. Am. J. Gastoenterol. 102, 1454–1460 (2007).

    Article  Google Scholar 

  137. 137.

    Virta, L. J., Kaukinen, K. & Collin, P. Incidence and prevalence of diagnosed coeliac disease in Finland: results of effective case finding in adults. Scand. J. Gastroenterol. 44, 933–938 (2009).

    PubMed  Article  PubMed Central  Google Scholar 

  138. 138.

    Alessandrini, S., Giacomoni, E. & Muccioli, F. Mass population screening for celiac disease in children: the experience in Republic of San Marino from 1993 to 2009. Ital. J. Pediatr. 39, 67 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Nordyke, K. et al. How do children experience participating in a coeliac disease screening? A qualitative study based on children’s written narratives. Scand. J. Public Health 38, 351–358 (2010).

    Article  Google Scholar 

  140. 140.

    Katz, K. D. et al. Screening for celiac disease in a North American population: sequential serology and gastrointestinal symptoms. Am. J. Gastroenterol. 106, 1333–1339 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Koppen van, E. J. et al. Long-term health and quality-of-life consequences of mass screening for childhood celiac disease: a 10-year follow-up study. Pediatrics 123, 582–588 (2009).

    Article  Google Scholar 

  142. 142.

    Kiefte-de Jong, J. C. et al. Levels of antibodies against tissue transglutaminase during pregnancy are associated with reduced fetal weight and birth weight. Gastroenterology 144, 726–735 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  143. 143.

    Kurppa, K. et al. Benefits of a gluten-free diet for asymptomatic patients with serologic markers of celiac disease. Gastroenterology 147, 610–617 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  144. 144.

    Mahadev, S., Gardner, R., Lewis, S. K., Lebwohl, B. & Green, P. H. Quality of life in screen-detected celiac disease patients in the United States. J. Clin. Gastroenterol. 50, 393–397 (2015).

    Google Scholar 

  145. 145.

    Jansen, M. A. et al. Growth trajectories and bone mineral density in anti-tissue transglutaminase antibody-positive children: the Generation R Study. Clin. Gastroenterol. Hepatol. 13, 913–920 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  146. 146.

    US Preventive Services Task Force. Screening for celiac disease: US preventive services task force recommendation statement. JAMA 317, 1252–1257 (2017).

    Google Scholar 

  147. 147.

    See, J. A., Kaukinen, K., Makharia, G. K., Gibson, P. R. & Murray, J. A. Practical insights into gluten-free diets. Nat. Rev. Gastroenterol. Hepatol. 12, 580–591 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  148. 148.

    Šuligoj, T., Gregorini, A., Colomba, M., Ellis, H. J. & Ciclitira, P. J. Evaluation of the safety of ancient strains of wheat in coeliac disease reveals heterogeneous small intestinal T cell responses suggestive of coeliac toxicity. Clin. Nutr. 32, 1043–1049 (2013).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  149. 149.

    Malalgoda, M., Meinhardt, S. W. & Simsek, S. Detection and quantitation of immunogenic epitopes related to celiac disease in historical and modern hard red spring wheat cultivars. Food Chem. 264, 101–107 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  150. 150.

    Wild, D., Robins, G. G., Burley, V. J. & Howdle, P. D. Evidence of high sugar intake, and low fibre and mineral intake, in the gluten-free diet. Aliment. Pharmacol. Ther. 32, 573–581 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  151. 151.

    Lebwohl, B. et al. Long term gluten consumption in adults without celiac disease and risk of coronary heart disease: prospective cohort study. BMJ 357, j1892 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Codex Alimentarius International Food Standards. Standard for foods for special dietary use for persons intolerant to gluten. Codex Stan 118–1979. Codex Alimentarius www.fao.org/input/download/standards/291/CXS_118e_2015.pdf (2008).

  153. 153.

    Collin, P., Thorell, L., Kaukinen, K. & Mäki, M. The safe threshold for gluten contamination in gluten-free products. Can trace amounts be accepted in the treatment of coeliac disease? Aliment. Pharmacol. Ther. 19, 1277–1283 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  154. 154.

    Méndez, E., Vela, C., Immer, U. & Janssen, F. W. Report of a collaborative trial to investigate the performance of the R5 enzyme linked immunoassay to determine gliadin in gluten-free food. Eur. J. Gastroenterol. Hepatol. 17, 1053–1063 (2005).

    PubMed  Article  PubMed Central  Google Scholar 

  155. 155.

    Akobeng, A. K. & Thomas, A. G. Systematic review: tolerable amount of gluten for people with coeliac disease. Aliment. Pharmacol. Ther. 27, 1044–1052 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  156. 156.

    Catassi, C. et al. A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am. J. Clin. Nutr. 85, 160–166 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  157. 157.

    van Overbeek, F. M. et al. The daily gluten intake in relatives of patients with coeliac disease compared with that of the general Dutch population. Eur. J. Gastroenterol. Hepatol. 9, 1097–1099 (1997).

    PubMed  Article  PubMed Central  Google Scholar 

  158. 158.

    Hall, N. J., Rubin, G. & Charnock, A. Systematic review: adherence to a gluten-free diet in adult patients with coeliac disease. Aliment. Pharmacol. Ther. 30, 315–330 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  159. 159.

    Villafuerte-Galvez, J. et al. Factors governing long-term adherence to a gluten-free diet in adult patients with coeliac disease. Aliment. Pharmacol. Ther. 42, 753–760 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  160. 160.

    Ukkola, A. et al. Patients’ experiences and perceptions of living with coeliac disease — implications for optimizing care. J. Gastrointestin. Liver Dis. 21, 17–22 (2012).

    PubMed  PubMed Central  Google Scholar 

  161. 161.

    Halmos, E. P. et al. Food knowledge and psychological state predict adherence to a gluten-free diet in a survey of 5310 Australians and New Zealanders with coeliac disease. Aliment. Pharmacol. Ther. 48, 78–86 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  162. 162.

    Aziz, I. et al. Change in awareness of gluten-related disorders among chefs and the general public in the UK: a 10-year follow-up study. Eur. J. Gastroenterol. Hepatol. 26, 1228–1233 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  163. 163.

    Branchi, F. et al. Celiac disease and drug-based therapies: inquiry into patients demands. Digestion 93, 160–166 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  164. 164.

    Clemens, R. & van Klinken, B. J. The future of oats in the food and health continuum. Br. J. Nutr. 112, S75–S79 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  165. 165.

    Peräaho, M. et al. Oats can diversify a gluten-free diet in celiac disease and dermatitis herpetiformis. J. Am. Diet. Assoc. 104, 1148–1150 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  166. 166.

    Arentz-Hansen, H. et al. The molecular basis for oat intolerance in patients with celiac disease. PLOS Med. https://doi.org/10.1371/journal.pmed.0010001 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Peräaho, M. et al. Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study. Scand. J. Gastroenterol. 39, 27–31 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  168. 168.

    Sjöberg, V. et al. Noncontaminated dietary oats may hamper normalization of the intestinal immune status in childhood celiac disease. Clin. Transl Gastroenterol. 5, e58 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  169. 169.

    Silano, M. et al. Avenins from different cultivars of oats elicit response by coeliac peripheral lymphocytes. Scand. J. Gastroenterol. 42, 1302–1305 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  170. 170.

    Comino, I. et al. Identification and molecular characterization of oat peptides implicated on coeliac immune response. Food Nutr. Res. 60, 30324 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  171. 171.

    Ludvigsson, J. F. et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut 63, 1210–1228 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  172. 172.

    Herman, M. L. et al. Patients with celiac disease are not followed up adequately. Clin. Gastroenterol. Hepatol. 10, 893–899 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  173. 173.

    Haines, M. L., Anderson, R. P. & Gibson, P. R. Systematic review: the evidence base for long-term management of coeliac disease. Aliment. Pharmacol. Ther. 28, 1042–1066 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  174. 174.

    Bebb, J. R., Lawson, A., Knight, T. & Long, R. G. Long-term follow-up of coeliac disease — what do coeliac patients want? Aliment. Pharmacol. Ther. 23, 827–831 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  175. 175.

    Johansson, K., Malmberg Hård Af Segerstad, E., Mårtensson, H. & Agardh, D. Dietitian visits were a safe and cost-effective form of follow-up care for children with celiac disease. Acta Paediatr. https://doi.org/10.1111/apa.14411 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Pekki, H. et al. Performing routine follow-up biopsy 1 year after diagnosis does not affect long-term outcomes in coeliac disease. Aliment. Pharmacol. Ther. 45, 1459–1468 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  177. 177.

    Wessels, M. M. et al. Complementary serologic investigations in children with celiac disease is unnecessary during follow-up. J. Pediatr. 169, 55–60 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  178. 178.

    Newnham, E. D., Shepherd, S. J., Strauss, B. J., Hosking, P. & Gibson, P. R. Adherence to the gluten-free diet can achieve the therapeutic goals in almost all patients with coeliac disease: a 5-year longitudinal study from diagnosis. Gastroenterol. Hepatol. 31, 342–349 (2016).

    CAS  Article  Google Scholar 

  179. 179.

    Hære, P. et al. Long-term mucosal recovery and healing in celiac disease is the rule — not the exception. Scand. J. Gastroenterol. 51, 1439–1446 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  180. 180.

    Malamut, G. et al. Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. Gastroenterology 136, 81–90 (2009).

    PubMed  Article  PubMed Central  Google Scholar 

  181. 181.

    Abdulkarim, A. S., Burgart, L. J., See, J. & Murray, J. A. Etiology of nonresponsive celiac disease: results of a systematic approach. Am. J. Gastroenterol. 97, 2016–2021 (2007).

    Article  Google Scholar 

  182. 182.

    van Wanrooij, R. L. et al. Outcome of referrals for non-responsive celiac disease in a tertiary center: low incidence of refractory celiac disease in the Netherlands. Clin. Transl Gastroenterol. 8, e218 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  183. 183.

    Rubio-Tapia, A. et al. Clinical staging and survival in refractory celiac disease: a single center experience. Gastroenterology 136, 99–107 (2009). This paper shows the poor prognosis of RCD.

    PubMed  Article  PubMed Central  Google Scholar 

  184. 184.

    Biagi, F. et al. PROgnosticating COeliac patieNts SUrvivaL: the PROCONSUL score. PLOS ONE 9, e84163 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  185. 185.

    Kaukinen, K. et al. Persistent small bowel mucosal villous atrophy without symptoms in coeliac disease. Aliment. Pharmacol. Ther. 25, 1237–1245 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  186. 186.

    Laurikka, P. et al. Gastrointestinal symptoms in celiac disease patients on a long-term gluten-free diet. Nutrients 8, E429 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  187. 187.

    Paarlahti, P. et al. Predictors of persistent symptoms and reduced quality of life in treated coeliac disease patients: a large cross-sectional study. BMC Gastroenterol. 13, 75 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  188. 188.

    Laurikka, P. et al. Dietary factors and mucosal immune response in celiac disease patients having persistent symptoms despite a gluten-free diet. J. Clin. Gastroenterol. https://doi.org/10.1097/MCG.0000000000001013 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Ilus, T., Kaukinen, K., Virta, L. J., Pukkala, E. & Collin, P. Incidence of malignancies in diagnosed celiac patients: a population-based estimate. Am. J. Gastroenterol. 109, 1471–1477 (2014).

    PubMed  Article  PubMed Central  Google Scholar 

  190. 190.

    Lebwohl, B. et al. Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study. Ann. Intern. Med. 159, 169–175 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  191. 191.

    Ludvigsson, J. F., West, J., Ekbom, A. & Stephansson, O. Reduced risk of breast, endometrial and ovarian cancer in women with celiac disease. Int. J. Cancer. 131, E244–E250 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  192. 192.

    Di Sabatino, A. et al. Splenic hypofunction and the spectrum of autoimmune and malignant complications in celiac disease. Clin. Gastroenterol. Hepatol. 4, 179–186 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  193. 193.

    Ludvigsson, J. F., Montgomery, S. M., Ekbom, A., Brandt, L. & Granath, F. Small-intestinal histopathology and mortality risk in celiac disease. JAMA 302, 1171–1178 (2009). This large population-based study indicates increased mortality in clinically diagnosed coeliac disease with villous atrophy as well as in patients with mild enteropathy.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  194. 194.

    Abdul Sultan, A. et al. Causes of death in people with coeliac disease in England compared with the general population: a competing risk analysis. Gut 64, 1220–1226 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  195. 195.

    Jordan, N. E. et al. Development and validation of a celiac disease quality of life instrument for North American children. J. Pediatr. Gastroenterol. Nutr. 57, 477–486 (2013).

    Article  Google Scholar 

  196. 196.

    Häuser, W., Gold, J., Stallmach, A., Caspary, W. F. & Stein, J. Development and validation of the Celiac Disease Questionnaire (CDQ), a disease-specific health-related quality of life measure for adult patients with celiac disease. J. Clin. Gastroenterol. 41, 157–166 (2007).

    PubMed  Article  PubMed Central  Google Scholar 

  197. 197.

    Dorn, S. et al. The development and validation of a new coeliac disease quality of life survey (CD-QOL). Aliment. Pharmacol. Ther. 31, 666–675 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  198. 198.

    Ukkola, A. et al. Diet improves perception of health and well-being in symptomatic, but not asymptomatic, patients with celiac disease. Clin. Gastroenterol. Hepatol. 9, 118–123 (2011).

    PubMed  Article  PubMed Central  Google Scholar 

  199. 199.

    Midhagen, G. & Hallert, C. High rate of gastrointestinal symptoms in celiac patients living on a gluten-free diet: controlled study. Am. J. Gastroenterol. 98, 2023–2026 (2003). This article reports that patients with coeliac disease may have persistent symptoms despite adherence to a long-term strict gluten-free diet.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  200. 200.

    Roos, S., Kärner, A. & Hallert, C. Psychological well-being of adult coeliac patients treated for 10 years. Dig. Liver Dis. 38, 177–182 (2006).

    CAS  Article  Google Scholar 

  201. 201.

    Rothbaum, F., Wolfer, J. & Visintainer, M. Coping behavior and locus of control in children1. J. Personal. 47, 118–135 (1979).

    Article  Google Scholar 

  202. 202.

    Compas, B. E. et al. Coping with chronic illness in childhood and adolescence. Annu. Rev. Clin. Psychol. 8, 455–480 (2012).

    PubMed  Article  PubMed Central  Google Scholar 

  203. 203.

    Vriezinga, S. et al. E-Healthcare for celiac disease — a multicenter randomized controlled trial. J. Pediatr. 195, 154–160 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  204. 204.

    Zarkadas, M. et al. Living with coeliac disease and a gluten-free diet: a Canadian perspective. J. Hum. Nutr. Diet. 26, 10–23 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  205. 205.

    Sollid, L. M. & Jabri, B. Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat. Rev. Immunol. 13, 294–302 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  206. 206.

    Marietta, E. et al. A new model for dermatitis herpetiformis that uses HLA-DQ8 transgenic NOD mice. J. Clin. Invest. 114, 1090–1097 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  207. 207.

    Bethune, M. T. et al. A non-human primate model for gluten sensitivity. PLOS ONE 3, e1614 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  208. 208.

    DePaolo, R. W. et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471, 220–224 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  209. 209.

    Werkstetter, K. J. et al. Accuracy in diagnosis of celiac disease without biopsies in clinical practice. Gastroenterology 153, 924–935 (2017). This prospective multicentre study shows that a non-invasive serology-based diagnostic approach is feasible in coeliac disease.

    PubMed  Article  PubMed Central  Google Scholar 

  210. 210.

    Moreno, M. L. et al. Detection of gluten immunogenic peptides in the urine of patients with coeliac disease reveals transgressions in the gluten-free diet and incomplete mucosal healing. Gut 66, 250–257 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  211. 211.

    Kelly, C. P. et al. Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study. Aliment. Pharmacol. Ther. 37, 252–262 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  212. 212.

    Leffler, D. A. et al. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial. Gastroenterology 148, 1311–1319 (2015). This paper describes the performance of a new therapeutic compound affecting small intestine mucosal barrier function in the treatment of coeliac disease.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  213. 213.

    Lähdeaho, M.-L. et al. Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease. Gastroenterology 146, 1649–1658 (2014). This pioneering paper reports that unfavourable gluten-induced small intestinal mucosal damage can be attenuated with gluten-degrading proteolytic enzyme therapy.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  214. 214.

    Syage, J. A., Murray, J. A., Green, P. H. R. & Khosla, C. Latiglutenase improves symptoms in seropositive celiac disease patients while on a gluten-free diet. Dig. Dis. Sci. 62, 2428–2432 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  215. 215.

    Goel, G. et al. Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies. Lancet Gastroenterol. Hepatol. 2, 479–493 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  216. 216.

    Ludvigsson, J. F. et al. Outcome measures in coeliac disease trials: the Tampere recommendations. Gut 67, 1410–1424 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  217. 217.

    Adriaanse, M. P. M. et al. Progress towards non-invasive diagnosis and follow-up of celiac disease in children; a prospective multicentre study to the usefulness of plasma I-FABP. Sci. Rep. 7, 8671 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  218. 218.

    Choung, R. S., Murray, J. A., Marietta, E. V., Van Dyke, C. T. & Ross, A. B. Serum alkylresorcinols as biomarkers of dietary gluten exposure in coeliac disease. Aliment. Pharmacol. Ther. 45, 643–652 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  219. 219.

    Owen, D. R. & Owen, D. A. Celiac disease and other causes of duodenitis. Arch. Pathol. Lab. Med. 142, 35–43 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  220. 220.

    DeGaetani, M. et al. Villous atrophy and negative celiac serology: a diagnostic and therapeutic dilemma. Am. J. Gastroenterol. 108, 647–653 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  221. 221.

    Adelman, D. C. et al. Measuring change in small intestinal histology in patients with celiac disease. Am. J. Gastroenterol. 113, 339–347 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank for the Academy of Finland, the Sigrid Juselius Foundation and the Competitive State Research Financing of the Expert Area of Tampere University Hospital (K. Kaukinen, K.L. and K. Kurppa); the European Commission (FP6-FP7); Stichting Coeliakie Onderzoek Nederland; the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN; M.L.M.); the Indian government and non-government organizations (G.K.M.), the US NIH (J.A.M.); the Canadian Institutes of Health Research and Crohn’s Colitis Canada grants; the Nestle Research Center; and Biocodex (E.F.V.) for support and funding. J.A.M. also acknowledges philanthropic support from the Mayo Foundation.

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Nature Reviews Disease Primers thanks C. Catassi, T. Not and the other anonymous referee(s) for the peer review of this work.

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Contributions

Introduction (K. Kaukinen and K.L.); Epidemiology (K. Kaukinen, K.L., G.K.M. and J.A.M.); Mechanisms/pathophysiology (K. Kaukinen, K.L. and E.F.V.); Diagnosis, screening and prevention (K. Kaukinen, K.L. and M.L.M.); Management (K. Kaukinen, K.L., K. Kurppa and K.E.A.L.); Quality of life (K. Kaukinen, K.L. and C.C.); Outlook (K. Kaukinen, K.L., C.C., K. Kurppa, K.E.A.L., G.K.M., M.L.M., J.A.M. and E.F.V.); Overview of the Primer (K. Kaukinen).

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Correspondence to Katri Kaukinen.

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Competing interests

None of the authors declares any financial competing interests. The authors have the following non-financial competing interests. K. Kaukinen, K.L. and K. Kurppa are members of the Scientific Advisory Board of the Finnish Coeliac Society. K. Kaukinen and K. Kurppa are members of the Finnish Coeliac Disease Current Care Guidelines committee. K. Kaukinen is a vice chairman of the Finnish Society of Internal Medicine. G.K.M. holds the post of Secretary General of the Indian Society of Gastroenterology, is a board member of the International Society for Studies on Coeliac Disease, is Co-Chair of the Research Committee of the World Gastroenterology Organization, serves as Coordinator of the Indian National Taskforce on Inflammatory Bowel Disease and is co-inventor of a device for faecal incontinence. J.A.M. is Section Editor for Mayo Clinic Proceedings. E.F.V. holds a Canada Research Chair and is an advisory board member of Innovate Pharmaceuticals, is President of the Society for the Study of Coeliac Disease, is Treasurer of the Canadian Association of Gastroenterology (CAG) and is an executive board member of CAG and the Canadian Digestive Health Foundation.

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Lindfors, K., Ciacci, C., Kurppa, K. et al. Coeliac disease. Nat Rev Dis Primers 5, 3 (2019). https://doi.org/10.1038/s41572-018-0054-z

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