Celiac disease is a common autoimmune disorder that has genetic, environmental, and immunologic components. It is characterized by an immune response to ingested wheat gluten and related proteins of rye and barley that leads to inflammation, villous atrophy, and crypt hyperplasia in the intestine. The disease is closely associated with genes that code for human leukocyte antigens DQ2 and DQ8. Transglutaminase 2 appears to be an important component of the disease, both as a deamidating enzyme that can enhance the immunostimulatory effect of gluten and as a target autoantigen in the immune response. Sensitive and specific serologic tests, including those for anti-transglutaminase antibody, are facilitating fast and noninvasive screening for celiac disease. Thus, they are contributing to a more accurate estimate of the prevalence of the disease and its association with other disorders. Celiac disease is associated with increased rates of anemia, osteoporosis, cancer, neurologic deficits, and additional autoimmune disorders. A gluten-free diet is the mainstay of safe and effective treatment of celiac disease, although its effect on some of the extraintestinal manifestations of the disease remains to be determined.

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Coeliac disease is a common disorder that can arise at any age and typically presents with a broad spectrum of symptoms. The disease is thought to be underdiagnosed, in part owing to the fact that coeliac disease is often characterized by associated conditions and extraintestinal manifestations that can misdirect and impede diagnosis. Some of these manifestations are direct consequences of autoimmunity, such as dermatitis herpetiformis or gluten ataxia, whereas others are indirectly related to inflammation and/or malabsorption including anaemia, osteoporosis, short stature and delayed puberty. Any organ from the central nervous system to joints, liver or teeth can be affected. In some cases, extraintestinal symptoms are the only clinical manifestations of coeliac disease or occur in conjunction with diarrhoea and malabsorptive symptoms. An increased awareness among medical practitioners of the variety of extraintestinal manifestations of coeliac disease is essential to improve diagnosis and treatment.

Background & Aims Celiac disease (CeD) is a prevalent autoimmune condition. Recurrent signs and symptoms are common despite treatment with a gluten free diet (GFD), yet no approved or proven non-dietary treatment is available. Methods In this multicenter randomized, double-blind, placebo-controlled study, we assessed larazotide acetate 0.5, 1, or 2 mg three times daily to relieve ongoing symptoms in 342 adults with CeD who had been on a GFD for ≥12 months and maintained their current GFD during the study. The study included a 4-week placebo run-in, 12-week treatment, and 4-week placebo run-out phase. The primary endpoint was the difference in average on-treatment Celiac Disease Gastrointestinal Symptom Rating Scale score (CeD-GSRS). Results The primary endpoint was met at the 0.5 mg dose of larazotide acetate with fewer symptoms compared with placebo by Modified Intention to Treat (n=340) (ANCOVA p=0.022, MMRM p=0.005). The 0.5mg dose showed effect on exploratory endpoints including, 26% decrease in Celiac Disease Patient Reported Outcome Symptomatic Days (p=0.017); 31% increase in Improved Symptom Days (p=0.034); ≥50% reduction from baseline of weekly average Abdominal Pain Score for ≥6 out of 12 weeks of treatment (p=0.022); and a decrease in Non-GI symptoms of headache and tiredness (p=0.010). The 1 and 2 mg doses were no different than placebo for any endpoint. Safety was comparable to placebo. Conclusions Larazotide acetate 0.5 mg reduced signs and symptoms in CeD patients on a GFD better than a GFD alone. While results were mixed, this study represents the first successful trial of a novel therapeutic agent targeting Tight Junction regulation in patients with CeD who are symptomatic despite a GFD. Clinicaltrials.gov, NCT01396213

SUMMARY Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4+/Vδ1+ intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4+/Vδ1+ IELs was accompanied by the expansion of gluten-sensitive, interferon-γ-producing Vδ1+ IELs bearing T cell receptors (TCRs) with a shared non-germ-line-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vγ4+/Vδ1+ subset among TCRγδ+ IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRγδ+ IEL compartment in CeD.

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Background: Celiac disease (CD) is increasingly recognized in North America and is associated with a peripheral neuropathy.Objective: To report the clinical characteristics and skin biopsy results in patients with CD and small-fiber neuropathy symptoms.

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