Gluten-related disease—more than a gut punch

Patients often ask me in clinic whether going on a gluten-free diet will help treat their rheumatoid arthritis or lupus, improve their energy, or reduce their fatigue and alopecia. Sometimes I hear from a patient that they tried going “gluten-free” and found that their arthritis, fatigue, or other symptoms improved. I have heard this from occasional patients who have been appropriately tested for and do not have celiac disease.

Sharma and colleagues¹ in this issue of the Journal discuss the distinction between true celiac disease and other defined gluten- and wheat-sensitivity disorders. As I was reading the manuscript, not surprisingly my mind wandered to consider the apparent link between nonceliac gluten “sensitivity,” gluten allergy, celiac disease, and manifestations of systemic autoimmune disease. Although a patient’s subjective symptom relief while adhering to a very rigid gluten-free diet can easily be dismissed as being due to a placebo effect, this may not be the complete explanation. Patients with celiac disease or other gluten-sensitivity disorders have a documented increase in objective findings of systemic autoimmune disease and autoantibodies,^2,3 both of which may be ameliorated by sticking to a gluten-free diet.

Some patients with celiac disease manifest the fairly unique autoimmune complication dermatitis herpetiformis. This and other extraintestinal manifestations may precede gastrointestinal symptoms. The predilection to develop extraintestinal autoimmune disease has not been fully explained, but in patients with classic celiac disease it likely relates to the immunogenetic background of having specific heterodimers genetically coded at the human leukocyte antigen (HLA)-DQ2 and HLA-DQ8 loci that confer a high risk for celiac disease. These alleles are also present more frequently in several nonceliac systemic autoimmune diseases. In those patients with intestinal injury due to celiac disease or gluten or wheat allergy, autoimmune disease may be triggered by increased intestinal permeability, with resultant systemic exposure to novel immunogens or migrating activated T cells.

The biology supporting celiac disease as an autoimmune process linked to gluten peptide–associated T-cell activation is strong. In genetically susceptible individuals, gluten peptides that have been deamidated by transglutaminase 2 (TG2; also known as tissue transglutaminase) have enhanced binding to specific HLA-DQ2 and -DQ8 molecules on antigen-presenting cells. The deamidation results in a more positively charged gluten peptide that more readily adheres to the negatively charged antigen-binding groove of the HLA molecule. This triggers a CD4+ T-cell–mediated immune response, resulting in the clinical and histopathologic phenotype of intestinal celiac disease.

Approximately one-third of the population in the United States, independent of race, carry the celiac disease–associated DQ2 or DQ8 haplotype.⁴ While less than 5% of individuals with these haplotypes will develop celiac disease, nearly 100% of patients with celiac disease have them. What is unique about the patients at genetic risk who develop fully expressed celiac disease is incompletely understood.

The presence of (mainly) immunoglobulin A antibodies against the TG2 enzyme is the hallmark biomarker for diagnosing celiac disease. These antibodies will “disappear” in the absence of gluten; hence, patients with seropositive celiac disease may appear seronegative if tested when faithfully adhering to a gluten-free diet. Surprisingly, despite the strength of anti-TG2 antibody as a biomarker, the antibody does not seem to be pathogenic, although experimentally it has some effects on the intestinal histology in the presence of gluten.

The association between celiac disease and other autoimmune disorders has been recognized since the 1970s. As screening for anti-TG2 antibody became universally available for diagnosis, it became clear that celiac disease is often present (perhaps 10 times more commonly) in patients with other autoimmune diseases. Muddling our understanding of the pathophysiology linking celiac- and gluten-associated systemic diseases is the observation that nonceliac gluten-sensitive patients (by definition seronegative for anti-TG2, and not nearly as enriched with the DQ2 and DQ8 haplotypes) also seem to have an increase in nonspecific clinical symptoms such as fatigue, brain fog, and arthralgias, as well as Hashimoto thyroiditis, dermatitis herpetiformis, and varied rheumatologic and neurologic syndromes.⁵

Hashimoto thyroiditis is the most commonly codiagnosed autoimmune disease in patients with celiac disease. Type 1 diabetes mellitus is also over 2 times more prevalent in patients with celiac disease compared with the general population, and is especially prevalent in patients with juvenile-onset celiac disease. The prevalence of systemic lupus erythematosus, Sjögren syndrome, and biliary cirrhosis is also increased.^3,6 It has been suggested that testing for celiac disease should be considered in adults with defined systemic autoimmune diseases who have unusual features or don’t respond as expected to therapy, particularly those with symptoms that cannot be directly attributed to disease-related organ damage.⁷

So while I don’t routinely recommend gluten-free diets to all my patients, I have grown to listen more intentionally, and less dismissively, to my patients who describe their positive experiences with going gluten-free.

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