Treatment of gluten-related disorders

A gluten-free diet (GFD) is the current standard of care for all patients with celiac disease (CeD) including its classic, nonclassic, and silent forms, as well as for dermatitis herpetiformis, gluten ataxia, and nonceliac gluten sensitivity. Following a GFD involves restricting certain food items, thus care must be taken to ensure a balanced diet that provides both macronutrients and micronutrients. Further, a GFD requires major lifestyle changes for the patients and their families. Moreover, despite attempts to maintain a strict GFD, gluten exposure is common given the extensive use of gluten in the food industry. Hence, repeated and accurate counseling of patients and their families by skilled/specialized dieticians forms an essential part of the treatment. Other best practices to be considered by physicians include monitoring and correction of nutritional deficiencies related to CeD, prevention of bone loss, vaccinations for certain infections, voluntary screening of family members, and keeping a high index of suspicion for CeD-associated autoimmune disorders and extraintestinal manifestations affecting the liver, bone, etc. All patients with CeD should be assessed at regular intervals for improvement and adherence on a GFD, since almost a third of patients fail to show a satisfactory response. Monitoring and appropriate treatment of issues uniquely associated with a GFD, including a higher risk of metabolic syndrome, fatty liver, dietary deficiencies, and constipation, are also important. Interestingly, insights gleaned into the pathogenesis of CeD over the past two decades have provided options for targeted therapies that may be useful as alternatives/adjunctive to a GFD. Based on their mechanisms of action, these therapies may be classified as belonging to one of the following approaches. The first approach involves decreasing the immunogenicity of gluten, using glutenases like latiglutenase or kuma, genetic modification of wheat that is the most common source of gluten, microwave thermal treatment of hydrated wheat kernels, and gluten pretreatment prior to ingestion, with either bacterial/fungal-derived endopeptidases or microbial transglutaminase. The second approach involves intraluminal gluten-binding drugs like polymer p(HEMA-co-SS), single-chain fragment variable, and antigluten antibody AGY. The third approach antagonizes zonulin, a molecule regulating intestinal epithelial tight junctions that mediate gliadin transport. The fourth approach involves intestinal tissue transglutaminase enzyme inhibition to decrease deamidation of gliadin peptides taken-up by the mucosa, into epitopes with enhanced immunogenicity, using agents like ZED1227, si-RNA therapy, etc. The fifth approach seeks to prevent downstream immune activation after exposure to gliadin peptides, using Human Leukocyte Antigen blockers that prevent presentation of gluten-derived antigens by dendritic cells to T cells, immune-tolerizing therapies like the vaccine Nexvax2 and the nanoparticle-based Tolerogenic Immune Modifying Particles-Glia, cathepsin inhibitors, corticosteroids, elafin, etc., and anticytokine agents targeting interleukin-15/interleukin-21, CCR9–CCL25 interaction, γc receptor, etc. Overall, among the novel therapies on the anvil, glutenases, and strategies that modulate immune activation appear to be some of the promising therapies based on preliminary results.