Immune-Targeting Therapies in Coeliac Disease Management
Currently, no immune-targeting therapies can be recommended for use in coeliac disease outside of clinical trials, as the gluten-free diet remains the only proven effective treatment. 1
Current Standard of Care
The cornerstone of coeliac disease management remains a strict, lifelong gluten-free diet (GFD), which is effective for most patients but presents significant challenges:
- Adherence difficulties due to cost, restrictive nature, and perceived decreased quality of life 2
- Inadvertent gluten exposure is common despite strict adherence attempts 3
- Some patients experience incomplete mucosal healing despite dietary compliance 3
- A subgroup of patients does not respond adequately to dietary treatment 2
Emerging Immune-Targeting Therapeutic Approaches
Several novel immune-targeting approaches are in development, targeting different aspects of coeliac disease pathophysiology:
1. Gluten Modification Strategies
- Prolyl endopeptidases (PEPs): Enzymes capable of breaking down immunotoxic gluten peptides before they trigger immune responses
- Clinical trials have evaluated combinations with glutamine-specific endoproteases against 2g gluten challenges 1
- Aim to reduce threshold response rather than enable normal gluten consumption
2. Intestinal Barrier Protection
- Larazotide acetate: Tight junction regulator that maintains intestinal barrier function
- Phase IIA trials showed limited effects on intestinal permeability but beneficial effects on symptoms after gluten ingestion 1
- Works by preventing gluten peptides from crossing the epithelial barrier
3. Immunomodulatory Approaches
- Transglutaminase 2 (TG2) inhibitors: Block the enzyme that modifies gluten peptides to enhance immunogenicity
- Peptidomimetic blockers have entered clinical trials 1
- Potential limitation: TG2 is involved in multiple physiological processes, raising concerns about side effects
4. Immunotherapy
- Subcutaneous injection of immunotoxic gliadin peptides: Aims to stimulate immunoregulatory T-cell responses
- Responses would be specific to HLA-DQ2 or DQ8 haplotypes 1
- Phase II trials ongoing
- Hookworm exposure: Being explored as an alternative to GFD but unlikely to benefit all patients 1
5. Genetic Approaches
- Cereal genomics: Attempts to genetically modify wheat cultivars incapable of expressing immunotoxic peptides
- RNA interference techniques may reduce gliadin expression 1
- Limited by high copy numbers in gliadin genes
Clinical Implications and Future Directions
The role of these therapies is likely to be:
Adjunctive to GFD: Most therapies are being developed to reduce the impact of inadvertent gluten exposure rather than replace the GFD 4
Management of refractory disease: Particularly for patients with refractory coeliac disease type I and II who don't respond to dietary management 4
Improving quality of life: By allowing for occasional intentional gluten consumption or reducing anxiety about accidental exposure 5
Practical Considerations
- None of these therapies are currently approved for clinical use outside of research settings 1
- The first generation of pharmacologic agents for coeliac disease may become available within the next 5 years 5
- Patients interested in these approaches should be referred to centers conducting clinical trials
Pitfalls and Caveats
- Immune-targeting therapies may have systemic effects beyond the gut
- Long-term safety data is lacking for most novel approaches
- Cost-effectiveness will be a consideration when these therapies become available
- Therapies will likely complement rather than replace the gluten-free diet 4
- Patient selection will be crucial, as not all patients will benefit equally from these approaches
While promising advances are being made in immune-targeting therapies for coeliac disease, the gluten-free diet remains the mainstay of treatment. Patients should be encouraged to maintain strict dietary adherence while research continues to develop effective pharmacological alternatives.