Coeliac Disease (CD) Quiz

Coeliac Disease (CD)

• CD is a chronic immune-mediated systemic disease triggered by gluten and related prolamins in genetically susceptible individuals.
• The only effective treatment available is a strict lifelong gluten-free diet (GFD), which can be difficult to adhere to and may lead to nutritional deficiencies.
• Non-adherence to a GFD is estimated to be as high as 50%, particularly among adolescents and young adults.

Definition and Prevalence

• CD is a multifactorial illness triggered by a genetically predisposed environment in relation to gluten ingestion.
• The cumulative risk of CD up to the age of 15 is augmented by more than 10-fold when at least one HLA risk allele is present.
• 95-97% of coeliac patients possess DQ2, and the rest exhibit DQ8.
• The prevalence of CD in the general population ranges between 0.1 and 1% in countries such as Spain, France, Italy, and Finland.

Pathophysiology and Clinical Manifestations

• CD is a complex immune-mediated enteropathy that can occur in genetically predisposed people of all ages after ingesting gluten.
• Gluten intake leads to an immune response in the small bowel of CD patients, resulting in small intestinal inflammation.
• The clinical presentation of CD has evolved over the past few decades, with a trend towards an increased symptomatic prevalence and the observation of non-classical or subclinical phenotypes.

Current Management Guidelines

• The only current treatment for CD is a strict gluten-free diet, which can be a source of anxiety and depression.
• Life-long adherence to a gluten-free diet is necessary, and regular contact with a dietitian can provide ongoing support and improve quality of life.
• Even small amounts of gluten (20mg per day) can cause an immune response and further damage to the intestine.

Pharmacological Interventions

• There is a need for non-dietary treatments for CD, as the current gluten-free diet is not always effective or easy to follow.
• Novel approaches to gluten intolerance include preventing the immune response to gluten, rather than breaking down the gluten itself.
• Biologics, such as monoclonal antibodies, and local anti-cytokine therapy are potential avenues for treating CD.
• Therapies that target multiple pathways within the immune response may be required to treat CD.

Enzyme Supplements

• Enzyme supplements, such as prolyl endopeptidases (PEPs), can break down gluten into smaller, non-immunogenic peptides.
• The inhibitory effect of PPIs on common PEPs is a concern, and dosage frequency and form are important factors to consider.

Immunosuppressive Agents

• Immunosuppressive agents, such as azathioprine or methotrexate, may be used in patients with refractory CD, but they can have significant side effects.

Novel Therapeutic Approaches

• ALV003, a 6-mer peptide, has been shown to degrade gluten and reduce the immune response to gluten.
• Larazotide acetate, a mucolytic enzyme, is currently being investigated in phase II trials.
• Atvaercept, a mixed IL-2/IL-15 antagonist, has been shown to improve histological and serological duodenal lesions in a phase 1 trial.

Glutenase Enzymes

• Glutenase enzymes can be used to break down gluten into smaller, non-immunogenic peptides.
• The currently evaluated dosage of glutenase enzymes varies from 0.4 to 50 AU per gram of gluten ingested.
• Synthetic work is ongoing to optimize the therapeutic effect of glutenase enzymes.### Clinical Trials and Enzyme Formulations
• Clinical trials have shown that enzyme formulations can decrease GI symptoms after gluten intake when administered together with a meal containing 11g of gluten.
• Additional data is required, especially on the possible preferential administration of this drug in newly diagnosed celiac patients before adhering to a gluten-free diet.

Limitations of Gluten-Free Diet

• Celiac disease (CD) is primarily treated by a strict gluten-free diet (GFD), which is not completely effective and difficult to maintain.
• A recent prospective study showed that 88% of CD patients do not adhere strictly to a GFD.
• This leads to higher rates of disease persistence, relapse, and complications associated with poor response to a GFD.

Alternative Therapeutic Strategies

• Rational non-diet responsive strategies for CD management include the adjunctive use of specific drugs acting against gluten, parallel to an incomplete compliance to a GFD.
• Pancreatic proteases and glutenases enzymes have been tested for gluten breakdown and could be included in formulations to improve gluten hydrolysis in the gastrointestinal tract.

Vaccine Development

• Molecules like ZED1227, a small molecular mass inhibitor of transglutaminase-2, can block the amplification step of the gluten immune response.
• Alternative therapeutic strategies include immune modulation, such as Treg induction or local secretory IgA induction, to dampen the local intestinal immune response.
• Treatments based on supporting epithelial barrier integrity and decreasing gut inflammation are also being explored.

Gluten Neutralization

• Gluten neutralization is an alternative therapeutic strategy that involves the "enzymatic break down" of gluten peptides in the gut that are resistant to gastric and pancreatic digestion.
• Several research groups are developing mixtures of proteolytic enzymes to destroy deamidation potential and/or T-cell stimulating epitopes in the gut.

Clinical Trials and Evidence-Based Medicine

• Novel targets for drug discovery in celiac disease include enzyme therapy, amylase/trypsin inhibitor, and FasL inhibitor, among others.
• Clinical trials are ongoing to evaluate the efficacy and safety of these novel therapies.

Novel Nondietary Therapies for Celiac Disease

• Patients with celiac disease must maintain a stringent lifetime gluten-free diet, but additional treatment options are needed.
• Recently, the focus has shifted towards immunological, regulatory, and epithelial targets, which may yield more specific and less toxic treatments.
• Several novel therapies have shown promise in clinical trials, including vilazodone, larazotide acetate, and anti-IL-15 antibodies.

Outcome Measures in Coeliac Disease Trials

• Patients with coeliac disease suffer from ongoing symptoms and slow and incomplete mucosal healing during a gluten-free diet.
• Alternative treatments are needed, and a large number of potential targets for treatments have been identified.
• Outcome measures in CD therapeutic trials have been summarized by a recent study and expert-based recommendations, including patient perspectives.

Future Directions in Celiac Disease

• In 2016, a study demonstrated that colorectal T lymphocytes can be selectively eliminated using the humanized monoclonal antibody anti-CD3 visilizumab, inducing remission in 45% of patients with operative anemia who failed to respond to a gluten-free diet.
• Another promising therapeutic approach is to reduce the specific inflammatory response to gluten-derived peptides.
• Silencing genes that encode HLA-DQ2 and HLA-DQ8 using small inhibitory RNA may be a viable approach.
• Monoclonal antibodies that inhibit the traffic of mucosal T cells exposed to gluten-derived peptides, such as natalizumab, may be helpful in treating refractory celiac disease.
• Other drugs being explored include vedolizumab, rebrocholimab, and cilengitide.

Patient Education and Adherence

• Not all celiac patients find dietary compliance to be simple to achieve due to complexities such as identifying gluten-containing components in food packaging, dining out, and socializing.
• Dietitians receive favorable overall assessments for providing dietary advice to patients.
• Celiac disease is a systemic disorder triggered by gluten ingestion in genetically susceptible individuals and is more frequent than formerly believed.
• The only successful therapy for celiac disease is a gluten-free diet, which excludes wheat, rye, and barley.

Importance of Education and Counseling

• Physicians should properly educate and counsel patients to ensure compliance with medications and prevent drug-nutrient interactions, adverse reactions, and side effects.
• Patients' education and counseling are crucial when prescribing medications to improve adherence and prevent long-term use of certain drugs.
• Pharmacotherapy for celiac disease involves the use of systemic or topical medicinal substances to prevent, ameliorate, or cure part of the disease or its symptoms as an adjunct to a gluten-free diet and vitamin and mineral supplementation.

Strategies for Improving Adherence

• New therapeutic targets have been identified, including the characterisation of Th1 and Th17 driven IFN- and IL-17A-driven inflammation.
• Targeting Zonulin receptor (ZOT-R) has a compelling biological rationale and has led to a recent large phase IIa trial with a micronutrient conjugated, ZOT-R-inactivating monoclonal antibody.
• Technologies designed to assist safe gluten consumption, including advice, smartphone applications, monitoring devices, shared care packages, meal plans, and dietary aids, can help educate patients and improve GFD adherence.
• A strict, lifelong gluten-free diet is the cornerstone of managing celiac disease, but it is difficult to adhere to, with around 50% of patients having dietary transgressions during the preceding 6-12 months.

Conclusion and Future Perspectives

• The recent development of innovative drugs is expanding therapeutic opportunities for patients with celiac disease.
• The need to supplement GFD for persistent CD has resulted in the design of pharmacotherapy strategies differently from those devised for CD prevention.
• Treatment with anti-Zonulin is a genuine new strategy that targets the increased intestinal permeability of gluten-sensitive patients.
• The new induction of gluten-tolerance by gluten-oral delivery is a novel approach that may be considered for subjects who do not want preventive treatments but look for protection and eventual cure.