Table 3.

Selected milestones and current and future research objectives in diagnosis, management, therapeutics and prevention of coeliac disease

Feature (time frame)	Milestone	Research objectives
Diagnosis
Established diagnostic markers of coeliac disease (1950s–)	First descriptions of histological features of gluten enteropathy and subsequent development of capsule biopsy78 for histological diagnosis Advances in serodiagnostics and HLA-DQ genotyping have led to serology-based diagnosis without biopsy36	Future studies need to address the need for diagnosis confirmation by biopsy, particularly in adult populations; regular updates of evidence-based diagnostic guidelines informed by large, well-designed clinical trials
Novel diagnostic markers of gluten immunity and coeliac disease (2000s–)	Detection of peripheral blood CD4+ T cells enable redefinition of coeliac disease and diagnosis without requiring intestinal biopsy while regularly consuming gluten41	Well-designed clinical trials of novel diagnostics; development of accurate blood diagnostics that minimize invasive procedures; biomarkers indicative of gluten immunity that do not require sustained re-introduction of gluten
Management and therapeutics
Centres of clinical excellence and research (1950s–)	Paediatric centres established early, but adult centres for transition of care and the bulk of new diagnoses resulting from increased awareness since the ‘coeliac disease iceberg’ was identified have lagged Misdiagnosis and underdiagnosis of coeliac disease are commonplace, unnecessary use of GFD is widespread and follow-up of patients after diagnosis is inconsistent79	More centres for training health-care professionals in all aspects of medical care of coeliac disease are warranted to enhance current standard of care for diagnosis, management and follow-up of patients; centres integrating patient care and translational research in key areas such as immunology, dietetics and therapeutics development will drive future advances in clinical care
Monitoring on GFD (1960s)	Reversal of intestinal injury with strict GFD reported in children having follow-up capsule biopsy80 Follow-up serology poorly sensitive for mucosal injury on GFD81. Debate continues regarding the utility of follow-up biopsy Quantitative histology studies suggest villous atrophy is under-reported in treated, seronegative coeliac disease82,83 Tools that objectively detect gluten immunogenic peptides84 developed in 2000s	Enhance standard practice for handling and assessing small bowel biopsies to accurately assess villous atrophy; development of molecular markers that quantify mucosal injury; clinical guidelines for integration of new tests such as gluten immunogenic peptides in clinical use and follow-up; development of models of care for specialized dietitian and medical assessment during lifelong GFD
Repurposing drugs for coeliac disease (1970s–)	Many immunosuppressive drugs starting with prednisolone shown to reduce gluten-mediated intestinal injury, but undesirable long-term adverse effects deter their widespread use85	Assessment of pharmaceuticals approved for other indications that target key mediators of gluten-dependent disease and immunity and have acceptable safety profile
Drug development specifically for coeliac disease (2000s–)	‘Druggable’ targets identified: gluten, microorganism–gluten–immune interactions, transglutaminase, epithelial gluten transport, HLA-DQ and gluten-specific immunity53,86 Drug development evolves to include symptom and histological end points87,88 Regulatory approval for treatment of coeliac disease not achieved	Comprehensive assessment of immune and non-immune drug targets to augment or replace GFD; understand mechanisms and interventions to restore gluten-specific immune tolerance; identify cytokines responsible for pathology; advance understanding of transglutaminase effects on gluten and normal tissues; understand gluten metabolism in vivo
Prevention
Prevention of coeliac disease (2000s–)	Prospective gluten feeding studies in at-risk infants failed to identify a window of opportunity to decrease coeliac disease risk89. Gluten dose and infections and/or microbial changes might affect risk	Development of strategies to reduce the age of diagnosis and overall incidence of coeliac disease; understand potential coeliac disease and progression from health to development of active disease

GFD, gluten-free diet.