Annals of Medicine

Changing the Paradigm in the Diagnosis of Celiac Disease

Celiac disease, a systemic immune-mediated disorder triggered by gluten in genetically predisposed individuals, has traditionally been diagnosed through serological testing and confirmatory duodenal biopsy. While effective for detecting classic disease, these approaches are limited in identifying early, subclinical, or atypical presentations and are insufficient for diagnosing complex cases such as refractory coeliac disease. Recent technological advances now provide unprecedented resolution for characterizing disease predisposition and immune response. High-throughput next-generation sequencing enables precise HLA genotyping, revealing susceptibility profiles beyond conventional serotyping. Multiplex assays now enable automated, high-throughput measurement of disease-specific autoantibodies with high diagnostic accuracy using minimal sample volumes, making them well suited for large-scale screening. Emerging biomarkers, such as interleukin-2 (IL-2), capture gluten-specific T-cell activation and can be used to detect disease even in patients adhering to a gluten-free diet. Additionally, advanced immunostaining combined with artificial intelligence–driven image analysis provides objective, high-throughput evaluation of histopathology slides, uncovering subtle mucosal changes undetectable by traditional microscopy. As diagnostic capabilities evolve and highlight the importance of extra-intestinal manifestations and systemic immune features, there is a growing move to consider redefining celiac disease as a systemic immune disorder rather than solely an enteropathy, embracing a broader conceptualisation that reflects its diverse clinical presentations.

Current diagnostic algorithms fail to capture the complexity and early manifestations of celiac disease, particularly in asymptomatic or atypical cases. Conventional serology and biopsy-centered approaches often miss subtle immune activation and early mucosal changes, overlooking the dynamic interplay between genetic susceptibility, environmental triggers, and immunological perturbations. High-resolution HLA profiling through next-generation sequencing provides precise risk stratification, while multiplex autoantibody assays including LIPS, ADAP, and chemiluminescent immunoassays, offer sensitive detection of early immune responses. Furthermore, immunostaining combined with artificial intelligence–driven analysis of histopathology slides allows objective, high-throughput evaluation, revealing changes invisible to traditional microscopy. Integrating these molecular, immunological, and digital pathology approaches addresses critical diagnostic gaps, enabling earlier detection, more accurate risk assessment, and improved patient stratification, ultimately supporting a shift toward precision, proactive management of celiac disease across its clinical spectrum. Further, as the systemic nature of celiac disease becomes evident, there is a need to consider redefining it as a systemic immune disorder rather than solely an enteropathy.

We propose a paradigm shift in celiac disease diagnosis, moving from reactive, biopsy-dependent approaches to proactive, precision-based strategies that capture the full spectrum of disease. Leveraging high-resolution HLA genotyping, multiplex autoantibody detection, and biomarkers such as IL-2 that identify gluten-specific T cell at the core of celiac disease pathogenesis. Together, these advances may enable earlier, more accurate detection and risk assessment of patients. Complementing these molecular and immunological tools, immunostaining coupled with AI–driven histopathology provides objective, quantitative assessment of subtle intestinal changes, enhancing diagnostic sensitivity and reproducibility. This integrated framework enables a precision medicine approach including early intervention, individualized monitoring, and precise risk stratification. Beyond improving clinical outcomes, this approach reshapes understanding of celiac disease pathophysiology, highlighting the continuum from genetic predisposition and immune activation to intestinal damage. By uniting next-generation diagnostics with digital pathology, we establish a translational model for the early detection and management of autoimmune disorders, redefining the clinical and research landscape.

Keywords:

1. Celiac disease diagnosis
2. Next-generation HLA sequencing
3. Multiplex autoantibody assays
4. IL-2 biomarker
5. Digital pathology

Guest Advisors

Daniel Agardh. Celiac disease and Diabetes Unit, Department of Clinical Sciences, Lund University

Daniel Agardh, MD, PhD, is a clinical researcher and paediatric gastroenterologist specializing in celiac disease and autoimmune disorders. He focuses on translational immunology, using next-generation HLA sequencing and multiplex autoantibody assays such as ADAP to improve early diagnosis and screen at-risk populations. He leads multicenter screening and intervention studies, including TEDDY and TRIAD, aimed at understanding disease onset and implementing preventive strategies. He has published extensively in peer-reviewed journals and coordinates international collaborations to redefine population-based diagnostic and intervention approaches in celiac disease.

Jason A. Tye-Din. Walter and Eliza Hall Institute Royal Melbourne Hospital, Australia

Jason Tye-Din leads the Coeliac Research Laboratory at WEHI, is a gastroenterologist at The Royal Melbourne Hospital, and serves as Director of the Snow Centre for Immune Health. His research focuses on gluten immunity to advance understanding, diagnosis, and management of coeliac disease. He collaborates with academic and industry partners, leads the Coeliac Theme of the ENDIA longitudinal study to investigate disease development, and oversees a drug trials site at The Royal Melbourne Hospital.

Kalle Kurppa. Faculty of Medicine and Health Technology, Tampere University, Finland

Kalle Kurppa is Professor of Promotion of Pediatric and Adolescent Health at Tampere University. Following his basic training in pediatrics, he has worked as a clinician, researcher, and Professor of Pediatrics. Dr. Kurppa has authored over 200 peer-reviewed international publications in the fields of clinical and translational gastroenterology, with a particular focus on celiac disease.

All manuscripts submitted to this Article Collection will undergo a full peer-review; the Guest Advisors for this Collection will not be handling the manuscripts (unless they are an Editorial Board member).

The Guest Advisors declare the following Conflicts of Interests:

• Daniel Agardh is a member of the Scientific Advisory Board for Sanofi.
• Jason A. Tye-Din has privately or via his institute been a consultant or advisory board member for Anatara, Anokion, Barinthus Biotherapeutics, Chugai Pharmaceuticals, DBV Technologies, Dr Falk, EVOQ Therapeutics, Equillium, Forte Biosciences, IM Therapeutics, Janssen, Kallyope, Mozart Therapeutics, Sonoma Biotherapeutics, Takeda, TEVA and Topas, has received research funding from Barinthus Biotherapeutics, Chugai Pharmaceuticals, Codexis, DBV Technologies, Kallyope, Novoviah Pharmaceuticals, Topas and Tillotts Pharmaceuticals. He is an inventor on patents relating to the use of gluten peptides in celiac disease diagnosis and treatment.
• Kalle Kurppa has received lecture fees and been involved in consultations with the following companies: Sanofi, Takeda, and Thermo Fischer

Please review the journal scope and author submission instructions prior to submitting a manuscript.

The deadline for submitting manuscripts is 17th August 2026.

Please contact Commissioning Editor Francis Straw at [email protected] with any queries or for details about APC discounts. 

Please be sure to select the appropriate Article Collection from the drop-down menu in the submission system. Please select Gastroenterology from the list of available sections during submission. Failure to select the appropriate Article Collection or Section name can result in delays.