PERSONALIZED MANAGEMENT OF CELIAC DISEASE: RISK STRATIFICATION AND NOVEL STRATEGIES FOR COMPLICATED PATIENTS

SUMMARY Background. Celiac disease is a widespread autoimmune disease diagnosed at increasing frequency. Celiac patients regularly attend medical services and present a benign course. The knowledge of clinical and biological factors predictive of malignant evolution is poor. Thus, management of such a large population of patients still lacks evidence-based criteria in order to target diagnostic strategies to the subgroup ”at-risk” to develop small bowel complications. Aim. To identify celiac patients’ characteristics associated to a higher probability of complicated course and to evaluate the role of available screening and diagnostic approaches and coming biomarkers for the early diagnosis of small bowel malignancies in celiac disease. Methods. A population-based registry (Varese province) was used to estimate the risk of intestinal lymphomas in undiagnosed celiac subjects, taking into consideration different settings of celiac prevalence and relative risks for intestinal lymphomas in comparison with the incidence of the lymphomas in the population. Treated celiac patients were selected on the basis of clinical flags of non-responsiveness or lack of compliance to treatment for targeted small bowel endoscopic examinations, evaluating the diagnostic yield of capsule endoscopy and double-balloon enteroscopy in the recognition of intestinal tumors at an early stage. miRNA profiles in type I and II enteropathy-associated T cell lymphoma were explored to identify eventual celiac related signature to be applied to subgroups of patients with different levels of risk for stratification purpose. Results. In the considered population (815,362 inhabitants), during a five years period, the relative risks of undiagnosed celiac disease for gastrointestinal B- and T-cell lymphomas ranged from 1.0 to 2.0 for 1:100 celiac disease prevalence. In the selected series of 105 celiac patients, the diagnostic yield of capsule endoscopy and double-balloon enteroscopy for malignancies was 2.9%. When compared to the registered population, the relative risk for adenocarcinoma and neuroendocrine tumors in the studied cohort was 410 (CI 95% 102-1640, P<0.0001). Double-balloon enteroscopy was useful to histologically characterize even minor lesions detected at capsule endoscopy. A single miRNA (under patent) resulted upregulated in type I enteropathy-associated T cell lymphoma with confirmation at qPCR (p=0.0012). When mucosa specimen were evaluated, miRNA profiling of refractory patients was highly homogeneous (p=0.001 vs both type I and II enteropathy-associated T cell lymphoma). Conclusions. Undiagnosed/untreated celiac patients did not show a different risk of developing gastrointestinal lymphomas than the general population. Capsule endoscopy and double-balloon enteroscopy could be considered at an early stage in the diagnostic management of a subset of celiac patients at risk for small bowel malignancies. We expect to identify miRNA signatures as a novel biomarker predictive of disease aggressiveness to support the implementation of a personalized clinical approach, in order to optimize resources employment and, through a timely pharmacological intervention, improve prognosis of these subset of celiac patients.