Caracterização clínico molecular das doenças inflamatórias intestinais de início muito precoce

Abstract

Introduction: Very early onset inflammatory bowel disease (VEOIBD) represents a subgroup of Pediatric Inflammatory Bowel Disease (IBD) with symptoms occurring before the age of 6, accounting for 4 to 10% of IBD cases. Its incidence has been increasing by about 7% per year. Children present severe cases with pancolonic involvement, low response to treatment, and high morbidity and mortality. Genetics plays a strong role in etiology, making molecular diagnosis essential to guide more assertive treatment. Objective: This study aimed to characterize VEOIBD and demonstrate the importance of molecular diagnosis. Methods: Children with a confirmed diagnosis of IBD and symptom onset before the age of 6 underwent a targeted genetic panel (TGP) for Inborn Errors of Immunity (IEI). Information on clinical presentation, diagnosis, and treatment was compiled retrospectively from a semi-structured questionnaire prepared by the researchers. Patients were recruited from different services, chosen randomly, and included in the study after obtaining consent from legal guardians. Genetic test results were analyzed, and genes associated or possibly associated with IBD were selected. Results: Thirty-two participants were included, with a mean age of symptom onset of 2 years and 3 months and a diagnosis age of 4 years and 2 months, with a median of 10 months for diagnostic confirmation. There was a predominance of females and a positive family history of IBD in 22%. Half of the patients were diagnosed with Ulcerative Colitis (UC), 40.63% with Crohn’s Disease (CD), and 9.37% with unclassified IBD (IBD-U). Bloody diarrhea was the most prevalent symptom, followed by abdominal pain. Weight deficit was observed in 43.75% and extraintestinal manifestations in 40.62%. Anemia was observed in 47%, elevated systemic inflammatory markers in 84%, and thrombocytosis in all patients. Fecal calprotectin was elevated in all patients who had their levels measured. Moderate to severe disease activity, with predominant colonic involvement and little ileal involvement, was prevalent. In histological evaluation, chronic lymphoplasmacytic inflammatory infiltrate with marked activity was the most common finding. Corticosteroids were used to induce remission in all patients. Biologics were the first choice in two patients. Thiopurines were widely used in combination therapy. Mesalazine was used in a few patients with UC. Half of the patients were escalated to anti-tumor necrosis factor alpha (anti-TNF). Initial treatment failure was observed in 59.63%. In the evaluation of genetic tests, molecular diagnosis was possible in 34% of patients, including seven patients with pathogenic variants, with recurrence of the TNFRSF13B gene, and four patients with increased risk variants for IBD related to NOD2. Regarding variants of uncertain significance (VUS), five patients had variants with possible association with IBD. Conclusion: The study demonstrated the more aggressive nature of VEOIBD, requiring early use of combined immunosuppressants and biologics. Additionally, the importance of molecular diagnosis for more accurate diagnosis and better understanding of immune interactions in these patients was highlighted, allowing for targeted therapeutic choices for the specific pathological pathway involved.