D2.337 - REMA Score Outperforms C-kit and Tryptase in Identifying Mast Cell Disorders in Hymenoptera Venom Allergy

Accurately identifying underlying mast cell disorders (MCD), such as systemic mastocytosis and monoclonal mast cell activation syndrome (MMAS), is vital for managing severe Hymenoptera venom allergy (HVA). These patients face a significantly higher risk of recurrent, life-threatening reactions. Current screening includes the Risk Evaluation of Mastocytosis in Anaphylaxis (REMA) score, baseline serum tryptase, and peripheral blood c-kit D816V mutation analysis. We evaluated the effectiveness of these markers in identifying MCD.

We analysed a single-center cohort of 101 patients referred for venom immunotherapy (VIT). The cohort was 52% female and 48% male. Patients were sensitised to wasp venom in 73 cases (72%), bee venom in 25 (25%), and dual sensitisation in 3 (3%). Reaction severity was graded using the Ring and Messmer scale. Screening markers (REMA score, tryptase, and c-kit mutation) were correlated with confirmed MCD diagnoses using Spearman’s rho.

Seven patients were diagnosed with confirmed MCD: five with systemic mastocytosis, one with MMAS, and one undergoing characterisation. All seven cases experienced high-grade systemic reactions (severity ≥3) and achieved a REMA score ≥2, demonstrating excellent predictive sensitivity. Peripheral blood c-kit mutations were detected in four cases. Notably, two patients with bone marrow-confirmed mastocytosis had negative peripheral c-kit results, while a third bone marrow confirmed case did not undergo peripheral c-kit mutation testing. One patient with confirmed MCD presented with a normal baseline tryptase (<11 μg/L). Conversely, in two patients with REMA <2 and elevated baseline tryptase, MCD was excluded by bone marrow biopsy, suggesting hereditary alpha-tryptasemia (HAT) although this was not confirmed by genetic testing. Correlation analysis showed c-kit had the strongest correlation with MCD (rho=0.805), followed by REMA score (rho=0.424) and baseline tryptase (rho=0.387).

Our data highlight limitations of peripheral blood c-kit genetic testing and baseline tryptase as screening tools for MCD in HVA. The REMA score performed strongly even when standard molecular and biochemical markers were inconclusive. We support a lower threshold for hematology review when the REMA score is ≥2 to mitigate missed or delayed MCD diagnosis.