The challenge of early diagnosis of autoimmune lymphoproliferative syndrome in children with suspected autoinflammatory/autoimmune disorders.

To test the usefulness of an extended panel of lymphocyte subsets (LS) in combination with Oliveira's diagnostic criteria for the identification of autoimmune lymphoproliferative syndrome (ALPS) in children referred to a pediatric rheumatology center.patients referred from 2015 to 2018 to our Rheumatology Unit for an autoimmune or autoinflammatory condition were retrospectively analyzed. Oliveira's required criteria (chronic lymphoproliferation and elevated DNT) were applied as first screening. Flow cytometry study included double negative CD4-CD8-TCR αβ+T lymphocytes (DNT), CD25+CD3+, HLA-DR+CD3+T cells, B220+T cells, and CD27+B cells. Data were analyzed with an univariate logistic regression analysis, followed by a multivariate analysis. Sensitivity and specificity of the Oliveira's required criteria were calculated.264 patients were included in the study and classified as: i) autoimmune diseases (26); ii) juvenile idiopathic arthritis (JIA) (35) iii) monogenic systemic autoinflammatory disease (SAID) (27); iv) PFAPA syndrome (100); v) systemic undefined recurrent fever (SURF) (45); vi) undetermined-SAID (14); vii) ALPS (17). Oliveira's required criteria displayed a sensitivity of 100% and specificity of 79%. When compared with other diseases the TCRαβ+B220+ lymphocytes were significantly increased in ALPS patients. The multivariate analysis revealed 5 clinical/laboratory parameters positively associated to ALPS: splenomegaly, female gender, arthralgia, elevated DNT and TCRαβ+B220+lymphocytes.Oliveira's required criteria are useful for the early suspicion of ALPS. TCRαβ+B220+ lymphocytes should be added in the diagnostic work-up of patients referred to pediatric rheumatology unit for a suspected autoimmune or autoinflammatory condition, providing a relevant support in the early diagnosis of ALPS.

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Authors: Leonardo Oliveira Mendonça, Caterina Matucci-Cerinic, Paola Terranova, Federica Casabona, Francesca Bovis, Roberta Caorsi, Francesca Fioredda, Elena Palmisani, Alice Grossi, Daniela Guardo, Marta Bustaffa, Stefano Volpi, Isabella Ceccherini, Angelo Ravelli, Carlo Dufour, Maurizio Miano, Marco Gattorno