Secondary hemophagocytic lymphohistiocytosis: prognostic model and early markers in patients with systemic juvenile idiopathic arthritis. Results of a cohort retrospective study
Authors:   National Medical Research Center of Children's Health, Moscow, Russian Federation, Kriulin I.A. ,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Alexeeva E.I. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation,   Association of Pediatric Rheumatologists, Moscow, Russian Federation, Shilkrot I.Yu. ,   Association of Pediatric Rheumatologists, Moscow, Russian Federation,   National Association of Non-Governmental Medical Organizations, Moscow, Russian Federation, Dvoryakovskaya T.M. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation,   Association of Pediatric Rheumatologists, Moscow, Russian Federation
Published: March 2023

Background. Secondary hemophagocytic lymphohistiocytosis (sHLH) is a potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA) characterized by hyperinflammation and a variety of clinical and laboratory manifestations. This condition is also referred to as macrophage activation syndrome (MAS) in patients with rheumatic diseases, including those with sJIA. In this article, we use the term sHLH. Approximately 40% of sHLH cases are asymptomatic, especially in patients who receive biologicals. Thus, the development of a prognostic model and identification of early sHLH markers in sJIA patients will enable timely initiation of anti-inflammatory and immunosuppressive therapy. Objective. To develop a prognostic model and identify early sHLH markers in sJIA patients. Methods. This study included 100 sJIA patients who were examined and treated in the Department of Rheumatology, National Medical Research Center for Children's Health between August 2010 and May 2021. A total of 114 sHLH episodes were registered among study participants. We analyzed medication history, as well as clinical and laboratory parameters reflecting the activity of sHLH and sJIA as potential early markers of sHLH. Multivariate logistic regression analysis was used to assess the predictive value of these markers for sHLH development. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each factor to evaluate its significance. Receiver operating characteristic (ROC) curves were constructed to assess the sensitivity and specificity of the model. Results. We analyzed a number of factors as potential early sHLH markers, including medication history (treatment with oral or injectable glucocorticoids (GCs) before sHLH, immunosuppressants (methotrexate, cyclosporine, or leflunomide), and biologicals (tocilizumab, canakinumab, adalimumab, etanercept)), clinical signs (fever, rash, hepatomegaly, splenomegaly, lymphadenopathy, myalgia, hemorrhagic syndrome, central nervous system (CNS) lesions, kidney lesions, lung lesions, heart lesions), and laboratory parameters (hemoglobin, absolute count of red blood cells (RBCs), white blood cells (WBCs), neutrophils, lymphocytes, and platelets, erythrocyte sedimentation rate (ESR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), creatinine, blood urea, c-reactive protein (CRP), ferritin, triglycerides, procalcitonin (PCT), total protein, albumin, blood electrolytes (sodium, potassium, chlorides, iron), coagulation parameters (Quick prothrombin, thrombin time, prothrombin time, international normalized ratio (INR), partial thromboplastin time (APTT), D-dimer, fibrinogen, fibrin monomer, von Willebrand factor, protein S, and protein C). Our prognostic model demonstrated that the following variables were significant predictors of sHLH in sJIA patients: lymphadenopathy, red blood cell count <4.34 × 106 cells/mL, platelets <208 × 103 cells/mL, serum chlorides <101.9 mmol/L, and serum lactate dehydrogenase >412 Units/L. The specificity of the model was 98.0%; the overall accuracy was 95.6%. The area under the ROC-curve (AUC) was 0.954 ± 0.027 (95% CI 0.902–1.000; р < 0.001). Conclusion. The most reliable prognostic markers of sHLH in sJIA patients are undoubtedly heterozygous mutations in the genes of primary (familial) hemophagocytic lymphohistiocytosis. In addition to that, lymphadenopathy, decreased RBC and platelet count, decreased serum level of chloride, and elevated serum LDH in sJIA patients can be interpreted as early sHLH markers and, therefore, considered as an indication to enhance anti-inflammatory and immunosuppressive therapy. Key words: secondary hemophagocytic lymphohistiocytosis, systemic juvenile idiopathic arthritis, early markers, prognostic model