Objective Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) characterised by a vicious cycle of immune amplification that can culminate in overwhelming inflammation and multiorgan failure. The clinical features of MAS overlap with those of active sJIA, complicating early diagnosis and treatment. We evaluated adenosine deaminase 2 (ADA2), a protein of unknown function released principally by monocytes and macrophages, as a novel biomarker of MAS.
Methods We established age-based normal ranges of peripheral blood ADA2 activity in 324 healthy children and adults. We compared these ranges with 173 children with inflammatory and immune-mediated diseases, including systemic and non-systemic JIA, Kawasaki disease, paediatric systemic lupus erythematosus and juvenile dermatomyositis.
Results ADA2 elevation beyond the upper limit of normal in children was largely restricted to sJIA with concomitant MAS, a finding confirmed in a validation cohort of sJIA patients with inactive disease, active sJIA without MAS or sJIA with MAS. ADA2 activity strongly correlated with MAS biomarkers including ferritin, interleukin (IL)-18 and the interferon (IFN)-γ-inducible chemokine CXCL9 but displayed minimal association with the inflammatory markers C reactive protein and erythrocyte sedimentation rate. Correspondingly, ADA2 paralleled disease activity based on serial measurements in patients with recurrent MAS episodes. IL-18 and IFN-γ elicited ADA2 production by peripheral blood mononuclear cells, and ADA2 was abundant in MAS haemophagocytes.
Conclusions These findings collectively identify the utility of plasma ADA2 activity as a biomarker of MAS and lend further support to a pivotal role of macrophage activation in this condition.
- adenosine deaminase 2
- macrophage activation syndrome
- systemic juvenile idiopathic arthritis
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Handling editor Josef S Smolen
Contributors PL and PAN conceived and designed the study. PL, YH, JS, YL, RB, AW and TD performed the experiments and acquired data. PL, GS, SC, KJH, OH, MHC, FD, EM, MSL, RS, ETR, JN, MBS, LAH and PAN recruited patients and collected samples. MSH provided the method for measuring ADA2 activity and in some cases confirmed results. PL, JS, YL and PAN analysed the data. PYL and PAN drafted the manuscript and all authors edited the manuscript.
Funding This work was supported by the National Institute of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) K08-AR074562 (PL), K08-AR072075 (GSS), R01-AR065538, R01-AR073201, R01-AR075906 and P30-AR070253 (PAN), a Rheumatology Research Foundation Investigator Award (PL), a Boston Children’s Hospital Faculty Career Development Award (PL) and the Fundación Bechara and the Arbuckle Family Fund for Arthritis Research (PAN).
Competing interests None declared.
Patient and public involvement statement This research was done without direct patient involvement beyond sample collection. Patients
did not participate in designing the study, analyzing the data, or drafting the manuscript.
Patient consent for publication Not required.
Ethics approval These studies were approved by the Institutional Review Boards at Boston Children’s Hospital (P00005723), Cincinnati Children’s Hospital Medical Center (2016-2234), University of Pittsburg (PRO16120025) and Brigham and Women’s Hospital (P000664). Informed consent was provided by participants or legal guardians.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.