Background/Purpose:       Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal pathologic inflammatory process resulting from impaired immune function due to inherited gene mutations or secondary to viral infections or immune-mediated disease.   Systemic Juvenile Idiopathic Arthritis (SoJIA) is also characterized by dysregulated pro-inflammatory cytokines and systemic inflammation.  SoJIA can lead to Macrophage Activation syndrome (MAS), a life threatening cytotoxic T cell dysfunction, often resembling HLH. MUNC13-4 mutation are found in up to 30% of children with inherited HLH as well as some patients with MAS secondary to SoJIA. The phenotypic overlap of SoJIA, MAS and HLH may reflect shared pathways of immune dysregulation leading to overwhelming inflammation.

Methods:              In an attempt to define the clinical spectra of MAS and HLH, we reviewed charts of children who met criteria for HLH (HLH-2004 criteria) and were later referred to Rheumatology for development of new immune-mediated disease. During the review period of 2008-2014, three children were referred for new symptoms of arthralgia or arthritis after completing HLH therapy. We abstracted clinical features, HLH associated biomarkers and genetic mutations both at HLH presentation and diagnosis of SoJIA by Rheumatology.  We documented response to therapy and clinical outcomes.

Results:               Three female patients (ages 16 months-14 years), met HLH criteria at presentation without prior history of autoimmune disease. All patients had fevers, bi-cytopenias, Ferritin levels > 20,000ng/ml (Range: 20,638 – 110,000), and Soluble IL2 receptor levels > 3,000units/ml (Range: 3545 – 10,271, normal 334-3,026). Two of the three patients had severely decreased or absent NK cell function at HLH diagnosis.  One patient had hemophagocytosis on BM biopsy. A diagnosis of an autoimmune or autoinflammatory disease was ruled out at HLH diagnosis after Rheumatology evaluation. All patients were treated with dexamethasone and an additional immunosuppressive agent (etoposide or cyclosporine) as per HLH protocol.  Only a teenage patient was found to have a disease-associated MUNC13-4 mutation.

 All patients developed SoJIA features (fever, rheumatoid rash, and polyarthritis) within 7 months of HLH presentation (Range: 5 – 7 months). SoJIA features without laboratory evidence of MAS developed after HLH remission and corticosteroid discontinuation (range: 1.5 – 5 months). An HLH flare was excluded by oncology due to normal ferritin and Soluble IL2 receptor levels. SoJIA clinical features and systemic inflammation responded to IL-1 blockade with anakinra and canakinumab in 2 children. The teenage patient with bi-allelic MUNC13-4 mutations had SoJIA manifestations that were refractory to TNF-alpha, IL-1 and IL-6 blockade (etanercept, anakinra, and tocalizumab), and ultimately underwent allogeneic hematopoietic cell transplant. 

Conclusion:      HLH and MAS are life threatening inflammatory conditions with underlying immune dysregulation. We describe a novel cohort of children developing SoJIA features after achieving HLH remission. Ongoing clinical follow up and whole exome sequencing studies of these patients may elucidate shared immune-pathway dysfunction of SoJIA, MAS, and HLH.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/development-of-systemic-juvenile-idiopathic-arthritis-manifestations-following-remission-of-hemophagocytic-lymphohistiocytosis/