001 Successful treatment of Epstein Barr virus-triggered macrophage activation syndrome in a patient with systemic juvenile idiopathic arthritis

Abstract

Background: Macrophage activation syndrome (MAS) is a potentially life-threatening complication of inflammatory rheumatic disorders, most commonly occurring in patients with systemic-onset juvenile idiopathic arthritis (JIA). It is characterised by an inappropriate, aggressive cascade of pro-inflammatory cytokine release from innate immune cells, driven by dysfunctional activation and uncontrolled expansion of macrophages and T-lymphocytes. Recognition of the clinical features of MAS is the first step in preventing mortality. Mortality rates in patients with JIA are in the region of 8%. Episodes of MAS triggered by host infection pose challenging therapeutic dilemmas for the treating clinician, including careful consideration of the balance between effective pharmacological blockade of immune over-stimulation, and avoidance of excessive immunosuppression in the face of pathogenic microbial threat. Methods: We performed a retrospective case review of the successful management of MAS triggered by significant Epstein Barr virus (EBV) infection, in a patient with systemic JIA in the rheumatic diseases unit, Edinburgh. Results: We report a case of a 22-year-old male with JIA, presenting with unremitting high fevers, widespread lymphadenopathy and splenomegaly. Preceding history suggested a viral prodrome prior to presentation to the emergency department. Laboratory abnormalities on presentation including thrombocytopenia (platelet count of 69 x109), hyperferritinemia (15,433 mg/l), hypertriglyceridemia (2.1mmol/ L), and low fibrinogen levels (1.2g/L), led to a diagnosis of MAS in accordance with the 2016 ACR/EULAR classification criteria. A thorough diagnostic work-up was performed revealing extremely elevated titres of EBV DNA (titre = 28,746 IU/L) in the peripheral blood. Clinical concerns of an EBV-associated lymphoma were eliminated following bone marrow biopsy and axillary lymph node sampling that revealed the presence of EBV-positive cells but no evidence of an EBV-associated lymphoproliferative disorder. In this case, the patient's usual immunosuppression was withheld on presentation (weekly oral methotrexate (5mg) and subcutaneous injections of the humanised anti-IL-6 receptor monoclonal antibody, tocilizumab). The patient was treated with intravenous methylprednisolone (3 pulses of 1000mg) and one dose of intravenous immunoglobulin (2g/kg). He was monitored as an inpatient for six days with supportive care including IV fluids and analgesia. Over the course of eight weeks EBV DNA viral load reduced without the need for anti-viral treatment and our patient made a full recovery. Usual immunosuppression was recommenced at five weeks post-presentation. Conclusion: Epstein Barr virus is an acknowledged trigger for macrophage activation syndrome in patients with autoimmune rheumatic disease. In this case MAS was successfully treated with intravenous immunoglobulin with concurrent cessation of immunosuppression following identification of the causative organism. We propose that treatment of MAS in rheumatic disorders may be stratified based on the precipitating cause e.g. viral, bacterial infection or others.