Fulminant myocarditis and macrophage activation syndrome secondary to adult-onset Still’s disease successfully treated with tocilizumab

Sir, Adult-onset Still’s disease (AOSD) is a rare multisystem inflammatory condition, the aetiology of which remains unknown. Studies have shown that IL-1β, IL-6, IL-18, IFN-γ and TNF play pathogenic roles [1]. Commonly used biologic agents in AOSD treatment include IL-1 receptor antagonists and TNF-α blockers [2]. Treatment with tocilizumab as both an initial agent and in multirefractory AOSD has been reported [3]. Its use in macrophage activation syndrome (MAS) has not. Refractory or untreated AOSD may progress to MAS. MAS results in excessive activation and expansion of T lymphocytes and macrophagic histiocytes that exhibit haemophagocytic activity. This leads to a massive systemic inflammatory response associated with three cardinal features: cytopenia, liver dysfunction and coagulopathy. MAS is a life-threatening condition with reported mortality rates of 20–50% [4]. We report the case of a 32-year-old man who presented with recurrent pyrexia and arthralgia. Investigations for infective causes including EBV, CMV and atypical pneumonia were negative. Autoimmune and HIV testing were also negative. Cardiac echo showed a left ventricular ejection fraction (LVEF) of >60%. Over a 4-week period he received numerous courses of i.v. antibiotics, including gentamicin, tazocin, meropenum, metronidazole and teicoplanin. However, he continued to spike temperatures to 41.3°C. CRP > 400 mg/l (normal <5) and a white cell count of 24 × 109/l (normal 4.0–10.0) were persistently elevated. Rheumatology evaluation elicited a rash and synovitis, in keeping with AOSD (as classified using Yamaguchi criteria) [5]. Serum ferritin was 11 683 μg/l (normal 1–325). An initial response was seen with prednisolone 40 mg/day. Over the following 48 h deterioration occurred, with hypertriglyceridaemia, anaemia, thrombocytopenia, tachycardia, hypotension, hypofibrinoginaemia and hyperferritinaemia (peaking at 30 739 μg/l). He required transfer to the intensive care unit, where inotropic support was commenced along with i.v. methylprednisolone and anakinra. An echocardiograph revealed a severely impaired LVEF of 30%. High-sensitivity cardiac troponin peaked at 154 ng/l (normal <14), with clinical findings suggestive of myocarditis. A bone marrow biopsy indicated a hypercellular film with myeloid hyperplasia and evidence of a left shift, with reduced erythropoiesis. Plentiful macrophages exhibiting haemophagocytosis were seen, in keeping with MAS. No improvement was noted following 3 days of anakinra. Our patient continued to decline, with increasing inotropic support, worsening lactic acidosis and persistent tachycardia. Immunoglobulins, 70 g over 3 days, and ciclosporin 3 mg/kg were commenced. Treatment failure necessitated tocilizumab 8 mg/kg. At this point intubation, vasopressor support and dialysis were required. Repeat echocardiography prior to tocilizumab infusion showed an estimated ejection fraction of 20%, with severe global impairment, a moderately dilated right ventricle, severely impaired systolic function and a mildly dilated right atrium. Cardiac arrest occurred within 48 h of the initial infusion of tocilizumab, in the setting of worsening cardiogenic shock. Return of spontaneous circulation was achieved after 10 min of cardiopulmonary resuscitation. It was felt that the cardiac arrest was incidental to tocilizumab, given that his condition had been deteriorating despite other therapies prior to this treatment. In fact, his marked deterioration was the reason tocilizumab was introduced. Successful extubation occurred 4 days after tocilizumab. One week later ferritin was 11 046 μg/l. Two weeks later LVEF was >60% and dialysis was no longer required. The patient was discharged from hospital 1 month after initiation of tocilizumab. MAS is challenging to treat [6, 7]. A previous case documents the use of tocilizumab in AOSD, however, subsequent MAS occurred following treatment [8]. In this reported case, tocilizumab was stopped during the MAS phase and was resumed following resolution of inflammatory symptoms. To our knowledge this is the first reported case of successful treatment of MAS using tocilizumab. Our patient continues to do well on tocilizumab as monotherapy. He has had one relapse following a missed infusion of treatment. This highlights the potential for targeted IL-6 blockade not only in AOSD, but also in the treatment of MAS. Tocilizumab can be an effective treatment for macrophage activation syndrome secondary to adult-onset Still’s disease. Disclosure statement: G.W. has served as a consultant to and received honoraria from Roche/Chugai Pharmaceuticals, the manufacturer of tocilizumab. All other authors have declared no conflicts of interest.