Rheumatology Advance Access originally published online on April 19, 2007
Rheumatology 2007 46(6):1043-1044; doi:10.1093/rheumatology/kem066
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Adult-onset Still's disease and myocarditis: successful treatment with intravenous immunoglobulin and maintenance of remission with etanercept
Department of Rheumatology, Addenbrooke's Hospital, Box 194 E6, Hills Road, Cambridge, CB2 2QQ and 1Department of Rheumatology, Princess Alexandra Hospital, Hamstel Road, Harlow, Essex, CM20 1QX, UK
Correspondence to: A. J. K. Östör. E-mail: andrew.ostor{at}addenbrookes.nhs.uk
SIR, Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown aetiology. The disease typically affects young adults and is characterized by spiking fever, arthralgia and an evanescent rash with other manifestations including pharyngitis, serositis and leucocytosis [1]. Myocarditis is rare but may result in cardiac failure or arrhythmia [2, 3].
We report a case of AOSD and fulminant myocarditis refractory to methotrexate and high-dose corticosteroids that responded favourably to intravenous immunoglobulin (IVIG). Remission was then maintained with the tumour necrosis factor 
(TNF) antagonist, etanercept (Enbrel®, Wyeth).
A 20-yr old man was diagnosed with AOSD at the age of 17 yrs according to the criteria of Yamaguchi et al. [1]. Six-monthly flares of fever, arthralgia and rash were controlled with methotrexate 20 mg weekly and high-dose corticosteroids (up to 40 mg/day); however, on two occasions his course was complicated by myopericarditis requiring more aggressive therapy with pulse intravenous methylprednisolone (500 mg for 3 days). He responded to this treatment with his cardiac function returning to normal on echocardiography, and disease remission was maintained with methotrexate 20 mg weekly and prednisolone 20 mg daily. Post discharge, he remained dependent on high-dose corticosteroids and an application for etanercept was made to the Primary Care Trust (PCT), the local funding authority, based on reports of success in refractory AOSD [4]. Funding, however, was denied.
One year later, the patient relapsed with his usual symptoms in addition to severe pleuritic chest pain following a quotidian pattern. On this occasion treatment with three pulses of intravenous methylprednisolone 500 mg daily was unsuccessful and the patient rapidly deteriorated with worsening cardiac failure. Clinical examination showed a persistent tachycardia, a third heart sound and reduced air entry to the lungs bilaterally.
Biochemical analysis revealed a C-reactive protein (CRP) >250 mg/l, erythrocyte sedimentation rate (ESR) 88 mm/h, neutrophilia 48 x 109/l and a troponin rise of 10.1 µg/l. Sinus tachycardia, rate 130/min, was noted on electrocardiogram with T-wave inversion laterally. Echocardiography demonstrated global left ventricular dysfunction with an ejection fraction of 35% and no evidence of pericardial effusion or valvular damage.
Further investigation revealed hyperferritinaemia (>5500 µg/l), normal immunoglobulin levels, normal renal and hepatic function, and autoantibody studies were negative. Computed tomography of the chest demonstrated cardiomegaly, bibasal atalectasis/consolidation and pleural effusions. Moderate splenomegaly was evident on imaging of the abdomen, but there was no lymphadenopathy.
A septic screen was performed including serial blood cultures, sputum analysis for bacteria and acid fast bacilli, and serological testing for viridae. No pathogen was identified; however, as the patient had prominent respiratory symptoms, empirical treatment for bacterial pneumonia was instituted with intravenous meropenem 1 g tds and clarithromycin 500 mg bd for 2 weeks.
The myocarditis remained refractory despite aggressive treatment. With limited therapeutic options, IVIG was employed at a dose of 0.4 g/kg/day for 6 days. Clinical improvement was rapid although the fever took several days to subside (Fig. 1). One week later, the CRP had fallen to 62 mg/l, neutrophils to 24 x 109/l and a repeat echocardiogram showed a normal left ventricle with an ejection fraction of 60%. With return of normal cardiac function and the exclusion of sepsis, etanercept was introduced at a dose of 25 mg subcutaneously biweekly. Concomitant therapy consisted of methotrexate 20 mg weekly and 5 mg prednisolone daily. The patient has remained symptomatically well for 7 months, with no fever and a normal acute phase response.
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The treatment of AOSD has traditionally centred on the use of non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs and corticosteroids. In recalcitrant cases, biologic agents have emerged as novel therapeutic options. Uncontrolled studies have demonstrated benefit in AOSD with the TNF
inhibitors, etanercept [4] and infliximab [5]; however, due to the potential for these agents to exacerbate cardiac failure, their use in our patient was contraindicated. Furthermore, the exclusion of sepsis was crucial prior to the introduction of biological therapy. IVIG was employed based on reports of success in a variety of autoimmune conditions, including inflammatory myocarditis [6]. Favourable responses have also been described in patients with AOSD refractory to NSAIDs, including a case complicated by collapsing glomerulonephropathy [7, 8].
The precise mechanism of action of IVIG remains unclear, however, treatment has been shown to exert both immunosuppressive and anti-inflammatory activity [9]. In a mouse model of autoimmune myocarditis, IVIG ameliorated symptoms by suppressing Th1 cytokine production [10]. The rapid recovery seen in our patient suggests that IVIG is a very effective treatment. Whether long-lasting remission can be achieved with IVIG is not clear. In our patient, etanercept was utilized for maintenance therapy. Although funding for etanercept was initially rejected, approval was eventually obtained.
Myocarditis is a known complication of AOSD. In our patient, the causality seemed clear given the temporal relationship of symptoms consistent with a typical flare. This is, to our knowledge, the first case of myocarditis secondary to AOSD successfully treated with IVIG. Although this mode of therapy can be difficult to obtain, treatment may be life saving when other therapies fail or are contraindicated.
The authors have declared no conflicts of interest.
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  K. A. Binymin Comment on: Adult-onset Still's disease and myocarditis: successful treatment with intravenous immunoglobulin and maintenance of remission with etanercept Rheumatology, November 1, 2007; 46(11): 1741 - 1742. [Full Text] [PDF]
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