Treating Heart Inflammation With Interleukin-1 Blockade in a Case of Erdheim–Chester Disease

Abstract

Pericarditis is an inflammatory heart disease, which may be idiopathic or secondary to autoimmune or auto-inflammatory diseases and often leads to severe or life-threatening complications. Colchicine and non-steroidal anti-inflammatory drugs represent the mainstay of treatment, whereas use of corticosteroids is associated with recurrence of disease flares. While effective and safe anti-inflammatory therapies remain an unmet clinical need, emerging clinical and experimental evidence points at a promising role of inhibition of the pro-inflammatory cytokine interleukin-1 (IL-1). We thus evaluated treatment with the IL-1 receptor antagonist anakinra in a case of extremely severe pericarditis with cardiac tamponade and heart failure secondary to Erdheim–Chester disease (ECD), a rare clonal disorder of macrophages characterized by rampant inflammation and multiorgan involvement. A 62-year-old man was admitted to the Emergency Department with severe pericardial effusion requiring the creation of a pleuro-pericardial window. A whole-body contrast-enhanced computed tomography pointed at a diagnosis of ECD with involvement of the heart and pericardium and of the retroperitoneal space. Over the following days, an echocardiography revealed a closure of the pleuro-pericardial window and a relapse of the pericardial effusion. Treatment with anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist, was started at a standard subcutaneous dose of 100 mg/day. After 2 days, we observed a dramatic clinical improvement, an abrupt reduction of the inflammatory markers, and a reabsorption of the pericardial effusion. Anakinra was maintained as monotherapy, and the patient remained asymptomatic in the absence of disease flares for the following year. Recent studies point at inhibition of IL-1 activity as an attractive treatment option for patients with refractory idiopathic recurrent pericarditis. Anakinra treatment may also have a role in patients with pericarditis in the setting of systemic inflammatory disorders, such as ECD.

Anakinra Therapy for Non-cancer Inflammatory Diseases

“…Clinical manifestations include bone pain, neurological symptoms, retroperitoneal fibrosis, and congestive heart failure ( Cavalli et al, 2013a , b ; Ferrero et al, 2016 ; Iurlo et al, 2016 ; Chiapparini et al, 2018 ). Anakinra is effective in ameliorating skeletal, cardiac, retroperitoneal, and systemic manifestations ( Aouba et al, 2010 ; Killu et al, 2013 ; Franconieri et al, 2016 ; Tomelleri et al, 2018 ), thus substantiating the central role of macrophages in diseases responsive to IL-1 blockade ( Diamond et al, 2014 ; Berti et al, 2017 ; Cavalli et al, 2017a ). Interestingly, a traditional treatment option for ECD, that is, alpha interferon (IFNα), may exert beneficial effects via induction of IL-1Ra ( Tilg et al, 1993 ) and inhibition of inflammasome activation ( Guarda et al, 2011 ).…”

IL-1 receptor antagonist, anakinra, prevents myocardial dysfunction in a mouse model of Kawasaki disease vasculitis and myocarditis

“…Blocking tumor necrosis factor (TNF)-α in the LCWE-injected mice significantly decreases vascular inflammation and incidence of coronary arteritis, but had modest effects on preventing myocarditis development [21,48]. This is particularly important, as recent studies have established the beneficial role of IL-1 blockade to treat myocarditis and heart failure [50][51][52], as well as dilated cardiomyopathy [53] and pericarditis secondary to Erdheim-Chester disease [54]. The significance of myocarditis during acute KD for post-inflammatory myocardial fibrosis has not been adequately studied [16].…”

“…Therefore, it was of great interest to observe that IL-1Ra was able to reduce both coronary arterial and myocardial inflammation in the experimental KD vasculitis mouse model. This is particularly important, as recent studies have established the beneficial role of IL-1 blockade to treat myocarditis and heart failure [50][51][52], as well as dilated cardiomyopathy [53] and pericarditis secondary to Erdheim-Chester disease [54].…”

A novel therapy for an unusual problem: IL‐1 receptor antagonist for recurrent post‐transplant pericarditis

“…Additionally, he displayed classic features of idiopathic recurrent pericarditis including severe CRP elevation, pleural effusion, pericardial effusion, and systemic inflammatory symptoms. There are reports of further viral, autoimmune, and auto‐inflammatory investigation of idiopathic recurrent pericarditis cases leading to diagnoses of autoimmune and auto‐inflammatory conditions such as familial Mediterranean fever, tumor necrosis factor receptor‐associated periodic syndrome (TRAPS), adult‐onset Still's Disease, systemic lupus erythematosus, systemic‐onset juvenile idiopathic arthritis, Erdheim‐Chester Disease, Mhyre Syndrome, Sotos Syndrome, and many more . In our patient's case, an extensive investigation has been inconclusive, but further studies are ongoing including an Invitae Auto‐inflammatory Syndromes Panel that tests for 26 genes associated with auto‐inflammatory syndromes.…”