DOI: 10.31038/JCCP.2021422

Abstract

Acute pericarditis is characterized by severe inflammation of the fibrous and serous pericardial membranes covering the heart. It is caused by multifactorial conditions, such as systemic diseases, autoimmune inflammatory diseases, malignant tumours, bacterial and viral infections, including SARS-CoV-2. In Europe, most cases of acute pericarditis are idiopathic (80-90%), and may follow viral infections. In sub-Saharan Africa, the leading cause of effusive and constrictive pericarditis is tuberculous pericarditis, secondary to HIV/AIDS in about 70% of patients. Approximately, 30% of cases of acute pericarditis are recurrent despite the standard of care, and about 25-30% present as pericardial effusion which may lead to cardiac haemodynamic compromise (cardiac tamponade). Stepwise treatment of consists of aspirin, or any other non-steroidal anti-inflammatory drugs, colchicine, and corticosteroids. Interleukin-1 is a master proinflammatory cytokine existing in two isoforms, IL-1α and IL-1β, and the latter is the most studied, and is implicated in several autoinflammatory diseases, autoimmune diseases, metabolic syndromes, cardiovascular disease, including acute pericarditis. Anakinra is a recombinant, nonglycosylated human interleukin-1 receptor antagonist that competes and inhibits the effects of IL-1α and IL-1β, thus reducing their systemic inflammatory effects. Treatment with anakinra has been shown to be effective in the control of recurrent acute pericarditis in patients who are resistant to colchicine and corticosteroid-dependent. Additionally, treatment with anakinra results in more patients tapering or discontinuing corticosteroids, with no further recurrences of acute pericarditis. Furthermore, treatment with anakinra has been shown to prevent or reverse constrictive pericarditis. Rilonacept effectively acts as an “IL-1 trap” by binding to circulating IL-1α and IL- 1β molecules, inhibiting the downstream activation of IL-1β inflammatory cascade (Table 1).

Table 1: Causes of acute pericarditis and recurrent pericarditis.

Treatment with rilonacept has been shown to significantly relieve pain and other symptoms of pericarditis, and to rapidly resolve recurrent pericarditis. Additionally, rilonacept led to tapering or discontinuation of corticosteroids. Interleukin-1β antagonists should be initiated early in the course of acute pericarditis in order to avert the dreaded complications of acute pericarditis, such as recurrent pericarditis, tamponade, and constrictive pericarditis.

Keywords

Acute pericarditis, Anakinra, Colchicine, Interleukin-1, Interleukin-1 inhibitors

Introduction

Acute pericarditis is characterized by severe inflammation of the fibrous and serous pericardial membranes covering the heart [1,2]. It is caused by multifactorial conditions, such as systemic diseases, autoimmune inflammatory diseases, connective vascular diseases, neoplastic tumours, bacterial, fungal, and viral infections [3-6]. However, in Europe and North America, most cases of pericarditis are idiopathic (80-90%) [6], and may follow viral infection. In sub-Saharan Africa, the leading cause of chronic pericarditis is opportunistic tuberculous pericarditis (70%) [7,8], secondary to HIV/AIDS in about 70% of patients [8-11]. Recently, acute and recurrent pericarditis has been reported to be associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [12-17].

Approximately, 20-30% of cases of acute pericarditis are recurrent despite the standard of care (SoC) [1,3,18-22], and about 25-30% present as pericardial effusion which may lead to cardiac tamponade [3,4,12,23-25]. Cardiac tamponade is a life-threatening condition resulting in compression of the heart, reduced cardiac filling, haemodynamic compromise, and heart failure [25,26]. Constrictive pericarditis is another ominous complication of acute pericarditis [27,28]. It occurs in about 9% of patients with acute pericarditis, and may require pericardiectomy [29], which is lumbered by 5%-10% perioperative mortality [30].

Treatment of pericarditis is challenging, recurrent pericarditis with effusion is frequent, despite treatment with the standard of care (SoC). The stepwise treatment acute pericarditis based on the 2015 European Society of Cardiology guidelines for the management of recurrent pericarditis [1], consists of aspirin, or any other non-steroidal anti-inflammatory drugs (NSAIDs), such as ibrufen, indomethacin, and naproxen; colchicine; and corticosteroids [6,18-22,31-33]. At the top of the ladder treatment, azathioprine, and intravenous immunoglobulins may be added if symptoms persist, or if patients develop complications, such as recurrent pericarditis, and effusive constrictive pericarditis. However, some of the patients become unresponsive to the SoC [34,35]. About 5% of the patients despite treatment with standard dosages of aspirin or NSAIDs, colchicine, and prednisone continue to complain of symptoms, or have recurrent pericarditis with effusion. This sub-group of patients is resistant to colchicine and azathioprine, and become corticosteroid-dependent [36-41]. They require innovative therapies, such as IL-1β inhibitors (anakinra, or rilonacept) which block the inflammatory cascade implicated in pathogenesis of acute pericarditis [42,43].

Interleukin-1 Family

The interleukin-I (IL-1) family is ranked at the top of the hierarchy of innate immune signaling, and is comprised of 11 soluble molecules and 10 receptors [44-46]. It is divided into three subgroups, depending on the IL-1 consensus sequence, and the signaling receptor chain. It include cytokines with agonistic activity, such as IL-1α, IL-1βb, IL-18, IL-33, IL-36a, IL-36b, and IL-36g; receptors antagonists, including IL-1Ra, IL-36Ra, and IL-38, and an anti-inflammatory cytokine IL-37 [44-47]. The IL-1 family signaling is via 10 receptors, coreceptors, decoy receptors, and inhibitory receptors with similar and different immunopathological effects [48,49]. Interleukin-1 receptors, and decoy receptors are potential targets for blockade, and have been exploited in the development of several biologics for the treatment of several diseases, including cardiovascular diseases, and cancer.

Interleukin-1 and its most related family members IL-18, and IL-33 play different roles in innate immunity and inflammation in response to microbial, and environmental insults. Interleukin-18 mediates mostly type 1 innate immunity, and inflammatory responses [50], whereas, IL-33 plays a central role in type 2 innate and adaptive immunity, and inflammation [51]. IL-33 is an ‘alarmin’ cytokines secreted by epithelial cells, in response to microbial infections, cell death, necrosis, mechanical stress, and trauma [52], and plays a central role in the pathogenesis of eosinophilic asthma [52-55], and chronic rhinosinusitis with nasal polyps [56-59]. IL-1β and IL-18 are the most studied family members [44,45], and IL-1β has emerged as the most promising therapeutic target for the treatment of several autoimmune, and inflammatory diseases, including cardiovascular diseases [60,61].

Interleukin-1β

Interleukin-1 is a master pro-inflammatory cytokine which exists in two isoforms, including IL-1α, and IL-β, with proinflammatory and pyogenic properties [62,63]. It is produced principally in monocytes and macrophages, but also in neutrophils.  IL-1β is a key up-regulator of inflammatory mediators, such as cyclo-oxygenase-2 (COX-2), and prostaglandins. Interleukin-1β, and the inflammatory mediators it induces for secretion are responsible for the inflammation, hyperaemia, hyperesthesia, and oedema characteristic of acute pericarditis [60,63-66]. IL-1β production and secretion is stimulated by NLRP3 inflammasome, pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and other inflammatory cytokines, such a TNFβ, IL-8, and in an autocrine fashion by IL-1β [67]. NLRP3 (NACHT LRR and PYD domains-containing protein 3) plays a very important role in the production of IL-1β and IL-18 from their precursor immature forms [68,69]. Interleukin-1β is produced as a 269-AA precursor protein, and is processed by caspase-1 activated in the inflammasomes into its mature active form [70-73].

Interleukin-1β signaling is via two surface receptors, IL-1R1, and IL-1 type 2 receptor (IL-1R2), a decoy receptor. IL-1 binds to IL-1R1, which requires formation of a heterodimer with IL-1 type 3 receptor (IL-1R3) before binding [74]. Subsequently, MyD88 (myeloid differentiation factor 88) binding triggers a proinflammatory signaling via a cascade of phosphorylation resulting in activation of NF-kB (nuclear factor-kB) [74,75]. NF-kB translocates into the nucleus, henceforth, promoting transcription and translation of several proinflammatory genes, especially for the precursors of IL-1β, and IL-18, as well as components of the NLRP3 inflammasome [75]. Interleukin 1β and its receptors, coreceptor, and decoy receptor are favourable therapeutic targets in cardiovascular diseases [76-78], including acute and recurrent pericarditis [64-67].

Anakinra

Anakinra (Kineret; Swedish Orphan Biovitrum, Stockholm, Sweden) is a recombinant, nonglycosylated human interleukin-1 receptor 1 antagonists that competes and inhibits the effects of IL-1α and IL-1β, thus reducing their systemic inflammatory effects. It is approved for the treatment of several diseases, including rheumatoid arthritis, cryopyrin-associated periodic syndrome (CAPS), a multisystematic IL-1β-mediated disease due to a gain of function in NLRP3, and neonatal-onset multisystem inflammatory disease (NOMID). It is given as 100 mg subcutaneouly once daily. Anakinra when administered early has been shown to be very effective in in the treatment of colchicine resistant, and corticosteroid-dependent recurrent pericarditis [79,80]. Treatment with anakinra has been shown to be effective in the control of symptoms due to acute pericarditis, and in preventing recurrent pericarditis, and pericardial effusion [79-81], and reversing constrictive pericarditis [82]. Additionally, treatment with anakinra results in more patients tapering or discontinuing corticosteroids, with no further recurrences of acute pericarditis. Furthermore, treatment with anakinra has been shown to prevent or reverse constrictive pericarditis. Adverse events related to treatment with anakinra are listed in Table 2.

Table 2: Anakinra adverse effects.

Rilonacept

Rilonacept  (Arcalyst; Regeneron Phamaceuticals, Tarrytown, NY) is a dimeric fusion protein that consists of ligand binding domains of the extracellular portions of the IL-1 receptor component (IL-R1), and the IL-1 receptor accessory protein that is linked to the Fc portion of human IgG1. Rilonacept effectively act as an “IL-1 trap” by binding to circulating IL-1α and IL- 1β molecules, effectively blocking the engagement of IL-1β to pro-inflammatory cell surface receptors, and inhibiting the downstream activation of IL-1β inflammatory cascade. It is approved for the treatment of CAPS, and is administered as a loading dose of 320 mg subcutaneously once, then followed by 160 mg every 2 weeks. Treatment with rilonacept has been shown to significantly relieve pain and other symptoms of pericarditis, and to rapidly resolve recurrent pericarditis [83]. Additionally, rilonacept led to tapering or discontinuation of corticosteroids [83]. Notably, rilonacept has been demonstrated to reverse constrictive pericarditis [83]. Adverse effects of rilonacept include injection-site reaction, and neutropnea with danger of susceptibility to infections. Rilonacept was approved by the US Food and Drug Administration (FDA) in March 2021 for the treatment of pericarditis, in patients aged 12 years and older.

Interleukin-1 Antagonists And Covid-19

Interleukin-1 blockade causes neutropnenia and susceptibility to infection. However, it seems that anakinra and rilonacept do not influence the epidemiology, and clinical outcome of SARS-CoV-2. Moreover, several studies have reported that anakinra is associated with reduced mortality and need for mechanical ventilation, and has a good safety profile in patients with SARS-CoV-2 [84-90].

Conclusion

Acute pericarditis is characterized by severe inflammation of the fibrous and serous pericardial membranes covering the heart. The stepwise treatment of acute pericarditis consists of aspirin or NSAIDs, colchicine, and prednisone. About 5% of the patients with acute pericarditis develop resistance to colchicine, and are corticosteroid-dependent. Interleukin-1β antagonists, such as anakinra and rilonacept should be initiated early in the course of acute pericarditis in order to avert the troublesome complications of acute pericarditis, such as recurrent pericarditis, cardiac tamponade, and constrictive pericarditis.

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