Current Drug Treatment for Acute and Recurrent Pericarditis

Abstract

Pericarditis is the most frequent pericardial disease and presents with a relatively benign course when treated according to guideline-directed therapies at first presentation. Recurrence is the most frequent complication and may occur more frequently after a first episode, in patients with autoimmune etiology, in patients who received glucocorticoids, or after rapid (i.e., within 1 month) tapering of anti-inflammatory drugs. The therapeutic armamentarium for pericarditis includes high-dose nonsteroidal anti-inflammatory drugs (NSAIDs) that are tapered rapidly once symptoms are controlled. Colchicine is necessary to both relieve symptoms and reduce the rate of recurrences and is continued for at least 3–6 months. Low- to moderate-dose glucocorticoids are reserved for patients with a first recurrence for which NSAIDs and colchicine failed and/or who have an autoimmune disorder, with a slow tapering. Interleukin-1 blockers—anakinra, rilonacept, and goflikicept—are used as a third-line option in patients who cannot come off glucocorticoids or as second-line therapy after NSAIDs and colchicine in patients with contraindications to glucocorticoids or in those with high-risk features (i.e., multiple episodes, markedly elevated inflammatory markers, or extensive abnormalities at pericardial imaging) in whom treatment with glucocorticoids is unlikely to succeed.

Key Points

Recurrent pericarditis is the most frequent complication after a first episode, with a recurrence risk that progressively increases after every flare.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine are the cornerstone of the treatment, whereas low- to moderate-dose glucocorticoids are reserved for patients with a first recurrence for which NSAIDs and colchicine failed or are not tolerated or are contraindicated and/or who have an autoimmune disorder.

Interleukin-1 blockers—anakinra, rilonacept, and goflikicept—are used as a third-line therapy in patients who cannot come off glucocorticoids or as second-line therapy after NSAIDs and colchicine in patients with contraindications to glucocorticoids or in those with high-risk features (i.e., multiple episodes, markedly elevated inflammatory markers or extensive abnormalities at pericardial imaging) in whom treatment with glucocorticoids is unlikely to succeed.

Introduction

Pericarditis—the inflammation of the pericardial sac—is the most frequent pericardial disease and has a generally benign course [1, 2]. However, complications include myocardial involvement (myopericarditis or perimyocarditis), cardiac tamponade, or evolution to constriction [3]. The most frequent complication is recurrent pericarditis (i.e., subsequent flares of inflammation after 4–6 weeks free from the acute episode [1, 4]), which can also occur among individuals with an initially uncomplicated course [5]. After a first episode of acute pericarditis, recurrences occur in 15–30% of patients within 18 months [6, 7], whereas 25–50% of patients experience additional flares after a first recurrence [8, 9], and 20–40% of patients experience further recurrence after two or more previous recurrences [10]. Reasons for this are many.

First, as patients with recurrences are predisposed to future relapses, they need close medical referral. In addition, this condition is troublesome for patients and may negatively affect their quality of life (QoL) and their ability to work and perform physical activity [11, 12]. Etiology is an essential aspect since pericarditis as a manifestation of an autoimmune disorder (e.g., systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis) is associated with more recurrences than idiopathic/viral cases or post-cardiac injury syndrome [13, 14]. In these cases, careful clinical evaluation and more rational management of the underlying disease with its specific autoimmune background is required [15]. High-dose glucocorticoids have been associated with increased rates of recurrences [16]. Finally, in some cases, recurrences are likely after rapid (i.e., within 1 month) tapering and suspension of anti-inflammatory therapies [17] that is not guided by resolution of clinical symptoms and normalization of inflammatory markers, as suggested by guidelines [1].

Great advancements in the pathophysiology of pericarditis have been made over recent decades [18–21], and this has improved the therapeutic management of patients with recurrent pericarditis [11, 19, 22–24]. In particular, the interleukin (IL)-1 blockers anakinra, rilonacept, and goflikicept have revolutionized the treatment of recurrences as they stimulate a longer disease-free period with an acceptable rate of non-serious adverse events [25–28] (Fig. 1).

Fig. 1.

Pathogenic mechanisms driving pericardial inflammation and mechanisms of action of anti-inflammatory drugs. Injury to the pericardium triggers the release of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), leading to the activation of nuclear factor kappa light-chain enhancer of activated b (NF-kB) cells, which enhances the transcription of inflammatory precursors and associated cytokines (such as NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 [NLRP3], apoptosis-associated speck-like protein containing a caspase-recruiting domain [ASC], and pro-caspase-1 and pro-interleukin [IL]-1β) necessary for the formation of the NLRP3 inflammasome. This process ultimately results in the release of IL-1β. NF-kB also promotes the synthesis of phospholipase-A2, driving the arachidonic acid pathway and the production of prostaglandins (PG) and thromboxanes (TXA). The IL-1 receptor (IL-1R) plays a key role, as IL-1α acts as an alarmin or DAMP during tissue injury, and IL-1β is processed and released by the inflammasome, amplifying the inflammatory response. Also, IL-1R activation on endothelial cells plays a role in immune cell migration. CBD, cannabidiol; COX, cyclooxygenase; NSAID, nonsteroidal anti-inflammatory drug; PLA2, phospholipase A2; TLR, toll-like receptor.

In this review, we discuss general concepts about current treatments for acute and recurrent pericarditis and drugs in the pipeline. Throughout the article, we refer to all forms not related to specific etiologies unless otherwise specified but we refrain from defining these cases as “idiopathic”. The term “idiopathic” suggests diagnostic ignorance or an unwillingness to look for a specific diagnosis and can be alarming for patients [29]. In acute pericarditis, most “idiopathic” cases are related to a viral infection at the time of the first attack, and recurrences are often caused by an extremely rapid tapering of the drug regimen [29, 30].

Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the cornerstone of the treatment of pain in acute and recurrent pericarditis [1] (Fig. 2) and are also safe and effective for the treatment of perimyocarditis (i.e., acute pericarditis with increased levels of troponin without newly developed focal or diffuse impairment of the left ventricle) [31–33]. Non-selective NSAIDs reduce levels of C-reactive protein (CRP) in various inflammatory conditions [34–37]. In a small placebo-controlled trial, ibuprofen and indomethacin improved fever, pericardial pain, effusion, and pericardial rubs in patients with post-pericardiotomy syndrome [38]. Whether NSAIDs improve outcomes (including recurrences and evolution toward constriction) in patients with pericarditis of other causes has not been studied in a clinical trial, so the optimal use of NSAIDs or acetylsalicylic acid (ASA; aspirin) is unknown. NSAIDs and ASA are effective in the treatment of pain associated with pericarditis, but it is unclear how this may affect the duration of the disease. NSAIDs and ASA are also associated with significant adverse effects, such as gastritis, renal dysfunction, and bleeding. A recent international position statement recommended the use of full-dose NSAIDs and ASA for 1–2 weeks, followed by gradual reduction according to symptoms and inflammatory markers (e.g. CRP) [39].

Fig. 2.

Flowchart for the management of recurrent pericarditis. When first-line therapies fail, interleukin (IL)-1 blockers should be considered in patients with recurrent pericarditis, either in case of resistance to colchicine and dependence on glucocorticoids or in the presence of high-risk features such as multiple episodes, markedly elevated inflammatory markers, or extensive abnormalities at pericardial imaging. CMR, cardiac magnetic resonance; CRP, C-reactive protein; IVIG, intravenous immunoglobulins; NRS, numerical rating scale; NSAIDs, nonsteroidal anti-inflammatory drugs. Modified with permission from Del Buono et al. [132].

The selection of a specific NSAID should be based on physician experience and the patient’s medical history and allergies. ASA is preferred in older patients or those with ischemic heart disease [1, 39]; however, ibuprofen was shown experimentally to be a coronary vasodilator and to reduce infarct size [40, 41]. During a recurrence, it is reasonable to choose the NSAID that was effective in the previous flare and to use it at the highest dose for 2–4 weeks [39]. NSAIDs must be administered at the appropriate anti-inflammatory dose to avoid treatment failure (Table 1) [17, 42]. Since there is no universally accepted duration of treatment, this must be tailored on a case-by-case basis. In patients with difficult-to-treat recurrent pericarditis, NSAIDs can be used for longer periods, for example, from 2 to 4 years [43]. Co-administration with proton pump inhibitors must be recommended with consideration of risk factors in accordance with relevant guidelines [44]. Close follow-up of kidney function should be considered in older patients with comorbidities.

Table 1.

Nonsteroidal anti-inflammatory drugs for acute and recurrent pericarditis as per 2015 guidelines from the European Society of Cardiology [1]

Drug	Doses	Suggested tapering
ASA	750–1000 mg every 8 h for 1–2 weeks	250–500 mg every 1–2 weeks based on clinical assessmenta
Ibuprofen	600–800 mg every 8 h	200–400 mg every 1–2 weeks based on clinical assessmenta
Indomethacin	25–50 mg every 8 h  Starting with lower dosing and titrating to avoid headache and dizziness  IV administration is possible in the acute phase (i.e., in the ED or during hospital admission)	25 mg every 1–2 weeks based on clinical assessmenta

ASA, acetylsalicylic acid (aspirin); ED, emergency department; h, hour(s); IV, intravenous

^aTapering should be performed after a complete clinical evaluation (symptoms, echocardiographic findings, C-reactive protein reduction or normalization)

Colchicine

The use of colchicine for the treatment of recurrent pericarditis was first proposed in 1987 [45]. Since then, clinical trials have highlighted the efficacy of colchicine in reducing the incidence of recurrent pericarditis [46], as summarized in various meta-analyses [47–50]. As such, it is now used in combination with NSAIDs from the first episode to treat both acute and recurrent pericarditis [1] (Fig. 2 and Table 2).

Table 2.

Randomized clinical trial results of first-line therapies for pericarditis

Setting	Trial (y)	Pts	Treatments	Primary outcome	Main findings
PPS	NSAIDs
	Horneffer et al. (1990) [38]	149 (mean age 54.1 y; 76.1% males)	600 mg IBU or 25 mg IND TID vs PL	Successful treatmenta	91% of pts receiving IBU and 88% of those receiving IND experienced symptom resolution vs 59% with PL (p = 0.002). At follow-up, 50% of those receiving PL required further treatment vs 25% for both drug groups. Therapeutic success was 76% (IBU) and 71% (IND) vs 45% (PL) ( p = 0.03). No significant difference was noted in the rate of side effects
	COL
	Finkelstein et al. (2002) [127]	111 pts (mean age 63.7 ± 10.9 y; 73% males)	COL (0.5 mg TID for 1 mo)b vs PLb	PPS incidence at 3 mo	No significant difference in the occurrence of PPS between COL and PL groups (10.6% vs 21.9%, p = 0.135)
	COPPS trial (2010) [58]	360 pts (mean age 65.7 ± 12.3 y; 66% males)	Standard therapy + COLb,c for 1 mo vs standard therapy + PLb	PPS incidence at 12 mo	COL reduced the incidence of PPS at 12 mo (8.9% vs 21.1%, p = 0.002, NNT = 8) and lowered the secondary endpoint, including PPS-related hospitalization, cardiac tamponade, constrictive pericarditis, and relapse at 18 mo (0.6% vs 5.0%, p = 0.024, NNT = 22). GI disturbances were more common in the COL group. No SAEs observed
	COPPS–2 trial (2014) [128]	360 pts (mean age 65.7 ± 12.3 y; 66% males)	COLd,e for 6 mo vs PLe	PPS incidence within 3 mo	COL decreased occurrence of PPS (19.4% vs 29.4%, p < 0.01, NNT = 10) but not of AF (34% vs 42%) or pericardial/pleural effusion (57% vs 59%). No SAEs reported
	Meurin et al. (2015) [129]	197 pts (mean age 64.5 ± 11.2 y; 86.3% males)	COLb,c vs PLb	Change in postoperative pericardial effusion grade after 14-day treatment	COL did not reduce pericardial effusion or late cardiac tamponade (7% vs 6%). Diarrhea frequently occurred among pts on COL. No SAEs observed
Acute pericarditis	COPE trial (2005) [6]	120 pts (mean age 56.9 ± 18.8 y; 54% males)	ASA + COLc for 3 mo vs ASA	Recurrence rate at 18 mo	COL plus ASA significantly reduced recurrence rates at 18 mo (10.7% vs 32.3% for ASA alone, p = 0.004, NNT = 5) and symptom persistence at 72 h (11.7% vs 36.7%, p = 0.003). No SAEs observed. COL was discontinued in 8.3% of cases due to diarrhea
	ICAP trial (2013) [7]	240 pts (mean age 52.1 ± 16.9 y; 60% males)	ASA/IBU + COLd for 3 mo vs ASA/IBU + PL	Incessant or recurrent pericarditis at 18 mo	COL significantly reduced occurrence of incessant or recurrent pericarditis (16.7% vs 37.5% for PL; RRR 0.56; 95% CI 0.30–0.72, p < 0.001; NNT = 4). No SAEs reported
	Sambola et al. (2019) [130]	110 pts (mean age 44 ± 18.3 y; 83.6% males)	ASA/NSAIDs + COLd vs ASA/NSAIDs	Recurrence rate at 24 mo	No significant difference in recurrence rate (13.5% vs 7.8%, p = 0.34)
Recurrent pericarditis	CORE trial (2005) [8]	88 pts (mean age 53.0 ± 16.6 y; 55.2% males)	ASA + COLC for 6 mo vs ASA	Recurrence rate at 18 mo	COL significantly lowered recurrence rate at 18 mo (24% vs 50%, p = 0.02, NNT = 4) and reduced symptom persistence at 72 h (10% vs 31%, p = 0.03). It extended the symptom-free period (17.2 ± 12.2 mo vs 10.6 ± 9.6 mo, p = 0.007). Diarrhea led to 7% of COL-treated pts discontinuing the drug. No SAEs observed
	CORP trial (2011) [9]	120 pts (mean age 47.6 ± 14.9 y; 52.5% males)	ASA/IBU + COLc for 6 mo vs ASA/IBU + PL	Recurrence rate at 18 mo	COL significantly lowered the recurrence rate (24% vs 55%, p < 0.001, NNT = 3), reduced symptom persistence at 72 h (23% vs 53%, p < 0.001), and improved the remission rate at 1 week (82% vs 48%, p < 0.001). GI intolerance was the primary side effect and was similar between groups. No SAEs reported
	CORP-2 trial (2014) [10]	240 pts (mean age 48.7 ± 14.6 y; 50% males) with ≥ 2 recurrences	ASA/NSAIDs + COLd for 6 mo vs ASA/NSAIDs + PL	Recurrence rate at 18 mo	COL significantly lowered recurrences (21.6% vs 42.5%; RR 0.49, 95% CI 0.24–0.65, p < 0.001; NNT = 5) and reduced symptom persistence at 72 h (19.2% vs 44.2%, p < 0.001). It was effective in achieving remission at 1 wk (83.3% vs 59.2%, p < 0.001), reducing the incessant course (8.3% vs 26.7%, p < 0.001), and lowering pericarditis-related hospital admissions (1.7% vs 10%, p = 0.001). GI intolerance was the primary side effect, occurring at similar rates in both groups. No SAEs observed.

AF, atrial fibrillation; ASA, acetylsalicylic acid (aspirin); CI, confidence interval; COL, colchicine; GI, gastrointestinal; h, hour(s); IBU, ibuprofen; IND, indomethacin; mo, month(s); NNT, number needed to treat; NSAID, nonsteroidal anti-inflammatory drug; PL, placebo; PPS, post-pericardiectomy syndrome; pt(s), patient(s); RR, relative risk; RRR, relative risk reduction; SAE, serious adverse event; TID, three times daily; wk, weeks; y, year(s)

^aSymptom remission

^bOn 3rd postoperative day

^cLoading dose: 1 mg on day 1 followed by 0.5 mg daily if body weight <70 kg; same dosages twice daily if body weight ≥70 kg

^d0.5 mg daily if body weight <70 kg; same dosages twice daily if body weight ≥70 kg

^eFrom 48 to 72 h before surgery

The mechanisms of action of colchicine are not completely characterized. It blocks microtubule polymerization and reduces neutrophil chemiotaxis, degranulation, and phagocytosis [51], as its concentration within the leukocytes is higher than in plasma [52] and it can inhibit the formation of the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome, thus reducing the release of IL-1β [53] (Fig. 1).

A dose of 0.5/0.6 mg twice daily is sufficient to achieve therapeutic effect. A reduced dose of 0.5/0.6 mg daily should be considered in patients aged > 70 years and in those weighing < 70 kg [1]. In patients with chronic kidney disease, dose reduction and close monitoring is needed for an estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m², considering a dose of 0.5/0.6 mg once daily for eGFR 35–49 mL/min/1.73 m² and 0.5/0.6 mg every 2–3 days for eGFR 10–34 mL/min1.73 m² [54, 55]. Chronic use of colchicine with an eGFR < 10 mL/min1.73 m² is not safe. Close monitoring for new-onset muscle pain should be undertaken because of possible interactions between colchicine and statins. When possible, it may be reasonable to avoid atorvastatin, lovastatin, and simvastatin and to prefer rosuvastatin [56, 57]. Tapering is not mandatory; however, it can be considered based on symptoms and inflammatory markers by weaning from 0.5/0.6 mg twice daily to once daily for at least 1 or 2 months [39]. However, the duration of the treatment and modification of dosing can be adjusted according to the clinical picture during follow-up so that patients with difficult-to-treat recurrent pericarditis could be given colchicine for a longer period (up to 4 years) [43].

Colchicine reduces the risk of recurrences compared with NSAIDs alone and induces a longer time free from disease in both acute and recurrent pericarditis [6–10]. Symptoms are rapidly resolved in patients receiving colchicine in addition to NSAIDs [6–8]. Colchicine was found to be effective in the prevention of post-pericardiotomy syndrome and its complications when administered for 4 weeks after cardiac surgery [58]. Recently, colchicine was reported to reduce the risk of recurrences in patients with myopericarditis [59] and in patients with recurrent pericarditis when administered on top of anakinra [60]. Since the efficacy of colchicine was evaluated almost exclusively in combination with other drugs (NSAIDs or glucocorticoids), the use of colchicine alone is not recommended. Colchicine should be continued for at least 3 months after the first episode of pericarditis and at least 6 months in case of recurrences [10], although its continuation might be evaluated on a case-by-case basis with consideration of the patient’s comorbidities, for example, for secondary cardiovascular prevention [61].

Colchicine is generally safe, and the most commonly reported adverse effects are gastrointestinal (diarrhea, abdominal pain, dyspepsia), which are reversible after dose reduction or eventually drug withdrawal [6, 8]. Less commonly, colchicine may cause muscle injury and transient bone marrow suppression, which resolve as soon as the drug dosing is tapered or eventually suspended.

Glucocorticoids

Although glucocorticoids are frequently used for acute and recurrent pericarditis, no randomized clinical trials have been undertaken. High-dose glucocorticoids (i.e., 1 mg/kg daily) and rapid tapering are associated with a high risk of recurrences [16, 62]. Low-to-moderate doses of 0.2–0.5 mg daily are recommended only in patients with contraindications to or experiencing adverse events with NSAIDs and colchicine (true allergy, recent peptic ulcer or gastrointestinal bleeding, moderate-to-severe chronic kidney disease, need for anticoagulation, pregnancy after the 20^th gestational week) or on top of NSAIDS and colchicine when these drugs are not effective [2, 3] (Fig. 2). Other indications include systemic autoimmune disease, management of symptoms in post-cardiac injury syndromes when colchicine is not completely effective, in post-vaccination forms, and in immune checkpoint inhibitor–associated pericarditis [2, 63]. Although glucocorticoids are not recommended for tuberculous and bacterial pericarditis, they may be given in cases of tuberculous constrictive pericarditis in the absence of human immunodeficiency virus coinfection, along with anti-tuberculous chemotherapy [3].

Potential adverse effects of long-term glucocorticoids include hyperglycemia, osteoporosis, adrenal failure, and weight gain [1]. Bone preservation therapies should be considered in patients with or at risk for osteoporosis (i.e., men aged ≥ 50 years and postmenopausal women undergoing long-term treatment with glucocorticoids at a dose ≥ 5 mg/daily of prednisone or equivalent) who are starting glucocorticoids. Acid-suppressant therapy should also be prescribed in patients with or at risk for gastroesophageal reflux disease.

IL-1 Blockers

IL-1 is the most important pro-inflammatory cytokine and is released by the NLRP3 inflammasome, a large macromolecular complex that releases inflammatory cytokines in response to danger, as better detailed elsewhere [64]. Two isoforms of IL-1 exist: IL-1α and IL-1β. The former is constitutively present in mesenchymal cells and does not need any processing to become active, thus working as an alarmin when released by injured cells [65]. IL-1β must be processed by the NLRP3 inflammasome to be activated and secreted and binds to the IL-1 receptor type 1 (IL-R1). Finally, the IL-1 receptor antagonist (IL-1Ra) is a soluble receptor antagonist binding IL-R1 without activating intracellular signaling. IL-1Ra is naturally produced together with IL-1β and is part of a negative feedback mechanism to fine tune the inflammatory response [66].

The positive results of the AIRTRIP (Anakinra-Treatment of Recurrent Idiopathic Pericarditis) trial [67] and of another small trial [68] testing anakinra in acute and recurrent pericarditis initially supported the hypothesis of a central role of the NLRP3 inflammasome in the pathophysiology of the disease, as later demonstrated in a translational study by our group [18, 23] (Table 3). These findings were later confirmed with rilonacept in the RHAPSODY (Rilonacept Inhibition of Interleukin-1 Alpha and Beta for Recurrent Pericarditis: a Pivotal Symptomatology and Outcomes Study) trial [69] and the goflikicept trial [28] (Table 3). No randomized clinical trials have been conducted with canakinumab (a fully human monoclonal antibody selectively binding IL-1β), and experience in the treatment of pericarditis is scant and limited to case reports and case series [70–74].

Table 3.

Randomized clinical trial results with interleukin (IL)-1 inhibitors in recurrent pericarditis

Drug	Trial (y)	Pts	Treatment	Follow-up	Primary outcome	Main findings
ANA	AIRTRIP trial [67]	21 pts (mean age 45.4 ± 14.3 y; 33.3% males) with COL-resistant, GC-dependent RP	ANA 2 mg/kg/day (up to 100 mg) for 2 mo, then randomization to ANA or PL for 6 mo or until first recurrence for pts who experienced resolution of pericarditis	14 mo	Pericarditis recurrence rate at 8 mo and time to RP after randomization	Reduction in incidence of RP in ANA- vs PL-treated pts (18.2% vs 90%). Median time to flare was not reached in the ANA group vs 72 days in the PL group (p < 0.001)
RIL	Phase II RHAPSODY trial [131]	25 pts (mean age 42.8 ± 10.5 y; 40% males) with active idiopathic or post-pericardiotomy RP (≥ 2 recurrences) or, if asymptomatic, GC-dependence with ≥ 2 prior recurrences	RIL 320 mg as LD followed by 160 mg wkly maintenance for 6 wks followed by an optional 18-wk on-treatment extension period	22 wks	Pericarditis pain and inflammation for symptomatic pts; disease activity after GC taper for GC-dependent pts	Improvement in symptoms and CRP reduction within wk 6 (median time to CRP normalization: 9 days). RIL contributed to discontinuation in nearly 90% of pts on GCs at baseline
	Phase III RHAPSODY trial [69]	86 pts (mean age 44.7 ± 16.1 y; 43% males) with RP (≥ 2 recurrences)	RIL 320 mg as LD and 160 mg wkly maintenance for 12 wks (run-in phase), followed by randomization to RIL or PL and an additional 24-wk open-label treatment period	50 wks	Time to first pericarditis recurrence	RIL reduced the median time to first recurrence (HR 0.04; 95% CI 0.01–0.18; p < 0.001) and the rate of pts with recurrences vs PL (7% vs 74%)
GOF	Goflikicept trial [28]	22 pts (median age 48.5, 37–58 y; 22.7% males) with RP, with and without recurrence	Run-in period with SoC + GOF (80 mg every 2 wks or LD of 160 mg, followed by 80 mg at wk 1 and wk 2 and 80 mg every 2 wks for 12–24 wks) for 12–24 wks followed by randomization to GOF (80 mg every 2 wks) or PL	8 wks	Time to first pericarditis recurrence in the withdrawal period	In the run-in period, treatment response to GOF was achieved in 88.9% of pts with RP along with a rapid reduction in CRP levels, chest pain, and pericardial effusion. Within 24 wks from randomization, no recurrences were observed with GOF vs 90% of pts with PL (p < 0.001). No deaths or safety signals identified

ANA, anakinra; CI, confidence interval; COL, colchicine; CRP, C-reactive protein; GC, glucocorticoid; GOF, goflikicept; HR, hazard ratio; LD, loading dose; mo, month(s); PL, placebo; pts, patients; RIL, rilonacept; RP, recurrent pericarditis; SoC, standard of care; wk, week(s); y, year(s)

The IL-1 blockers anakinra, rilonacept, and goflikicept are used as third-line treatment in patients with recurrent pericarditis who cannot come off glucocorticoids or as second-line therapy after NSAIDs and colchicine in patients with contraindications to glucocorticoids (bacterial infections, including tuberculosis) or in those with high-risk features or an autoinflammatory phenotype (i.e., extensive abnormalities at pericardial imaging, multiple episodes, markedly elevated inflammatory markers, pleuropericardial involvement) [39, 75, 76] in whom treatment with glucocorticoids is unlikely to succeed [39] (Fig. 2). Importantly, discontinuation of IL-1 inhibitors in patients with recurrent pericarditis is associated with a significant risk of further recurrences [3, 39]. Both treatment duration and discontinuation should take into account the burden and severity of the disease, the tolerability of IL-1 inhibitors and other drugs, and patient acceptability of recurrence after discontinuation. To date, no randomized controlled trials are available to inform on the optimal treatment duration or discontinuation strategies, whereas colchicine re-introduction or continuation may be beneficial during tapering of IL-1 inhibitors [60]. Before starting treatment with IL blockers, all patients should be screened for any active infection, and, among those at risk, latent tuberculous infection must be excluded by Quantiferon test, which could be repeated annually [66].

Anakinra

Anakinra is the recombinant, nonglycosylated form of the naturally occurring IL-1Ra and is approved for the treatment of cryopyrin-associated period syndromes, a group of genetic conditions characterized by increased NLRP3 inflammasome activity [77]. By binding IL-1R1, anakinra blocks the activities of both IL-1α and IL-1β. Its half-life is about 4–6 h, and it is administered via subcutaneous injection at a dose of 100 mg once daily (Fig. 1). The safety profile is favorable, and the most frequent adverse event is local injection site reactions, which are generally mild and self-limiting after some days. Transient transaminase elevation and, more rarely, production of neutralizing autoantibodies can be observed. No adjustment for liver function is required, whereas dose reduction to every other day may be considered for creatinine clearance <30 mL/min [53], although the full dose can be administered with close follow-up without any remarkable side effects. The sudden suspension of anakinra increases recurrence rates [78, 79], so tapering is suggested. Different approaches have been proposed: dose reduction of anakinra by 100–300 mg/week every 1–2 months while monitoring for symptoms and inflammatory biomarkers, or prolongation of intervals between injections, starting from every 7 days and progressively moving toward longer intervals up to 50% every 2–4 weeks after at least 6 months of daily therapy [80]. However, in clinical practice, 80% of patients might not be able to completely withdraw anakinra [43] and need to progressively reduce the number of weekly injections every 2–4 weeks until they try to stop, depending on their clinical response. To this end, the recently reported R202Q (c.605G>A, p.Arg202Gln) missense variant of the MEFV gene in a young woman with glucocorticoid-dependent recurrent pericarditis [81] may suggest that patients unable to suspend anakinra present with an autoinflammatory phenotype, thus needing prolonged IL-1 blockade.

The first evidence of beneficial effects from anakinra in refractory, recurrent pericarditis was in 2009, when Picco et al. [82] reported the positive effects of anakinra in three children with glucocorticoid-dependent recurrent pericarditis. In 2012, the first report of three adults with drug-resistant recurrent pericarditis treated with anakinra was published [83]. Other reports confirmed the beneficial effects of anakinra in patients whose disease was resistant to conventional treatments [78, 84–86].

Anakinra was tested in the AIRTRIP trial [67] and the IRAP (International Registry of Anakinra for Pericarditis) study [79] in patients with recurrent pericarditis. The AIRTRIP trial included 21 patients with recurrent pericarditis (three or more flares) that was not responding to colchicine and was dependent on glucocorticoids. In the first, open-label, phase of the study, all patients showed a rapid improvement of symptoms and signs of inflammation and stopped glucocorticoids. At day 60, they were randomized to continue anakinra or to placebo. The placebo group displayed a net increase in recurrence rates (90% vs 18%, incidence rate difference − 1.95%; 95% confidence interval [CI] − 3.3 to − 0.6) and a shorter disease-free period [67]. In the IRAP study, 244 patients with colchicine-resistant, glucocorticoid-dependent recurrent pericarditis (three or more episodes)—mainly idiopathic—who were treated with anakinra in the same way as in the AIRTRIP trial experienced a net reduction in recurrences (rate ratio 0.17; 95% CI 0.14–0.20) [79]. Almost 75% of patients receiving glucocorticoids stopped the treatment. Patients treated with anakinra for > 3 months experienced a longer recurrence-free period at the 18- month follow-up than patients undergoing rapid tapering (≤ 3 months) [79]. In a small study, anakinra was administered in patients with acute pericarditis while NSAIDs and colchicine were suspended for 24 h [68]. Anakinra significantly reduced chest pain at 6 and 24 h and reduced IL-6 levels at 24 h with no need for rescue pain medication [68].

Anakinra was tested in patients with glucocorticoid-dependent, colchicine-resistant recurrent or incessant pericarditis who developed constrictive pericarditis. In 63% of patients, anakinra led to complete resolution of pericardial constriction within a median of 1.2 months; in the remaining patients, constriction became chronic, requiring pericardiectomy within a median of 2.8 months, irrespective of CRP levels [87]. These findings were also confirmed in some case reports [88, 89].

Rilonacept

Rilonacept is an engineered dimeric fusion protein made up of the extracellular portion of IL-1R1 and the IL-1 receptor accessory protein linked to the fragment crystallizable portion of the human immunoglobulin G1. [80]. Rilonacept acts as an IL-1α and IL-1β cytokine trap that blocks their binding with the receptor and consequent initiation of IL-1-mediated inflammation [27] (Fig. 1). Most common side effects are injection site reactions and upper respiratory infections. Concurrent administration of rilonacept with tumor necrosis factor-blocking agents is not recommended because it may predispose the patient to serious infections. According to RHAPSODY trial data, tapering of rilonacept might not be necessary because of the gradual washout pharmacokinetics of the drug over 5–8 weeks [90]. However, progressive tapering is generally suggested after 6–24 months of controlled symptoms and could be performed by delaying the interval of drug administration of 1 week every 2 weeks across a period of 3–6 months, although additional data are needed in this regard.

The US Food and Drug Administration has approved rilonacept for the treatment of cryopyrin-associated period syndromes and, since 2021, for recurrent pericarditis in adults and children aged ≥ 12 years without specification of the etiology in light of the positive results from the RHAPSODY trial [69]. This study enrolled patients with recurrent pericarditis (two or more flares) presenting with signs and symptoms of an acute episode and an increase in CRP levels while on NSAIDs, colchicine, or oral glucocorticoids in any combination. In the 12-week run-in period, patients were weaned off the pre-enrollment treatment with a weekly injection of rilonacept (160 mg, after a loading dose of 320 mg); 71% of patients achieved a clinical response, with normalization of CRP (mostly within 1 week), no or minimal pericardial pain (generally within 5 days), and no recurrences. They were randomly assigned to weekly rilonacept or placebo, and rilonacept provided a dramatic reduction in recurrences (− 96%). Indeed, pericarditis recurred in 74% of patients in the placebo group compared with 7% of patients in the rilonacept group (hazard ratio 0.04; 95% CI 0.01–0.18); the median time to recurrence could not be estimated for rilonacept and was 8.6 weeks (95% CI 4.0–11.7) for placebo [69]. Importantly, two recurrences were reported in the rilonacept group and were dependent on temporary suspension of 1–3 weekly doses [90]. In addition, at week 16 from the randomized withdrawal period, all secondary outcomes (persisting clinical response, improved patient QoL, no or minimal pericardial symptoms) highlighted a clear benefit of rilonacept over placebo [69]. The trial offered an option to continue rilonacept for additional 24 months in an open-label fashion, and these results were published recently [91]. During the extension period, the incidence of recurrences was low compared with oral therapies. Only 1 of 33 (3%) patients continuing rilonacept experienced a recurrence 4 weeks after treatment interruption, whereas 75% of patients stopping rilonacept experienced a recurrence after nearly 12 weeks, meaning a 98% reduction in risk of recurrences [91]. The beneficial effect of rilonacept was also confirmed in patients receiving vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or experiencing coronavirus disease 2019 (COVID-19). In fact, no recurrences were associated with vaccination or with COVID-19, the severity of which was mild in most patients [92]. Additional analyses from the RHAPSODY trial reported improved QoL in patients receiving rilonacept, whereas it worsened during a recurrence in patients receiving placebo and improved following rilonacept bailout [12]. Rilonacept monotherapy also allowed for rapid discontinuation (7.9 weeks) of oral anti-inflammatory therapies without triggering recurrences, irrespective of a sequential or concurrent taper approach [93]. A RHAPSODY trial sub-study looked at whether pericardial late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) was associated with time to pericarditis recurrence. More recurrences and higher CRP levels were recorded in patients with moderate-to-severe pericardial LGE. Although patients with moderate/severe LGE had the same rate of recurrences than those with trace/mild LGE, the time to recurrence was significantly shorter in those with moderate/severe LGE than in those with trace/mild LGE [94]. However, among patients who entered the RHAPSODY long-term extension, despite clinical and CMR improvement during prolonged rilonacept treatment finding, an absence of or trace LGE while on treatment did not predict the absence of recurrence once rilonacept was withdrawn [95]. However, these findings should be considered with caution because of the small sample size and the low number of events of this sub-study. The prognostic role of CMR findings in recurrent pericarditis was demonstrated previously, with results showing pericardial thickening and pericardial LGE to be negative and positive predictors, respectively, of adverse events such as further recurrences, cardiac tamponade, and constrictive pericarditis [96].

Goflikicept

Goflikicept is a heterodimeric fusion protein that binds both isoforms of IL-1, with a higher affinity for IL-1β than for IL-1α or IL-1Ra [97] (Fig. 1). Its half-life is 10 days, which allows for subcutaneous administration every 2 weeks. Goflikicept is being studied in the treatment of conditions where IL-1 is involved, such as gout, familial Mediterranean fever, and acute ST-segment elevation myocardial infarction (NCT04067492 [study terminated for insufficient recruitment and company decision], NCT05092776, and NCT04463251, respectively). Goflikicept significantly reduced systemic inflammation (measured as area under the curve for high-sensitivity CRP) at both 14 and 28 days compared with placebo in patients with ST segment elevation myocardial infarction, without significant differences between 80 mg and 160 mg [98, 99].

Goflikicept was studied in a phase II/III double-blind, randomized withdrawal, placebo-controlled study in patients with recurrent pericarditis with an active or a previous flare, provided they experienced at least one recurrence [28]. After a 4-week screening period, patients entered the open-label run-in period (12 weeks for NSAID and/or colchicine treatment or 24 weeks for glucocorticoids) where patients were maintained on oral anti-inflammatory drugs at the same dosage for 14 days and then shifted to subcutaneous goflikicept monotherapy without tapering, except for glucocorticoids, which were reduced and stopped within the next 12 weeks. In this phase, a dose-finding approach was tested, suggesting a loading dose of 160 mg at baseline, then 80 mg at week 1, week 2, and every 2 weeks thereafter. Responders at day 14 (meaning a chest pain score ≤ 3 on a numeric rating scale [NRS], CRP concentration ≤ 5 mg/L, and absent or mild pericardial effusion on echocardiography) transitioned into the randomized withdrawal period and received goflikicept 80 mg or placebo for 24 weeks. Patients who completed the main study had the chance to be included in the open-label extension study lasting for 24 months. In total, 20 patients were randomized (10 per group). No recurrences occurred with goflikicept, but 90% of patients experienced recurrences with placebo, with a median time to recurrence of 49.5 days. Adverse events occurred mostly among goflikicept-treated patients and included injection site reactions and mild respiratory and gastrointestinal infections; no deaths were recorded in either group [28].

Other Therapies

Azathioprine was studied in patients with isolated recurrent pericarditis of different etiologies, excluding cases associated with systemic diseases to reduce as much as possible the dosage of glucocorticoids. In 63% of patients, no recurrences were reported after starting azathioprine and glucocorticoid tapering until suspension was possible, whereas the remaining participants experienced at least one recurrence while tapering glucocorticoids. Importantly, no differences in azathioprine dosages were observed between responders and non-responders [100]. Methotrexate and mycophenolate mofetil are effective and well tolerated in patients with recurrent pericarditis who do not respond to glucocorticoids or become glucocorticoid-dependent [101]. Scant evidence is available about intravenous immunoglobulins [102, 103].

Pericardiectomy should be considered in refractory cases (persisting chest pain while on best medical therapy causing poor QoL) and performed in high-volume centers with large experience [104]. Characteristics of best candidates, timing of the procedure, and complications still represent challenges, and limited evidence has been published in recent years [105–108]. Operative and perioperative mortality, although reduced, is not negligible, especially in older patients with comorbidities, chest irradiation, and prior cardiac surgery [109].

Future Perspectives

Cannabidiol is the primary non-psychoactive compound of cannabis [110]. It exerts anti-inflammatory and antioxidant effects through the nuclear factor-κB and interferon-β pathways [111] and blocks NLRP3 inflammasome activation by reducing inflammasome priming [112–114] (Fig. 1). Cannabidiol also reduces neutrophil activation [115, 116] and lymphocyte proliferation [117, 118]. This wealth of beneficial effects has led to cannabidiol being studied in different cardiovascular diseases, such as diabetic cardiomyopathy, doxorubicin-induced cardiotoxicity, ischemia-reperfusion injury, myocarditis, and pericarditis [119]. In a mouse model of acute pericarditis caused by intrapericardial injection of zymosan, cannabidiol suppressed IL-1β secretion by macrophages and decreased pericardial effusion and thickness [120]. MAvERIC-Pilot (Impact of CardiolRx^TM on Recurrent Pericarditis, NCT05494788) is an ongoing phase II study to assess the safety/tolerance of oral cannabidiol on top of NSAIDs, colchicine, or glucocorticoids and improvement in chest pain after 8 weeks of treatment. Positive interim results have been recently announced [121]. In this study, 27 patients with symptomatic recurrent pericarditis (two or more recurrences), an NRS pain score ≥ 4, an elevated CRP (≥ 10 mg/L), or CMR evidence of pericardial inflammation were enrolled at eight clinical sites in the USA. During progressive titration of cannabidiol up to 10 mg/kg twice daily, or the maximum tolerated dose, patients have continued baseline anti-inflammatory therapy, which will be weaned off in the extension period to assess recurrences (89% of patients were transitioned in this phase). The primary endpoint of patient-reported pericardial pain showed a mean reduction of 3.7 on the NRS after 8 weeks of treatment. In the same period, 80% of patients with a baseline CRP ≥10 mg/L normalized from 57 mg/L at baseline to 3 mg/L at 8 weeks.

In addition, the MAVERIC-2 study has been recently announced [122]. This randomized, double-blind, placebo-controlled phase II/III trial will be conducted in patients with stable recurrent pericarditis previously treated with an IL-1 blocker. They will be randomized to cannabidiol (CardiolRx™) or placebo after cessation of the IL-1 blocker to assess the impact of the drug on the time free from a new flare. Changes in patient-reported pericarditis chest pain score and CRP levels will also be evaluated [122].

Administration of a selective NLRP3 inhibitor [123] effectively reduced pericardial inflammation in terms of both pericardial effusion and pericardial thickening [18]. Although promising, selective NLRP3 inflammasome blockers need further investigation in this setting [64], which is now facilitated by several available animal models [124]. Future research should address the optimal timing to start inflammasome/IL-1-based therapies and whether and how anti-inflammatory drugs should be tapered, since data remain limited and—as yet—available only from the IRAP and RHAPSODY studies [69, 79]. Additionally, phenotyping of patients with pericarditis should take advantage of routine multimodality imaging, as summarized in a recent position statement [39], and look for alternative inflammatory biomarkers such as IL-6 to select the best anti-inflammatory treatment for each patient and the best duration of treatment. To this end, PERIPLO (Clinical Phenotypes in Pericarditis: IL-1RA Antibodies and suPAR Levels; NCT05925790) is an ongoing study evaluating the pathophysiology of recurrent pericarditis by assessing the role of autoantibodies against IL-1RA and levels of soluble urokinase plasminogen activator receptor (suPAR) to discriminate between inflammatory and non-inflammatory phenotypes and provide the best treatment for such patients.

Some evidence about the role of genetic variants in the pathogenesis of recurrent pericarditis is available. Thorolfsdottir et al. [125] reported a large meta-analysis of pericarditis genome-wide association studies in individuals with European genetic ancestry from five countries (22.6% with recurrent pericarditis) and described two independent common intergenic genetic variants associated with pericarditis in genes encoding for the majority of IL-1 cytokines, with one of them showing a stronger magnitude of association with recurrent than with acute pericarditis [125]. In a retrospective cohort of patients with recurrent pericarditis, whole-exome sequencing enabled the identification of gene variants related to the inflammatory response in 14.8% of patients, including genes known to be associated with recurrent pericarditis (NLRP3, TNFRSF1A, and MEFV) and others involved in inflammation/immunodeficiency (IFIH1, NFKBIA, JAK1, NOD2, and ALPK1) [126]. The role of the R202Q (c.605G>A, p.Arg202Gln) missense variant of the MEFV gene may have a role in cases of glucocorticoid-dependent recurrent pericarditis, suggesting an autoinflammatory phenotype similar to that of familial Mediterranean fever, where IL-1 blockers cannot be suspended due to subsequent relapse [81]. These findings suggest that future research should focus on a deeper understanding of the genetic background to improve risk stratification and treatment of patients with recurrent pericarditis.

Conclusion

In the past decade, advancements in the management of patients with acute and recurrent pericarditis have been made. This has been possible via multimodality imaging, improved risk stratification, and recognition of patients with an autoinflammatory phenotype who benefit the most from IL-1 blockers. Ongoing research is focused on further investigating the pathogenesis of complicated cases to improve diagnosis and develop targeted therapies. Alongside this, the management of such patients, especially those experiencing recurrences, needs close, dedicated follow-up, including clinical evaluation, measurement of inflammatory biomarkers, and cardiac imaging aimed at tapering anti-inflammatory drugs when inflammation is truly resolved and following up difficult-to-treat recurrences over time.

Declarations

Funding

The study received no funding.

Conflicts of interest

AA has served as a consultant for Kiniksa, Novo Nordisk, and Monte Rosa Therapeutics. All the other authors have nothing to disclose.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

Not applicable.

Code availability

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Author contributions

AB and AA conceived the general structure of the manuscript. AB, DS, and AA drafted the first version of the manuscript. DS drafted Fig. 1. AA critically revised the manuscript. All authors read and approved the final version of the manuscript.