Does the available evidence support the use of anakinra in the management of constrictive pericarditis?
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Introduction
Constrictive pericarditis (CP) is a progressive and debilitating condition characterized by the thickening and scarring of the pericardium (membrane surrounding the heart).1,2 This thickening reduces the pericardium’s elasticity, preventing the heart from fully expanding during diastole. Consequently, this restriction leads to decreased cardiac output and symptoms resembling heart failure with preserved ejection fraction, including fatigue, shortness of breath, peripheral edema, and abdominal swelling. Hepatomegaly, ascites, and pleural effusions may also occur in individuals with this condition.
The overall prevalence and incidence of CP is difficult to determine as the condition is relatively rare.1 In developed countries, the most frequently reported causes of CP are idiopathic or viral origins, post-cardiac surgery, and post-radiation therapy. Diagnosing CP is also challenging as it often presents unexpectedly and shares symptoms with various other conditions, including lung or liver disease. An electrocardiogram, cardiac imaging (computed tomography and/or cardiac magnetic resonance), cardiac catheterization, and laboratory markers provide complementary information that may be used to inform a diagnosis of CP.
Guidelines
Pericardiectomy is the definitive treatment for chronic constrictive pericarditis.1-3 However, when active pericardial inflammation is apparent through imaging or laboratory markers (elevated C-reactive protein [CRP], etc), deferring pericardiectomy and attempting anti-inflammatory therapy may be warranted to identify patients with transient CP that can be resolved without surgery. Notably, anti-inflammatory drugs may resolve transient CP occurring in 10% to 20% of cases of CP within a few months. Additionally, in cases where surgery is ultimately deemed necessary, anti-inflammatory therapy may contribute to a more successful pericardiectomy.3
Navigating anti-inflammatory treatment selection in the setting of CP is complex, and conventional treatments for acute pericarditis, including non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, may be unsuccessful and even detrimental in cases of CP.4-9 Both NSAIDs and corticosteroids can worsen water and sodium retention, which is a significant concern as most patients with CP present with congestion.4,5 Furthermore, corticosteroids may increase surgical risk by impeding wound healing, posing challenges if pericardiectomy ultimately becomes necessary.4 Anakinra, an interleukin-1 (IL-1) blocker has been evaluated off-label for patients with CP who have evidence or active inflammation.4-9 Of note, anakinra has also been studied for recurrent pericarditis, which is outside of the scope of this review.9
Literature
In December 2023, a PubMed search was conducted to locate primary literature on anakinra use in the setting of CP. One prospective cohort study6 and 3 case reports5,7,8 were identified that describe the use of anakinra in patients with CP and evidence of active inflammation (Table 1). A 2020 prospective cohort study by Andreis et al revealed that after initiating anakinra, 5 of 8 patients with confirmed CP experienced a reversal of constriction within a median of 1.2 months.6 The remaining 3 patients underwent pericardiectomy within a median of 2.8 months. Case reports by Schatz et al (2016), D’Elia et al (2015), and Lazros et al (2015) further support the effectiveness of anakinra in reversing CP with evidence of inflammation, demonstrating complete resolution or improvement in CP symptoms within weeks to months after initiating therapy.5,7,8 A consistent dosage of anakinra across all studies was 100 mg subcutaneously once daily.5-8 In some cases, other anti-inflammatory therapies (colchicine, etc) were administered along with anakinra. The duration of anakinra therapy varied between 3 and 18 months, with a taper commencing upon the resolution of symptoms or other indicators of constriction resolution (echocardiogram, imaging, etc).
It is important to note that caution is advised when using anakinra in certain populations, including older adults, due to their increased risk of infections, and in individuals with renal impairment, as the drug is excreted renally.10 Adverse reactions with anakinra may include injection site reactions and flu-like symptoms. Additionally, the drug has warnings regarding the increased risk of serious infections and hypersensitivity reactions. Anakinra is not recommended in combination with tumor necrosis factor blocking agents, and live vaccines should not be administered during treatment. Neutrophil counts should be assessed before starting anakinra and monitored regularly during treatment.
Conclusion
Constrictive pericarditis refers to inflammation of the pericardium that causes reduced compliance, which impedes diastolic filling and leads to symptoms of diastolic heart failure. Successful use of anakinra 100 mg subcutaneously once daily in patients with CP and evidence of active inflammation has been reported in 1 cohort study and several case reports. The optimal duration of therapy, tapering strategies, and the need for concurrent anti-inflammatory treatment with conventional agents (colchicine, etc) requires further study.
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| Table 1. Literature describing the use of anakinra for constrictive pericarditis.5-9 | |||
|---|---|---|---|
| Citation | Study Design/ Population | Treatment | Timeline/ Outcomes |
| Andreis et al (2020)6 | Prospective cohort N=39 patients with GC-dependent and colchicine-resistant recurrent or incessant pericarditis and clinical features of CP. Of these patients, 8 had confirmed CP. CRP elevation was reported in 7 of 8 patients with CP | Anakinra 100 mg SC once daily plus colchicine (8 patients), NSAID (5 patients), GC (7 patients) | Anakinra was continued for a median duration of 6 months (IQR, 4 to 7), then tapered for a median duration of 3 months (IQR, 0 to 6) Anakinra reversed CP in 5 of 8 patients within a median of 1.2 months (IQR, 1 to 4). The other 3 patients required pericardiectomy within a median of 2.8 months (IQR, 2 to 5). |
| Schatz et al (2016)7 | Case report 39 year-old women with RA affecting multiple joints found to have CP after an acute episode of pericarditis and failure of approximately 4 weeks of colchicine/NSAID/GC therapy CRP: NR | Anakinra 100 mg SC once daily | 1 week: complete resolution of symptoms 3 months: anakinra discontinued |
| D'Elia et al5 (2015) | Case report 47-year-old woman found to have CP after an acute episode of pericarditis and failure of colchicine/NSAID/GC/antibiotics for 1 month, followed by high-dose IV GC plus indomethacin that caused severe water retention CRP: 10 mg/dl | Anakinra 100 mg SC once daily plus colchicine | 2 weeks: improvement of constriction on echocardiogram 3 months: complete resolution of constriction on imaging and echocardiogram 6 months: anakinra was tapered by 100 mg per week every month 9 months: anakinra discontinued; colchicine continued |
| Lazros et al (2015)8 | Case report 46-year old man found to have effusive-CP after an episode of acute pericarditis successfully treated with colchicine/NSAID/GC approximately 4 months prior NSAIDs/colchicine were started at the subsequent hospitalization CRP: 31 mg/dL | Anakinra 100 mg SC once daily | Authors reported “prompt clinical remission and CRP normalization” 6 months: reduction of constriction on imaging 12 months: tapering of anakinra began 18 months: anakinra administered every other day |
| Abbreviations: CP, constrictive pericarditis; CRP, C-reactive protein; GC, glucocorticoids; IQR, interquartile range; IV, intravenous; NR, not reported; NSAID, non-steroidal anti-inflammatory drugs; RA, rheumatoid arthritis; SC, subcutaneously. |
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References:
- Welch TD. Constrictive pericarditis: diagnosis, management and clinical outcomes.Heart. 2018;104(9):725-731. doi:10.1136/heartjnl-2017-311683
- Chiabrando JG, bonaventura a, vecchié a, et al. Management of acute and recurrent pericarditis: JACC State-of-the-Art Review.J Am Coll Cardiol. 2020;75(1):76-92. doi:10.1016/j.jacc.2019.11.021
- Adler Y, Charron P, Imazio M, et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC)Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2015;36(42):2921-2964. doi:10.1093/eurheartj/ehv318
- Brucato A, Valenti A, Assolari A, Calabrese A, Imazio M, Martini A. Resolution of pericardial constriction with anakinra; possible role of C reactive protein. Int J Cardiol. 2017;234:150. doi:10.1016/j.ijcard.2016.11.312
- D’Elia E, Brucato A, Pedrotti P, et al. Successful treatment of subacute constrictive pericarditis with interleukin-1β receptor antagonist (anakinra). Clin Exp Rheumatol. 2015;33(2):294-295.
- Andreis A, Imazio M, Giustetto C, Brucato A, Adler Y, De Ferrari GM. Anakinra for constrictive pericarditis associated with incessant or recurrent pericarditis. Heart. 2020;106(20):1561-1565. doi:10.1136/heartjnl-2020-316898
- Schatz A, Trankle C, Yassen A, et al. Resolution of pericardial constriction with Anakinra in a patient with effusive-constrictive pericarditis secondary to rheumatoid arthritis. Int J Cardiol. 2016;223:215-216. doi:10.1016/j.ijcard.2016.08.131
- Lazaros G, Vasileiou P, Danias P, et al. Effusive-constrictive pericarditis successfully treated with anakinra. Clin Exp Rheumatol. 2015;33(6):945.
- Lazaros G, Tousoulis D. Interleukin-1 inhibition with anakinra: a valuable ally to reverse constrictive pericarditis?. Heart. 2020;106(20):1540-1542. doi:10.1136/heartjnl-2020-317187
- Kineret. Stockholm, Sweden: Swedish Orphan Biovitrum; 2020.
Prepared by:
Kathy Sarna, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
January 2024
The information presented is current as December 1, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.