Use of Interleukin-1 Blockers in Pericardial and Cardiovascular Diseases
Purpose of Review
This review aims to summarize the role of the interleukin-1 (IL-1) blocking agents in cardiovascular diseases, briefly describing the pathogenetic rationale and the most relevant clinical studies.
IL-1 is a pivotal cytokine of the innate immune system. Anti-IL-1 agents are currently used for the treatment of several autoimmune and autoinflammatory conditions. Recently, the role of IL-1 has also emerged in cardiovascular diseases. Indeed, two recent randomized controlled trials have shown that the IL-1 receptor antagonist anakinra is effective for the treatment of idiopathic recurrent pericarditis and the IL-1β blocking agent canakinumab is effective in reducing myocardial infarction in people at risk. Interestingly, interfering with IL-1 has proved to be also effective in other cardiovascular manifestations, such as myocarditis, arrhythmias, and heart failure.
Blocking the IL-1 pathway is a possible new therapeutic strategy, potentially leading to innovative therapies in many acute and chronic cardiovascular diseases.
KeywordsInterleukin-1 Anakinra Canakinumab Pericarditis Atherosclerosis Cardiovascular disease
Nucleotide-binding domain-like receptor
Caspase activation recruitment domain
Absent in melanoma
Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing
NLR-CARD (caspase activating and recruitment domain) containing
Pathogen-associated molecular patterns
Damage-associated molecular patterns
Myeloid differentiation primary response protein 88
Mitogen-activated protein kinase
Cryopyrin-associated periodic syndromes
Idiopathic recurrent pericarditis
Tumor necrosis factor receptor-1-associated periodic syndrome
Anakinra treatment of recurrent idiopathic pericarditis
Non-steroidal anti-inflammatory drugs
Anakinra (recombinant human interleukin-1 receptor antagonist) in heart failure
Acute decompensated heart failure
Left ventricle ejection fraction
Decompensated Heart failure Anakinra Response Trial
HF and preserved ejection fraction
New York Heart Association
Recently Decompensated Heart failure Anakinra Response Trial
Coronary artery disease
Virginia Commonwealth University - Anakinra Remodeling Trial
ST segment elevation
familial Mediterranean fever
Canakinumab Anti-inflammatory Thrombosis Outcome Study
Compliance with Ethical Standards
Conflict of Interest
Giacomo Emmi has received personal fees for consultancy from GSK and for advisory board from Novartis.
Maria Letizia Urban and Silvia Maestroni declare that they have no conflict of interest.
Massimo Imazio has received an Institutional Grant for Clinical Research from SOBI.
Marco Gattorno has received fees and unrestricted grants from SOBI and Novartis.
Giuseppe Lopalco has received speaker fees from Novartis and SOBI.
Luca Cantarini has received personal fees from Novartis and SOBI.
Domenico Prisco has received grants for advisory boards from Bayer, Daichi Sankyo, Boehringer Ingelheim, BMS Pfizer, and Baxter.
Antonio Brucato has received unrestricted grants from ACARPIA and SOBI and for advisory board from SOBI.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance•• Of major Importance
- 1.• Szekely Y, Arbel Y. A review of interleukin-1 in heart disease: where do we stand today? Cardiol Ther. 2018; https://doi.org/10.1007/s40119-018-0104-3. Relevant review focused on the role of IL-1 in heart diseases and potential therapeutic effects of anti-IL-1 treatments.
- 3.• Cavalli G, Dinarello CA. Treating rheumatological diseases and co-morbidities with interleukin-1 blocking therapies. Rheumatol Oxf Engl. 2015;54(12):2134–44. https://doi.org/10.1093/rheumatology/kev269. Clinical review highlighting the role of interfering with IL-1 in cardiovascular diseases and type 2 diabetes, conditions that are frequently encountered as co-morbidities in patients with rheumatic diseases. Google Scholar
- 4.•• Brucato A, Imazio M, Gattorno M, Lazaros G, Maestroni S, Carraro M, et al. Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: the AIRTRIP randomized clinical trial. JAMA. 2016;316(18):1906–12. https://doi.org/10.1001/jama.2016.15826. First controlled, randomized trial to determine the efficacy of anakinra for colchicine-resistant and corticosteroid-dependent recurrent pericarditis. PubMedGoogle Scholar
- 5.•• Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–31. https://doi.org/10.1056/NEJMoa1707914. First controlled randomized double-blind trial to evaluate the efficacy of canakinumab for patients with previous myocardial infarction and a high-sensitivity C-reactive protein. PubMedGoogle Scholar
- 16.• Cremer PC, Kumar A, Kontzias A, Tan CD, Rodriguez ER, Imazio M, et al. Complicated pericarditis: understanding risk factors and pathophysiology to inform imaging and treatment. J Am Coll Cardiol. 2016;68(21):2311–28. https://doi.org/10.1016/j.jacc.2016.07.785. Relevant review focused on complicated pericarditis, in particular risk factors, pathogenetic mechanisms, management, and imaging. PubMedGoogle Scholar
- 19.Martínez GJ, Celermajer DS, Patel S. The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation. Atherosclerosis. 2018 Feb;269:262–71. https://doi.org/10.1016/j.atherosclerosis.2017.12.027.PubMedGoogle Scholar
- 24.Vitale A, Insalaco A, Sfriso P, Lopalco G, Emmi G, Cattalini M, et al. A snapshot on the on-label and off-label use of the interleukin-1 inhibitors in Italy among rheumatologists and pediatric rheumatologists: a nationwide multi-center retrospective observational study. Front Pharmacol. 2016;7:380. https://doi.org/10.3389/fphar.2016.00380.PubMedPubMedCentralGoogle Scholar
- 25.Colafrancesco S, Priori R, Valesini G, Argolini L, Baldissera E, Bartoloni E, et al. Response to interleukin-1 inhibitors in 140 Italian patients with adult-onset Still’s disease: a multicentre retrospective observational study. Front Pharmacol. 2017;8:369. https://doi.org/10.3389/fphar.2017.00369.PubMedPubMedCentralGoogle Scholar
- 26.Fabiani C, Vitale A, Emmi G, Lopalco G, Vannozzi L, Guerriero S, et al. Interleukin (IL)-1 inhibition with anakinra and canakinumab in Behçet’s disease-related uveitis: a multicenter retrospective observational study. Clin Rheumatol. 2017;36(1):191–7. https://doi.org/10.1007/s10067-016-3506-4.PubMedGoogle Scholar
- 27.• Lazaros G, Antonatou K, Vassilopoulos D. The therapeutic role of interleukin-1 inhibition in idiopathic recurrent pericarditis: current evidence and future challenges. Front Med. 2017;4:78. https://doi.org/10.3389/fmed.2017.00078. Clinical review by opinion leaders in the field of treatment of recurrent pericarditis. Google Scholar
- 28.Adler Y, Charron P, Imazio M, Badano L, Barón-Esquivias G, Bogaert J, 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):2921–64. https://doi.org/10.1093/eurheartj/ehv318.PubMedGoogle Scholar
- 29.Picco P, Brisca G, Traverso F, Loy A, Gattorno M, Martini A. Successful treatment of idiopathic recurrent pericarditis in children with interleukin-1beta receptor antagonist (anakinra): an unrecognized autoinflammatory disease? Arthritis Rheum. 2009;60(1):264–8. https://doi.org/10.1002/art.24174.PubMedGoogle Scholar
- 33.Camprubí D, Mitjavila F, Arostegui JI, Corbella X. Efficacy of anakinra in an adult patient with recurrent pericarditis and cardiac tamponade as initial manifestations of tumor necrosis factor receptor-associated periodic syndrome due to the R92Q TNFRSF1A variant. Int J Rheum Dis. 2017;20(4):510–4. https://doi.org/10.1111/1756-185X.13029.PubMedGoogle Scholar
- 36.Schatz A, Trankle C, Yassen A, Chipko C, Rajab M, Abouzaki N, et al. Resolution of pericardial constriction with Anakinra in a patient with effusive-constrictive pericarditis secondary to rheumatoid arthritis. Int J Cardiol. 2016;223:215–6. https://doi.org/10.1016/j.ijcard.2016.08.131.PubMedGoogle Scholar
- 37.Finetti M, Insalaco A, Cantarini L, Meini A, Breda L, Alessio M, et al. Long-term efficacy of interleukin-1 receptor antagonist (anakinra) in corticosteroid-dependent and colchicine-resistant recurrent pericarditis. J Pediatr. 2014;164(6):1425–1431.e1. https://doi.org/10.1016/j.jpeds.2014.01.065.PubMedGoogle Scholar
- 40.Lazaros G, Vasileiou P, Koutsianas C, Antonatou K, Stefanadis C, Pectasides D, et al. Anakinra for the management of resistant idiopathic recurrent pericarditis. Initial experience in 10 adult cases. Ann Rheum Dis. 2014;73(12):2215–7. https://doi.org/10.1136/annrheumdis-2014-205990. PubMedGoogle Scholar
- 44.Ikonomidis I, Lekakis JP, Nikolaou M, Paraskevaidis I, Andreadou I, Kaplanoglou T, et al. Inhibition of interleukin-1 by anakinra improves vascular and left ventricular function in patients with rheumatoid arthritis. Circulation. 2008;117(20):2662–9. https://doi.org/10.1161/CIRCULATIONAHA.107.731877.PubMedGoogle Scholar
- 46.• Van Tassell BW, Abouzaki NA, Oddi Erdle C, Carbone S, Trankle CR, Melchior RD, et al. Interleukin-1 blockade in acute decompensated heart failure: a randomized, double-blinded, placebo-controlled pilot study. J Cardiovasc Pharmacol. 2016;67(6):544–51. https://doi.org/10.1097/FJC.0000000000000378. Interesting randomized, double-blinded, placebo-controlled pilot study to evaluate the role of anakinra in blocking acute inflammatory response during acute decompensated heart failure. PubMedPubMedCentralGoogle Scholar
- 47.Van Tassell BW, Arena R, Biondi-Zoccai G, Canada JM, Oddi C, Abouzaki NA, et al. Effects of interleukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study). Am J Cardiol. 2014;113(2):321–7. https://doi.org/10.1016/j.amjcard.2013.08.047.PubMedGoogle Scholar
- 48.Van Tassell BW, Buckley LF, Carbone S, Trankle CR, Canada JM, Dixon DL, et al. Interleukin-1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2). Clin Cardiol. 2017;40(9):626–32. https://doi.org/10.1002/clc.22719.PubMedGoogle Scholar
- 49.Van Tassell BW, Canada J, Carbone S, Trankle C, Buckley L, Oddi Erdle C, et al. Interleukin-1 blockade in recently decompensated systolic heart failure: results from REDHART (Recently Decompensated Heart Failure Anakinra Response Trial). Circ Heart Fail. 2017;10(11):e004373. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004373. PubMedGoogle Scholar
- 51.Ikonomidis I, Tzortzis S, Andreadou I, Paraskevaidis I, Katseli C, Katsimbri P, et al. Increased benefit of interleukin-1 inhibition on vascular function, myocardial deformation, and twisting in patients with coronary artery disease and coexisting rheumatoid arthritis. Circ Cardiovasc Imaging. 2014;7(4):619–28. https://doi.org/10.1161/CIRCIMAGING.113.001193.PubMedGoogle Scholar
- 52.Abbate A, Kontos MC, Grizzard JD, Biondi-Zoccai GGL, Van Tassell BW, Robati R, et al. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot study). Am J Cardiol. 2010;105(10):1371–1377.el. https://doi.org/10.1016/j.amjcard.2009.12.059.PubMedGoogle Scholar
- 53.Abbate A, Van Tassell BW, Biondi-Zoccai G, Kontos MC, Grizzard JD, Spillman DW, et al. Effects of interleukin-1 blockade with anakinra on adverse cardiac remodeling and heart failure after acute myocardial infarction [from the Virginia Commonwealth University-Anakinra Remodeling Trial (2) (VCU-ART2) pilot study]. Am J Cardiol. 2013;111(10):1394–400. https://doi.org/10.1016/j.amjcard.2013.01.287.PubMedPubMedCentralGoogle Scholar
- 54.• Abbate A, Kontos MC, Abouzaki NA, Melchior RD, Thomas C, Van Tassell BW, et al. Comparative safety of interleukin-1 blockade with anakinra in patients with ST-segment elevation acute myocardial infarction (from the VCU-ART and VCU-ART2 pilot studies). Am J Cardiol. 2015;115(3):288–92. https://doi.org/10.1016/j.amjcard.2014.11.003. Valuable patient-level pooled analysis on 40 patients from two previous pilot studies, showing that anakinra may prevent new-onset heart failure after STEMI at a long-term follow-up. PubMedGoogle Scholar
- 55.• Morton AC, Rothman AMK, Greenwood JP, Gunn J, Chase A, Clarke B, et al. The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study. Eur Heart J. 2015;36(6):377–84. https://doi.org/10.1093/eurheartj/ehu272. Interesting phase II, double-blinded, randomized, placebo-controlled trial showing the importance of anakinra in reducing inflammatory markers in acute coronary syndromes. PubMedGoogle Scholar
- 60.Ridker PM, Howard CP, Walter V, Everett B, Libby P, Hensen J, et al. Effects of interleukin-1β inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation. 2012;126(23):2739–48. https://doi.org/10.1161/CIRCULATIONAHA.112.122556.PubMedGoogle Scholar
- 61.Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ, et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet Lond Engl. 2018;391(10118):319–28. https://doi.org/10.1056/NEJMoa1707914.Google Scholar
- 62.•• Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ, et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet Lond Engl. 2017;390(10105):1833–42. https://doi.org/10.1016/S0140-6736(17)32247-X. Intriguing exploratory analysis on the reduction of mortality by lung cancer after blockade of interleukin-1β pathway. Google Scholar
- 64.Neri Serneri GG, Boddi M, Modesti PA, Cecioni I, Coppo M, Papa ML, et al. Immunomediated and ischemia-independent inflammation of coronary microvessels in unstable angina. Circ Res. 2003;92(12):1359–66. https://doi.org/10.1161/01.RES.0000079025.38826.E1.PubMedGoogle Scholar
- 65.Becatti M, Marcucci R, Bruschi G, Taddei N, Bani D, Gori AM, et al. Oxidative modification of fibrinogen is associated with altered function and structure in the subacute phase of myocardial infarction. Arterioscler Thromb Vasc Biol. 2014;34(7):1355–61. https://doi.org/10.1161/ATVBAHA.114.303785.PubMedGoogle Scholar
- 66.•• Becatti M, Emmi G, Silvestri E, Bruschi G, Ciucciarelli L, Squatrito D, et al. Neutrophil activation promotes fibrinogen oxidation and thrombus formation in Behçet disease. Circulation. 2016;133(3):302–11. https://doi.org/10.1161/CIRCULATIONAHA.115.017738. Important evidence that altered fibrinogen structure and impaired fibrinogen function are associated with neutrophil activation and enhanced reactive oxygen species production, suggesting a link between inflammation and thrombosis in systemic vasculitis. PubMedGoogle Scholar