Internal and Emergency Medicine

, Volume 13, Issue 4, pp 475–489 | Cite as

Management of idiopathic recurrent pericarditis in adults and in children: a role for IL-1 receptor antagonism

  • Antonio Brucato
  • Giacomo Emmi
  • Luca Cantarini
  • Andrea Di Lenarda
  • Marco Gattorno
  • Giuseppe Lopalco
  • Renzo Marcolongo
  • Massimo Imazio
  • Alberto Martini
  • Domenico Prisco


Recurrent pericarditis is one of the most frequent pericardial diseases, affecting up to 30% of the patients who have experienced acute pericarditis. While the diagnosis of acute pericarditis is sometime straight forward, its etiology and therapeutic management are still a challenge for physicians. In developed countries, the idiopathic form is the most frequent, and the search for an infectious etiology is almost invariably negative. Nevertheless, since standard treatment with nonsteroidal anti-inflammatory drugs and colchicine is not always able to neutralize pericardial inflammation in recurrent pericarditis, anakinra, an IL-1 receptor antagonist, has been proposed as a possible therapeutic alternative for refractory forms. IL-1 is a cytokine that exerts a pivotal role in innate immunity and in the pathogenesis of some autoimmune diseases, such as rheumatoid arthritis, and in autoinflammatory disorders, as familial Mediterranean fever and cryopyrin-associated periodic syndromes. The successful management of patients with acute idiopathic recurrent pericarditis (IRP) needs a teamwork approach, where cardiologists, rheumatologists, clinical immunologists and internists are involved. In this review, we will discuss the clinical and therapeutical challenges of IRP both in adults and children from a clinical practice standpoint. We will also briefly illustrate the main pathogenic mechanisms of IRP to provide internists and cardiologists with the rationale for approaching the use of anakinra in selected clinical cases.


Pericardial diseases Recurrent pericarditis Autoimmune diseases Autoinflammatory diseases Interleukin-1Ra Anakinra 



The authors would like to thank Maria L. Urban, Alessandra Bettiol, Stefano Salvati, Chiara Marvisi and Valerio Maniscalco for their help in preparing tables and figures.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Statement of human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent



  1. 1.
    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 36:2921–2964. CrossRefPubMedGoogle Scholar
  2. 2.
    Imazio M, Gaita F, LeWinter M (2015) Evaluation and treatment of pericarditis: a systematic review. JAMA 314:1498–1506. CrossRefPubMedGoogle Scholar
  3. 3.
    Brucato A, Brambilla G, Moreo A, Alberti A, Munforti C, Ghirardello A et al (2006) Long-term outcomes in difficult-to-treat patients with recurrent pericarditis. Am J Cardiol 98:267–271CrossRefPubMedGoogle Scholar
  4. 4.
    Brucato A, Imazio M, Gattorno M, Lazaros G, Maestroni S, Carraro M et al (2016) Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: the AIRTRIP randomized clinical trial. JAMA 316:1906–1912. CrossRefPubMedGoogle Scholar
  5. 5.
    Buckley L, Viscusi MM, Van Tassell B, Abbate A (2017) Interleukin-1 blockade for the treatment of pericarditis. Eur Heart J Cardiovasc Pharmacother. Google Scholar
  6. 6.
    LeWinter MM (2014) Clinical practice. Acute pericarditis. N Engl J Med 371:2410–2416. CrossRefPubMedGoogle Scholar
  7. 7.
    Imazio M, Gaita F (2015) Diagnosis and treatment of pericarditis. Heart 2101:1159–1168. CrossRefGoogle Scholar
  8. 8.
    Shakti D, Hehn R, Gauvreau K, Sundel RP, Newburger JW (2014) Idiopathic pericarditis and pericardial effusion in children: contemporary epidemiology and management. J Am Heart Assoc 7 3(6):e001483. CrossRefGoogle Scholar
  9. 9.
    Kytö V, Sipilä J, Rautava P (2014) Clinical profile and influences on outcomes in patients hospitalized for acute pericarditis. Circulation 130:1601–1606. CrossRefPubMedGoogle Scholar
  10. 10.
    Imazio M, Cecchi E, Demichelis B, Chinaglia A, Ierna S, Demarie D et al (2008) Myopericarditis versus viral or idiopathic acute pericarditis. Heart Br Card Soc 94:498–501. CrossRefGoogle Scholar
  11. 11.
    Søgaard KK, Farkas DK, Ehrenstein V, Bhaskaran K, Bøtker HE, Sørensen HT (2017) Pericarditis as a marker of occult cancer and a prognostic factor for cancer mortality. Circulation 12(136):996–1006. CrossRefGoogle Scholar
  12. 12.
    Imazio M, Brucato A, Cemin R, Ferrua S, Maggiolini S, Beqaraj F et al (2013) A randomized trial of colchicine for acute pericarditis. N Engl J Med 17(369):1522–1528. CrossRefGoogle Scholar
  13. 13.
    Imazio M, Brucato A, Cemin R, Ferrua S, Belli R, Maestroni S et al (2011) Colchicine for recurrent pericarditis (CORP): a randomized trial. Ann Intern Med 155:409–414. CrossRefPubMedGoogle Scholar
  14. 14.
    Imazio M, Bobbio M, Cecchi E, Demarie D, Pomari F, Moratti M et al (2005) Colchicine as first-choice therapy for recurrent pericarditis: results of the CORE (COlchicine for REcurrent pericarditis) trial. Arch Intern Med 165:1987–1991. CrossRefPubMedGoogle Scholar
  15. 15.
    Imazio M, Belli R, Brucato A, Cemin R, Ferrua S, Beqaraj F et al (2014) Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised trial. Lancet Lond Engl 383:2232–2237. CrossRefGoogle Scholar
  16. 16.
    Brucato A, Valenti A, Maisch B (2017) Acute and recurrent pericarditis: still idiopathic? J Am Coll Cardiol 69:2775. CrossRefPubMedGoogle Scholar
  17. 17.
    Cremer PC, Kumar A, Kontzias A, Tan CD, Rodriguez ER, Imazio M et al (2016) Complicated pericarditis: understanding risk factors and pathophysiology to inform imaging and treatment. J Am Coll Cardiol 29(68):2311–2328. CrossRefGoogle Scholar
  18. 18.
    Imazio M (2014) Idiopathic recurrent pericarditis as an immune-mediated disease: current insights into pathogenesis and emerging treatment options. Expert Rev Clin Immunol 10:1487–1492. CrossRefPubMedGoogle Scholar
  19. 19.
    Urowitz MB, Tselios K (2017) Cardiovascular and pulmonary manifestations of systemic lupus erythematosus. Curr Rheumatol Rev. PubMedGoogle Scholar
  20. 20.
    Vianello F, Cinetto F, Cavraro M, Battisti A, Castelli M, Imbergamo S et al (2011) Azathioprine in isolated recurrent pericarditis: a single centre experience. Int J Cardiol 147:477–478. CrossRefPubMedGoogle Scholar
  21. 21.
    Imazio M, Brucato A, Pluymaekers N, Breda L, Calabri G, Cantarini L et al (2016) Recurrent pericarditis in children and adolescents: a multicentre cohort study. J Cardiovasc Med Hagerstown Md 17:707–712. CrossRefGoogle Scholar
  22. 22.
    Caforio ALP, Brucato A, Doria A, Brambilla G, Angelini A, Ghirardello A et al (2010) Anti-heart and anti-intercalated disk autoantibodies: evidence for autoimmunity in idiopathic recurrent acute pericarditis. Heart Br Card Soc 96:779–784. CrossRefGoogle Scholar
  23. 23.
    Maestroni S, Di Corato PR, Cumetti D, Chiara DBLC, Ghidoni S, Prisacaru L et al (2012) Recurrent pericarditis: autoimmune or autoinflammatory? Autoimmun Rev 12:60–65. CrossRefPubMedGoogle Scholar
  24. 24.
    Cantarini L, Vitale A, Lucherini OM, De Clemente C, Caso F, Costa L et al (2015) The labyrinth of autoinflammatory disorders: a snapshot on the activity of a third-level center in Italy. Clin Rheumatol 34:17–28. CrossRefPubMedGoogle Scholar
  25. 25.
    Rigante D, Vitale A, Lucherini OM, Cantarini L (2014) The hereditary autoinflammatory disorders uncovered. Autoimmun Rev 13:892–900. CrossRefPubMedGoogle Scholar
  26. 26.
    Cattalini M, Soliani M, Lopalco G, Rigante D, Cantarini L (2016) Systemic and organ involvement in monogenic autoinflammatory disorders: a global review filtered through internists’ lens. Intern Emerg Med 11:781–791. CrossRefPubMedGoogle Scholar
  27. 27.
    de Torre-Minguela C, Mesa Del Castillo P, Pelegrín P (2017) The NLRP3 and pyrin inflammasomes: implications in the pathophysiology of autoinflammatory diseases. Front Immunol 8:43. PubMedPubMedCentralGoogle Scholar
  28. 28.
    Brucato A, Shinar Y, Brambilla G, Robbiolo L, Ferrioli G, Patrosso MC et al (2005) Idiopathic recurrent acute pericarditis: familial Mediterranean fever mutations and disease evolution in a large cohort of Caucasian patients. Lupus 14:670–674. CrossRefPubMedGoogle Scholar
  29. 29.
    Cantarini L, Lucherini OM, Brucato A, Barone L, Cumetti D, Iacoponi F et al (2012) Clues to detect tumor necrosis factor receptor-associated periodic syndrome (TRAPS) among patients with idiopathic recurrent acute pericarditis: results of a multicentre study. Clin Res Cardiol Off J Ger Card Soc 101:525–531. CrossRefGoogle Scholar
  30. 30.
    Emmi G, Barnini T, Silvestri E, Milco D’Elios M, Emmi L, Prisco D (2014) A new case of idiopathic recurrent acute pericarditis due to R104Q mutation in TNFRSF1A successfully treated with anakinra: expanding the questions. Clin Exp Rheumatol 32:297 Epub 2013 Dec 2 PubMedGoogle Scholar
  31. 31.
    Dodé C, André M, Bienvenu T, Hausfater P, Pêcheux C, Bienvenu J et al (2002) The enlarging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 46:2181–2188. CrossRefPubMedGoogle Scholar
  32. 32.
    Lachmann HJ, Papa R, Gerhold K, Obici L, Touitou I, Cantarini L et al (2014) The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Ann Rheum Dis 73:2160–2167. CrossRefPubMedGoogle Scholar
  33. 33.
    Imazio M, Spodick DH, Brucato A, Trinchero R, Adler Y (2010) Controversial issues in the management of pericardial diseases. Circulation 121:916–928. CrossRefPubMedGoogle Scholar
  34. 34.
    Imazio M, Cecchi E, Demichelis B, Ierna S, Demarie D, Ghisio A et al (2007) Indicators of poor prognosis of acute pericarditis. Circulation 115:2739–2744. CrossRefPubMedGoogle Scholar
  35. 35.
    Imazio M, Brucato A, Badano L, Charron P, Adler Y (2016) What’s new in 2015 ESC guidelines on pericardial diseases? J Cardiovasc Med Hagerstown Md 17:315–322. CrossRefGoogle Scholar
  36. 36.
    Vasileiou P, Tsioufis C, Lazaros G, Hadziyannis E, Kasiakogias A, Stefanadis C et al (2014) Interleukin-8 as a predictor of acute idiopathic pericarditis recurrences. A pilot study. Int J Cardiol 1 172(3):e463–e464. CrossRefGoogle Scholar
  37. 37.
    Imazio M, Brucato A, Trinchero R, Spodick D, Adler Y (2009) Individualized therapy for pericarditis. Expert Rev Cardiovasc Ther 7:965–975. CrossRefPubMedGoogle Scholar
  38. 38.
    Imazio M, Brucato A, Cumetti D, Brambilla G, Demichelis B, Ferro S et al (2008) Corticosteroids for recurrent pericarditis: high versus low doses: a nonrandomized observation. Circulation 118:667–671. CrossRefPubMedGoogle Scholar
  39. 39.
    Moretti M, Buiatti A, Merlo M, Massa L, Fabris E, Pinamonti B et al (2013) Usefulness of high-dose intravenous human immunoglobulins treatment for refractory recurrent pericarditis. Am J Cardiol 1(112):1493–1498. CrossRefGoogle Scholar
  40. 40.
    Gaspari S, Marsili M, Imazio M, Brucato A, Di Blasi Lo Cuccio C, Chiarelli F et al (2013) New insights in the pathogenesis and therapy of idiopathic recurrent pericarditis in children. Clin Exp Rheumatol 31:788–794 (epub 2 Aug 2013) PubMedGoogle Scholar
  41. 41.
    Lazaros G, Vasileiou P, Danias P, Koutsianas C, Vlachopoulos C, Tousoulis D et al (2015) Effusive-constrictive pericarditis successfully treated with anakinra. Clin Exp Rheumatol 33:945 Epub 2015 Oct 30 PubMedGoogle Scholar
  42. 42.
    Marcolongo R, Russo R, Laveder F, Noventa F, Agostini C (1995) Immunosuppressive therapy prevents recurrent pericarditis. J Am Coll Cardiol 26:1276–1279. CrossRefPubMedGoogle Scholar
  43. 43.
    Raatikka M, Pelkonen PM, Karjalainen J, Jokinen EV (2003) Recurrent pericarditis in children and adolescents: report of 15 cases. J Am Coll Cardiol 42:759–764CrossRefPubMedGoogle Scholar
  44. 44.
    Khandaker MH, Espinosa RE, Nishimura RA, Sinak LJ, Hayes SN, Melduni RM et al (2010) Pericardial disease: diagnosis and management. Mayo Clin Proc 85:572–593. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Cantarini L, Lopalco G, Cattalini M, Vitale A, Galeazzi M, Rigante D (2015) Interleukin-1: Ariadne’s thread in autoinflammatory and autoimmune disorders. Isr Med Assoc J IMAJ 17:93–97PubMedGoogle Scholar
  46. 46.
    Emmi G, Talarico R, Lopalco G, Cimaz R, Cantini F, Viapiana O et al (2016) Efficacy and safety profile of anti-interleukin-1 treatment in Behçet’s disease: a multicenter retrospective study. Clin Rheumatol 35:1281–1286. CrossRefPubMedGoogle Scholar
  47. 47.
    Vitale A, Insalaco A, Sfriso P, Lopalco G, Emmi G, Cattalini M et al (2016) 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 7:380. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Colafrancesco S, Priori R, Valesini G, Argolini L, Baldissera E, Bartoloni E et al (2017) Response to interleukin-1 inhibitors in 140 Italian patients with adult-onset Still’s disease: a Multicentre Retrospective Observational Study. Front Pharmacol 8:369. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Fabiani C, Vitale A, Emmi G, Lopalco G, Vannozzi L, Guerriero S et al (2017) Interleukin (IL)-1 inhibition with anakinra and canakinumab in Behçet’s disease-related uveitis: a multicenter retrospective observational study. Clin Rheumatol 36:191–197. CrossRefPubMedGoogle Scholar
  50. 50.
    Lazaros G, Antonatou K, Vassilopoulos D (2017) The therapeutic role of interleukin-1 inhibition in idiopathic recurrent pericarditis: current evidence and future challenges. Front Med 4:78. CrossRefGoogle Scholar
  51. 51.
    Picco P, Brisca G, Traverso F, Loy A, Gattorno M, Martini A (2009) Successful treatment of idiopathic recurrent pericarditis in children with interleukin-1beta receptor antagonist (anakinra): an unrecognized autoinflammatory disease? Arthritis Rheum 60:264–268. CrossRefPubMedGoogle Scholar
  52. 52.
    Vassilopoulos D, Lazaros G, Tsioufis C, Vasileiou P, Stefanadis C, Pectasides D (2012) Successful treatment of adult patients with idiopathic recurrent pericarditis with an interleukin-1 receptor antagonist (anakinra). Int J Cardiol 160:66–68. CrossRefPubMedGoogle Scholar
  53. 53.
    Camacho-Lovillo M, Méndez-Santos A (2013) Successful treatment of idiopathic recurrent pericarditis with interleukin-1 receptor antagonist (anakinra). Pediatr Cardiol 34:1293–1294. CrossRefPubMedGoogle Scholar
  54. 54.
    Scardapane A, Brucato A, Chiarelli F, Breda L (2013) Efficacy of an interleukin-1β receptor antagonist (anakinra) in idiopathic recurrent pericarditis. Pediatr Cardiol 34:1989–1991. CrossRefPubMedGoogle Scholar
  55. 55.
    Massardier C, Dauphin C, Eschalier R, Lusson JR, Soubrier M (2014) Resistant or recurrent acute pericarditis: a new therapeutic opportunity? Int J Cardiol 177(2):e75–e77. CrossRefPubMedGoogle Scholar
  56. 56.
    Cantarini L, Lucherini OM, Cimaz R, Galeazzi M (2010) Recurrent pericarditis caused by a rare mutation in the TNFRSF1A gene and with excellent response to anakinra treatment. Clin Exp Rheumatol 28:802 Epub 2010 Oct 22 PubMedGoogle Scholar
  57. 57.
    Camprubí D, Mitjavila F, Arostegui JI, Corbella X (2017) 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 20:510–514. CrossRefPubMedGoogle Scholar
  58. 58.
    D’Elia E, Brucato A, Pedrotti P, Valenti A, De Amici M, Fiocca L et al (2015) Successful treatment of subacute constrictive pericarditis with interleukin-1β receptor antagonist (anakinra). Clin Exp Rheumatol 33:294–295 Epub 2015 Jan 29 PubMedGoogle Scholar
  59. 59.
    Schatz A, Trankle C, Yassen A, Chipko C, Rajab M, Abouzaki N et al (2016) Resolution of pericardial constriction with anakinra in a patient with effusive-constrictive pericarditis secondary to rheumatoid arthritis. Int J Cardiol 223:215–216. CrossRefPubMedGoogle Scholar
  60. 60.
    Finetti M, Insalaco A, Cantarini L, Meini A, Breda L, Alessio M et al (2014) Long-term efficacy of interleukin-1 receptor antagonist (anakinra) in corticosteroid-dependent and colchicine-resistant recurrent pericarditis. J Pediatr 164(1425–1431):e1. Google Scholar
  61. 61.
    Jain S, Thongprayoon C, Espinosa RE, Hayes SN, Klarich KW, Cooper LT et al (2015) Effectiveness and safety of anakinra for management of refractory pericarditis. Am J Cardiol 116:1277–1279. CrossRefPubMedGoogle Scholar
  62. 62.
    Lazaros G, Vasileiou P, Koutsianas C, Antonatou K, Stefanadis C, Pectasides D et al (2014) Anakinra for the management of resistant idiopathic recurrent pericarditis. Initial experience in 10 adult cases. Ann Rheum Dis 73:2215–2217. CrossRefPubMedGoogle Scholar
  63. 63.
    Lopalco G, Rigante D, Giannini M, Galeazzi M, Lapadula G, Iannone F et al (2016) Safety profile of anakinra in the management of rheumatologic, metabolic and autoinflammatory disorders. Clin Exp Rheumatol 34:531–538 (epub 26 Feb 2016) PubMedGoogle Scholar
  64. 64.
    Emmi G, Silvestri E, Squatrito D, Vitale A, Bacherini D, Vannozzi L et al (2017) Long-term efficacy and safety of anakinra in a patient with Behçet’s disease and concomitant tuberculosis infection. Int J Dermatol 56:218–220. CrossRefPubMedGoogle Scholar
  65. 65.
    Şoyyiğit S, Kendirlinan R, Aydın O, Çelik GE (2014) Successful desensitization with anakinra in a case with immediate hypersensitivity reaction. Ann Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol 113:325–326. Google Scholar
  66. 66.
    Emmi G, Silvestri E, Cantarini L, Lopalco G, Cecchi L, Chiarini F et al (2017) Rapid desensitization to anakinra-related delayed reaction: need for a standardized protocol. J Dermatol 44:981–982. CrossRefPubMedGoogle Scholar

Copyright information

© SIMI 2018

Authors and Affiliations

  • Antonio Brucato
    • 1
  • Giacomo Emmi
    • 2
  • Luca Cantarini
    • 3
  • Andrea Di Lenarda
    • 4
  • Marco Gattorno
    • 5
  • Giuseppe Lopalco
    • 6
  • Renzo Marcolongo
    • 7
  • Massimo Imazio
    • 8
  • Alberto Martini
    • 5
  • Domenico Prisco
    • 2
  1. 1.Internal Medicine DivisionOspedale Papa Giovanni XXIIIBergamoItaly
  2. 2.Department of Experimental and Clinical MedicineUniversity of FirenzeFirenzeItaly
  3. 3.Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases, Behçet’s Disease Clinic and Rheumatology-Ophthalmology Collaborative Uveitis CenterUniversity of SienaSienaItaly
  4. 4.Cardiovascular CenterTriesteItaly
  5. 5.Unit of Autoinflammatory Diseases and Immunodeficiencies, Clinic of Pediatrics and Rheumatology“G. Gaslini” InstituteGenoaItaly
  6. 6.Rheumatology Unit, Department of Emergency and Organ TransplantationUniversity of BariBariItaly
  7. 7.Clinical Immunology, Department of MedicineAzienda Ospedaliera-UniversitàPaduaItaly
  8. 8.AOU Città della Salute e della Scienza di TorinoUniversity CardiologyTorinoItaly

Personalised recommendations