Current Otorhinolaryngology Reports

, Volume 6, Issue 1, pp 1–14 | Cite as

Treatment of Inflammatory Diseases with IL-1 Blockade

  • Charles A. Dinarello
Otology (A Vambutas, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Otology


Purpose of Review

To provide evidence that therapeutic blockade of IL-1 can provide benefit for patients with hearing loss. In this review, we assess clinical trials of the IL-1 receptor antagonist (anakinra), the soluble IL-1 receptor (rilonacept), antibodies to interleukin-1 beta (IL-1β) (canakinumab, gevokizumab), and anti-IL-1α (xilonix) for clinical indications not related to hearing loss but rather to disease conditions that are common to inflammatory diseases. One purpose of this review is to distinguish between autoinflammatory diseases and autoimmune diseases. Whereas autoinflammatory diseases are due to dysfunctional T cells and B cells, autoinflammatory diseases are due to overproduction of macrophage cytokines particularly IL-1β. A causative role for IL-1 in autoinflammatory diseases is derived from clinical studies blocking the IL-1 receptor or neutralizing monoclonal antibodies or soluble receptors.

Recent Findings

Off-label use of anakinra is common for a broad spectrum of inflammatory diseases. Neutralization of IL-1β is used to treat not only hereditary autoinflammatory diseases but also atherosclerosis. Rilonacept reduces arterial wall inflammation in patients with chronic kidney disease. Neutralization of IL-1α has prolonged life in patients with advanced metastatic colorectal cancer. Compared to other cytokine blocking therapies, reducing the activities of IL-1 has an excellent safety record.


Blocking IL-1 therapies can be used to treat a wide spectrum of acute and chronic inflammatory diseases.


Innate immunity Anakinra Canakinumab Xilonix Rilonacept Cancer 


Compliance with Ethical Standards

Conflicts of Interest

The author declares that he has no conflict of interest.

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 major importance

  1. 1.
    Kastner DL, Aksentijevich I, Goldbach-Mansky R. Autoinflammatory disease reloaded: a clinical perspective. Cell. 2010;140(6):784–90.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–68.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Drenth JP, van der Meer JW, Kushner I. Unstimulated peripheral blood mononuclear cells from patients with the hyper-IgD syndrome produce cytokines capable of potent induction of C-reactive protein and serum amyloid A in Hep3B cells. J Immunol. 1996;157(1):400–4.PubMedGoogle Scholar
  4. 4.
    Gattorno M, Piccini A, Lasiglie D, Tassi S, Brisca G, Carta S, et al. The pattern of response to anti-interleukin-1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2008;58(5):1505–15.PubMedCrossRefGoogle Scholar
  5. 5.
    Gattorno M, Tassi S, Carta S, Delfino L, Ferlito F, Pelagatti MA, et al. Pattern of interleukin-1beta secretion in response to lipopolysaccharide and ATP before and after interleukin-1 blockade in patients with CIAS1 mutations. Arthritis Rheum. 2007;56(9):3138–48.PubMedCrossRefGoogle Scholar
  6. 6.
    Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006;355(6):581–92.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med. 2005;201(9):1479–86.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Colina M, Pizzirani C, Khodeir M, Falzoni S, Bruschi M, Trotta F, et al. Dysregulation of P2X7 receptor-inflammasome axis in SAPHO syndrome: successful treatment with anakinra. Rheumatology (Oxford). 2010;49(7):1416–8.CrossRefGoogle Scholar
  9. 9.
    Mansfield E, Chae JJ, Komarow HD, Brotz TM, Frucht DM, Aksentijevich I, et al. The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments. Blood. 2001;98(3):851–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Chae JJ, Aksentijevich I, Kastner DL. Advances in the understanding of familial Mediterranean fever and possibilities for targeted therapy. Br J Haematol. 2009;146(5):467–78.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001;29(3):301–5.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Goldbach-Mansky R. Current status of understanding the pathogenesis and management of patients with NOMID/CINCA. Curr Rheumatol Rep. 2011;13(2):123–31.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97(1):133–44.PubMedCrossRefGoogle Scholar
  14. 14.
    Simon A, Park H, Maddipati R, Lobito AA, Bulua AC, Jackson AJ, et al. Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. Proc Natl Acad Sci U S A. 2010;107(21):9801–6.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Bulua AC, Simon A, Maddipati R, Pelletier M, Park H, Kim KY, et al. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med. 2011;208(3):519–33.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Stoffels M, Simon A. Hyper-IgD syndrome or mevalonate kinase deficiency. Curr Opin Rheumatol. 2011;23(5):419–23.PubMedCrossRefGoogle Scholar
  17. 17.
    Gosavi S, Chavez LL, Jennings PA, Onuchic JN. Topological frustration and the folding of interleukin-1 beta. J Mol Biol. 2006;357(3):986–96.PubMedCrossRefGoogle Scholar
  18. 18.
    Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633–52.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Harrison SR, McGonagle D, Nizam S, Jarrett S, van der Hilst J, McDermott MF, et al. Anakinra as a diagnostic challenge and treatment option for systemic autoinflammatory disorders of undefined etiology. JCI Insight. 2016;1(6):e86336.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Cicero AF, Salvi P, D'Addato S, Rosticci M, Borghi C, Brisighella Heart Study group. Association between serum uric acid, hypertension, vascular stiffness and subclinical atherosclerosis: data from the Brisighella Heart Study. J Hypertens. 2014;32(1):57–64.PubMedCrossRefGoogle Scholar
  21. 21.
    Athyros VG, Mikhailidis DP. Uric acid, chronic kidney disease and type 2 diabetes: a cluster of vascular risk factors. J Diabetes Complicat. 2014;28(2):122–3.PubMedCrossRefGoogle Scholar
  22. 22.
    Gustafsson D, Unwin R. The pathophysiology of hyperuricaemia and its possible relationship to cardiovascular disease, morbidity and mortality. BMC Nephrol. 2013;14:164.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Crisan TO, Cleophas MC, Oosting M, Lemmers H, Toenhake-Dijkstra H, Netea MG, et al. Soluble uric acid primes TLR-induced proinflammatory cytokine production by human primary cells via inhibition of IL-1Ra. Ann Rheum Dis. 2016;75(4):755–62.PubMedCrossRefGoogle Scholar
  24. 24.
    Crisan TO, Cleophas MCP, Novakovic B, Erler K, van de Veerdonk FL, Stunnenberg HG, et al. Uric acid priming in human monocytes is driven by the AKT-PRAS40 autophagy pathway. Proc Natl Acad Sci U S A. 2017;114(21):5485–90.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther. 2007;9(2):R28.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Announ N, Palmer G, Guerne PA, Gabay C. Anakinra is a possible alternative in the treatment and prevention of acute attacks of pseudogout in end-stage renal failure. Joint Bone Spine. 2009;76(4):424–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Cronstein BN, Sunkureddi P. Mechanistic aspects of inflammation and clinical management of inflammation in acute gouty arthritis. J Clin Rheumatol. 2013;19(1):19–29.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol. 2013;25(6):469–84.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Ghosh P, Cho M, Rawat G, Simkin PA, Gardner GC. Treatment of acute gouty arthritis in complex hospitalized patients with anakinra. Arthritis Care Res (Hoboken). 2013;65(8):1381–4.PubMedCrossRefGoogle Scholar
  30. 30.
    Lopalco G, Rigante D, Giannini M, Galeazzi M, Lapadula G, Iannone F, et al. Safety profile of anakinra in the management of rheumatologic, metabolic and autoinflammatory disorders. Clin Exp Rheumatol. 2016;34(3):531–8.PubMedGoogle Scholar
  31. 31.
    McGonagle D, Tan AL, Shankaranarayana S, Madden J, Emery P, McDermott MF. Management of treatment resistant inflammation of acute on chronic tophaceous gout with anakinra. Ann Rheum Dis. 2007;66(12):1683–4.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Rossi-Semerano L, Fautrel B, Wendling D, Hachulla E, Galeotti C, Semerano L, et al. Tolerance and efficacy of off-label anti-interleukin-1 treatments in France: a nationwide survey. Orphanet J Rare Dis. 2015;10:19.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Gillespie J, Mathews R, McDermott MF. Rilonacept in the management of cryopyrin-associated periodic syndromes (CAPS). J Inflamm Res. 2010;3:1–8.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Mitha E, Schumacher HR, Fouche L, Luo SF, Weinstein SP, Yancopoulos GD, et al. Rilonacept for gout flare prevention during initiation of uric acid-lowering therapy: results from the PRESURGE-2 international, phase 3, randomized, placebo-controlled trial. Rheumatology (Oxford). 2013;52(7):1285–92.CrossRefGoogle Scholar
  35. 35.
    Schumacher HR Jr, Evans RR, Saag KG, Clower J, Jennings W, Weinstein SP, et al. Rilonacept (interleukin-1 trap) for prevention of gout flares during initiation of uric acid-lowering therapy: results from a phase III randomized, double-blind, placebo-controlled, confirmatory efficacy study. Arthritis Care Res (Hoboken). 2012;64(10):1462–70.CrossRefGoogle Scholar
  36. 36.
    Terkeltaub R, Sundy JS, Schumacher HR, Murphy F, Bookbinder S, Biedermann S, et al. The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study. Ann Rheum Dis. 2009;68(10):1613–7.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Terkeltaub RA, Schumacher HR, Carter JD, Baraf HS, Evans RR, Wang J, et al. Rilonacept in the treatment of acute gouty arthritis: a randomized, controlled clinical trial using indomethacin as the active comparator. Arthritis Res Ther. 2013;15(1):R25.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Schlesinger N, Mysler E, Lin HY, De Meulemeester M, Rovensky J, Arulmani U, et al. Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study. Ann Rheum Dis. 2011;70(7):1264–71.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Schlesinger N, Alten RE, Bardin T, Schumacher HR, Bloch M, Gimona A, et al. Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Ann Rheum Dis. 2012;71(11):1839–48.PubMedCrossRefGoogle Scholar
  40. 40.
    Abbate A, Kontos MC, Grizzard JD, Biondi-Zoccai GG, 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):1371–7. e1PubMedCrossRefGoogle Scholar
  41. 41.
    Abbate A, Canada JM, Van Tassell BW, Wise CM, Dinarello CA. Interleukin-1 blockade in rheumatoid arthritis and heart failure: a missed opportunity? Int J Cardiol. 2014;171(3):e125–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Toldo S, Mezzaroma E, Van Tassell BW, Farkas D, Marchetti C, Voelkel NF, et al. Interleukin-1beta blockade improves cardiac remodelling after myocardial infarction without interrupting the inflammasome in the mouse. Exp Physiol. 2013;98(3):734–45.PubMedCrossRefGoogle Scholar
  43. 43.
    Abbate A, Van Tassell BW, Biondi-Zoccai GG. Blocking interleukin-1 as a novel therapeutic strategy for secondary prevention of cardiovascular events. BioDrugs. 2012;26(4):217–33.PubMedCrossRefGoogle Scholar
  44. 44.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Buckley L, Viscusi MM, Van Tassell B, Abbate A. Interleukin-1 blockade for the treatment of pericarditis. Eur Heart J Cardiovasc Pharmacother. 2017;in press.Google Scholar
  46. 46.
    Cantarini L, Lucherini OM, Cimaz R, Galeazzi M. Recurrent pericarditis caused by a rare mutation in the TNFRSF1A gene and with excellent response to anakinra treatment. Clin Exp Rheumatol. 2010;28(5):802.PubMedGoogle Scholar
  47. 47.
    Kuemmerle-Deschner JB, Lohse P, Koetter I, Dannecker GE, Reess F, Ummenhofer K, et al. NLRP3 E311K mutation in a large family with Muckle-Wells syndrome—description of a heterogeneous phenotype and response to treatment. Arthritis Res Ther. 2011;13(6):R196.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Gerfaud-Valentin M, Maucort-Boulch D, Hot A, Iwaz J, Ninet J, Durieu I, et al. Adult-onset still disease: manifestations, treatment, outcome, and prognostic factors in 57 patients. Medicine (Baltimore). 2014;93(2):91–9.CrossRefGoogle Scholar
  49. 49.
    Scott IC, Vijay Hajela V, Hawkins PN, Lachmann HJ. A case series and systematic literature review of anakinra and immunosuppression in idiopathic recurrent pericarditis. J Cardiology Cases. 2011;4:e93–e7.CrossRefGoogle Scholar
  50. 50.
    Scardapane A, Brucato A, Chiarelli F, Breda L. Efficacy of an interleukin-1beta receptor antagonist (anakinra) in idiopathic recurrent pericarditis. Pediatr Cardiol. 2013;34(8):1989–91.PubMedCrossRefGoogle Scholar
  51. 51.
    Vassilopoulos D, Lazaros G, Tsioufis C, Vasileiou P, Stefanadis C, Pectasides D. Successful treatment of adult patients with idiopathic recurrent pericarditis with an interleukin-1 receptor antagonist (anakinra). Int J Cardiol. 2012;160(1):66–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Camacho-Lovillo M, Mendez-Santos A. Successful treatment of idiopathic recurrent pericarditis with interleukin-1 receptor antagonist (Anakinra). Pediatr Cardiol. 2013;34(5):1293–4.PubMedCrossRefGoogle Scholar
  53. 53.
    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):1425–31. e1PubMedCrossRefGoogle Scholar
  54. 54.
    Imazio M. Idiopathic recurrent pericarditis as an immune-mediated disease: current insights into pathogenesis and emerging treatment options. Expert Rev Clin Immunol. 2014;10(11):1487–92.PubMedCrossRefGoogle Scholar
  55. 55.
    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.PubMedCrossRefGoogle Scholar
  56. 56.
    Cantarini L, Lopalco G, Selmi C, Napodano S, De Rosa G, Caso F, et al. Autoimmunity and autoinflammation as the yin and yang of idiopathic recurrent acute pericarditis. Autoimmun Rev. 2015;14(2):90–7.PubMedCrossRefGoogle Scholar
  57. 57.
    D'Elia E, Brucato A, Pedrotti P, Valenti A, De Amici M, Fiocca L, et al. Successful treatment of subacute constrictive pericarditis with interleukin-1beta receptor antagonist (anakinra). Clin Exp Rheumatol. 2015;33(2):294–5.PubMedGoogle Scholar
  58. 58.
    Jain S, Thongprayoon C, Espinosa RE, Hayes SN, Klarich KW, Cooper LT, et al. Effectiveness and safety of anakinra for management of refractory pericarditis. Am J Cardiol. 2015;116(8):1277–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Baskar S, Klein AL, Zeft A. The use of IL-1 receptor antagonist (anakinra) in idiopathic recurrent pericarditis: a narrative review. Cardiol Res Pract. 2016;2016:7840724.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Lazaros G, Imazio M, Brucato A, Vassilopoulos D, Vasileiou P, Gattorno M, et al. Anakinra: an emerging option for refractory idiopathic recurrent pericarditis: a systematic review of published evidence. J Cardiovasc Med (Hagerstown). 2016;17(4):256–62.CrossRefGoogle Scholar
  61. 61.
    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.PubMedCrossRefGoogle Scholar
  62. 62.
    Imazio M, Brucato A, Pluymaekers N, Breda L, Calabri G, Cantarini L, et al. Recurrent pericarditis in children and adolescents: a multicentre cohort study. J Cardiovasc Med (Hagerstown). 2016;17(9):707–12.CrossRefGoogle Scholar
  63. 63.
    Ambrose NL, O'Connell PG. Anti-TNF alpha therapy does not always protect rheumatoid arthritis patients against developing pericarditis. Clin Exp Rheumatol. 2007;25(4):660.PubMedGoogle Scholar
  64. 64.
    Devasahayam J, Pillai U, Lacasse A. A rare case of pericarditis, complication of infliximab treatment for Crohn's disease. J Crohns Colitis. 2012;6(6):730–1.PubMedCrossRefGoogle Scholar
  65. 65.
    Emsley HC, Smith CJ, Georgiou RF, Vail A, Hopkins SJ, Rothwell NJ, et al. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry. 2005;76(10):1366–72.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Singh N, Hopkins SJ, Hulme S, Galea JP, Hoadley M, Vail A, et al. The effect of intravenous interleukin-1 receptor antagonist on inflammatory mediators in cerebrospinal fluid after subarachnoid haemorrhage: a phase II randomised controlled trial. J Neuroinflammation. 2014;11:1.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Galea J, Ogungbenro K, Hulme S, Greenhalgh A, Aarons L, Scarth S, et al. Intravenous anakinra can achieve experimentally effective concentrations in the central nervous system within a therapeutic time window: results of a dose-ranging study. J Cereb Blood Flow Metab. 2011;31(2):439–47.PubMedCrossRefGoogle Scholar
  68. 68.
    Clark SR, McMahon CJ, Gueorguieva I, Rowland M, Scarth S, Georgiou R, et al. Interleukin-1 receptor antagonist penetrates human brain at experimentally therapeutic concentrations. J Cereb Blood Flow Metab. 2008;28(2):387–94.PubMedCrossRefGoogle Scholar
  69. 69.
    Ogungbenro K, Hulme S, Rothwell N, Hopkins S, Tyrrell P, Galea J. Study design and population pharmacokinetic analysis of a phase II dose-ranging study of interleukin-1 receptor antagonist. J Pharmacokinet Pharmacodyn. 2016;43(1):1–12.PubMedCrossRefGoogle Scholar
  70. 70.
    Helmy A, Guilfoyle MR, Carpenter KL, Pickard JD, Menon DK, Hutchinson PJ. Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial. J Cereb Blood Flow Metab. 2014;34(5):845–51.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Vezzani A, Maroso M, Balosso S, Sanchez MA, Bartfai T. IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain Behav Immun. 2011;25(7):1281–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Heida JG, Moshe SL, Pittman QJ. The role of interleukin-1beta in febrile seizures. Brain and Development. 2009;31(5):388–93.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Uludag IF, Bilgin S, Zorlu Y, Tuna G, Kirkali G. Interleukin-6, interleukin-1 beta and interleukin-1 receptor antagonist levels in epileptic seizures. Seizure. 2013;22(6):457–61.PubMedCrossRefGoogle Scholar
  74. 74.
    Uludag IF, Duksal T, Tiftikcioglu BI, Zorlu Y, Ozkaya F, Kirkali G. IL-1beta, IL-6 and IL1Ra levels in temporal lobe epilepsy. Seizure. 2015;26:22–5.PubMedCrossRefGoogle Scholar
  75. 75.
    Chou IC, Lin WD, Wang CH, Tsai CH, Li TC, Tsai FJ. Interleukin (IL)-1beta, IL-1 receptor antagonist, IL-6, IL-8, IL-10, and tumor necrosis factor alpha gene polymorphisms in patients with febrile seizures. J Clin Lab Anal. 2010;24(3):154–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Haspolat S, Baysal Y, Duman O, Coskun M, Tosun O, Yegin O. Interleukin-1alpha, interleukin-1beta, and interleukin-1Ra polymorphisms in febrile seizures. J Child Neurol. 2005;20(7):565–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Kanemoto K, Kawasaki J, Miyamoto T, Obayashi H, Nishimura M. Interleukin (IL)1beta, IL-1alpha, and IL-1 receptor antagonist gene polymorphisms in patients with temporal lobe epilepsy. Ann Neurol. 2000;47(5):571–4.PubMedCrossRefGoogle Scholar
  78. 78.
    Nakayama J, Arinami T. Molecular genetics of febrile seizures. Epilepsy Res. 2006;70(Suppl 1):S190–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Serdaroglu G, Alpman A, Tosun A, Pehlivan S, Ozkinay F, Tekgul H, et al. Febrile seizures: interleukin 1beta and interleukin-1 receptor antagonist polymorphisms. Pediatr Neurol. 2009;40(2):113–6.PubMedCrossRefGoogle Scholar
  80. 80.
    Kenney-Jung DL, Vezzani A, Kahoud RJ, LaFrance-Corey RG, Ho ML, Muskardin TW, et al. Febrile infection-related epilepsy syndrome treated with anakinra. Ann Neurol. 2016;80(6):939–45.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Schulert GS, Grom AA. Pathogenesis of macrophage activation syndrome and potential for cytokine- directed therapies. Annu Rev Med. 2015;66:145–59.PubMedCrossRefGoogle Scholar
  82. 82.
    van der Ven AJ, Netea MG, van der Meer JW, de Mast Q. Ebola virus disease has features of hemophagocytic lymphohistiocytosis syndrome. Front Med. 2015;2:4.Google Scholar
  83. 83.
    Kumar N, Goyal J, Goel A, Shakoory B, Chatham W. Macrophage activation syndrome secondary to human monocytic ehrlichiosis. Indian J Hematol Blood Transfus. 2014;30(Suppl 1):145–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Gatti S, Beck J, Fantuzzi G, Bartfai T, Dinarello CA. Effect of interleukin-18 on mouse core body temperature. Am J Physiol Regul Integr Comp Physiol. 2002;282(3):R702–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Robertson MJ, Mier JW, Logan T, Atkins M, Koon H, Koch KM, et al. Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer. Clin Cancer Res. 2006;12(14 Pt 1):4265–73.PubMedCrossRefGoogle Scholar
  86. 86.
    Lee JK, Kim SH, Lewis EC, Azam T, Reznikov LL, Dinarello CA. Differences in signaling pathways by IL-1beta and IL-18. Proc Natl Acad Sci U S A. 2004;101(23):8815–20.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Stuyt RJ, Netea MG, Verschueren I, Dinarello CA, Kullberg BJ, van der Meer JW. Interleukin-18 does not modulate the acute-phase response. J Endotoxin Res. 2005;11(2):85–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Pomerantz BJ, Reznikov LL, Harken AH, Dinarello CA. Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1beta. Proc Natl Acad Sci U S A. 2001;98(5):2871–6.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Abbate A, Van Tassell BW, Christopher S, Abouzaki NA, Sonnino C, Oddi C, et al. Effects of prolastin C (plasma-derived alpha-1 antitrypsin) on the acute inflammatory response in patients with ST-segment elevation myocardial infarction (from the VCU-alpha 1-RT pilot study). Am J Cardiol. 2015;115(1):8–12.PubMedCrossRefGoogle Scholar
  90. 90.
    Opal SM, Fisher CJJ, Dhainaut JF, Vincent J-L, Brase R, Lowry SF, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Crit Care Med. 1997;25:1115–24.PubMedCrossRefGoogle Scholar
  91. 91.
    Fisher CJJ, Slotman GJ, Opal SM, Pribble J, Bone RC, Emmanuel G, et al. Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. Crit Care Med. 1994;22:12–21.PubMedCrossRefGoogle Scholar
  92. 92.
    Fisher CJ Jr, Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA. 1994;271(23):1836–43.PubMedCrossRefGoogle Scholar
  93. 93.
    Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med. 2016;44(2):275–81.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Ikonomidis I, Tzortzis S, Lekakis J, Paraskevaidis I, Andreadou I, Nikolaou M, et al. Lowering interleukin-1 activity with anakinra improves myocardial deformation in rheumatoid arthritis. Heart. 2009;95(18):1502–7.PubMedCrossRefGoogle Scholar
  95. 95.
    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.PubMedCrossRefGoogle Scholar
  96. 96.
    Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011;162(4):597–605.PubMedCrossRefGoogle Scholar
  97. 97.
    Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA, Seifert B, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356(15):1517–26.PubMedCrossRefGoogle Scholar
  98. 98.
    Ridker PM, Howard CP, Walter V, Everett B, Libby P, Hensen J, et al. Effects of interleukin-1beta 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.PubMedCrossRefGoogle Scholar
  99. 99.
    Cavelti-Weder C, Babians-Brunner A, Keller C, Stahel MA, Kurz-Levin M, Zayed H, et al. Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes. Diabetes Care. 2012;35(8):1654–62.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54(23):2129–38.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    •• 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. This paper reports the results of a large trial in 10,061 patients testing the hypothesis that neutralization of IL-1β by canakinumab reduces a second myocardial infarction or stroke in high-risk subjects who have already experienced a heart attack or stroke. The subjects were at high risk because despite standard of car with statins, the level of CRP in the circulation was above 2 mg/L. Subjects were randomized to receive 50, 150, or 300 mg of canakinumab or placebo every three months for 4 years. The primary end point was a reduction in a composite of fatal or non-fatal myocardial infarctions or non-fatal stroke termed MACE. There were several secondary end points. Of these, a reduction in hospitalizations for acute coronary syndromes requiring rapid revascularization was determined. The study achieved primary and secondary end points. The dose of 150 mg was most effective, although a dose of 300 mg was also effective. The study revealed that canakinumab can reduce the incidence of cardiovascular events without affecting a change in serum lipids. Thus, a role for inflammation, in this case IL-1β, in the pathogenesis of atherosclerosis was demonstrated. PubMedCrossRefGoogle Scholar
  102. 102.
    Aganna E, Martinon F, Hawkins PN, Ross JB, Swan DC, Booth DR, et al. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum. 2002;46(9):2445–52.PubMedCrossRefGoogle Scholar
  103. 103.
    Rynne M, Maclean C, Bybee A, McDermott MF, Emery P. Hearing improvement in a patient with variant Muckle-Wells syndrome in response to interleukin 1 receptor antagonism. Ann Rheum Dis. 2006;65(4):533–4.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Kuemmerle-Deschner JB, Tyrrell PN, Koetter I, Wittkowski H, Bialkowski A, Tzaribachev N, et al. Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome. Arthritis Rheum. 2011;63(3):840–9.PubMedCrossRefGoogle Scholar
  105. 105.
    Kuemmerle-Deschner JB, Wittkowski H, Tyrrell PN, Koetter I, Lohse P, Ummenhofer K, et al. Treatment of Muckle-Wells syndrome: analysis of two IL-1-blocking regimens. Arthritis Res Ther. 2013;15(3):R64.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Stew BT, Fishpool SJ, Owens D, Quine S. Muckle-Wells syndrome: a treatable cause of congenital sensorineural hearing loss. B-ENT. 2013;9(2):161–3.PubMedGoogle Scholar
  107. 107.
    Kitley JL, Lachmann HJ, Pinto A, Ginsberg L. Neurologic manifestations of the cryopyrin-associated periodic syndrome. Neurology. 2010;74(16):1267–70.PubMedCrossRefGoogle Scholar
  108. 108.
    Ahmadi N, Brewer CC, Zalewski C, King KA, Butman JA, Plass N, et al. Cryopyrin-associated periodic syndromes: otolaryngologic and audiologic manifestations. Otolaryngol Head Neck Surg. 2011;145(2):295–302.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Klein AK, Horneff G. Improvement of sensoneurinal hearing loss in a patient with Muckle-Wells syndrome treated with anakinra. Klin Padiatr. 2011;222(4):266–8.CrossRefGoogle Scholar
  110. 110.
    Eungdamrong J, Boyd KP, Meehan SA, Latkowski JA. Muckle-Wells treatment with anakinra. Dermatol Online J. 2013;19(12):20720.PubMedGoogle Scholar
  111. 111.
    Gerard S, le Goff B, Maugars Y, Berthelot JM, Malard O. Lasting remission of a Muckle-Wells syndrome with CIAS-1 mutation using half-dose anakinra. Joint Bone Spine. 2007;74(6):659.PubMedCrossRefGoogle Scholar
  112. 112.
    Sibley CH, Plass N, Snow J, Wiggs EA, Brewer CC, King KA, et al. Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: a cohort study to determine three- and five-year outcomes. Arthritis Rheum. 2012;64(7):2375–86.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Nakanishi H, Kawashima Y, Kurima K, Chae JJ, Ross AM, Pinto-Patarroyo G, et al. NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy. Proc Natl Acad Sci U S A. 2017;114(37):E7766–E75.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Dinarello CA. Why not treat human cancer with interleukin-1 blockade? Cancer Metastasis Rev. 2010;29(2):317–29.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Lewis AM, Varghese S, Xu H, Alexander HR. Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment. J Transl Med. 2006;4:48.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Voronov E, Shouval DS, Krelin Y, Cagnano E, Benharroch D, Iwakura Y, et al. IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci U S A. 2003;100(5):2645–50.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Carmi Y, Voronov E, Dotan S, Lahat N, Rahat MA, Fogel M, et al. The role of macrophage-derived IL-1 in induction and maintenance of angiogenesis. J Immunol. 2009;183(7):4705–14.PubMedCrossRefGoogle Scholar
  118. 118.
    Carmi Y, Dotan S, Rider P, Kaplanov I, White MR, Baron R, et al. The role of IL-1beta in the early tumor cell-induced angiogenic response. J Immunol. 2013;190(7):3500–9.PubMedCrossRefGoogle Scholar
  119. 119.
    Pusztai L, Mendoza TR, Reuben JM, Martinez MM, Willey JS, Lara J, et al. Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine. 2004;25(3):94–102.PubMedCrossRefGoogle Scholar
  120. 120.
    Hickish T, Andre T, Wyrwicz L, Saunders M, Sarosiek T, Kocsis J, et al. MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2017;18(2):192–201.PubMedCrossRefGoogle Scholar
  121. 121.
    Hong DS, Janku F, Naing A, Falchook GS, Piha-Paul S, Wheler JJ, et al. Xilonix, a novel true human antibody targeting the inflammatory cytokine interleukin-1 alpha, in non-small cell lung cancer. Investig New Drugs. 2015;33(3):621–31.CrossRefGoogle Scholar
  122. 122.
    Biasucci LM, Liuzzo G, Fantuzzi G, Caligiuri G, Rebuzzi AG, Ginnetti F, et al. Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation. 1999;99(16):2079–84.PubMedCrossRefGoogle Scholar
  123. 123.
    Lust JA, Lacy MQ, Zeldenrust SR, Dispenzieri A, Gertz MA, Witzig TE, et al. Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1{beta}-induced interleukin 6 production and the myeloma proliferative component. Mayo Clin Proc. 2009;84(2):114–22.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Lust JA, Donovan KA. The role of interleukin-1 beta in the pathogenesis of multiple myeloma. Hematol Oncol Clin North Am. 1999;13(6):1117–25.PubMedCrossRefGoogle Scholar
  125. 125.
    Xiong Y, Donovan KA, Kline MP, Gornet MK, Moon-Tasson LL, Lacy MQ, et al. Identification of two groups of smoldering multiple myeloma patients who are either high or low producers of interleukin-1. J Interf Cytokine Res. 2006;26(2):83–95.CrossRefGoogle Scholar
  126. 126.
    Lust JA, Lacy MQ, Zeldenrust SR, Witzig TE, Moon-Tasson LL, Dinarello CA, et al. Reduction in C-reactive protein indicates successful targeting of the IL-1/IL-6 axis resulting in improved survival in early stage multiple myeloma. Am J Hematol. 2016;91(6):571–4.PubMedCrossRefGoogle Scholar
  127. 127.
    O'Shaughnessy C, Young RR, Levin MK, Baisch J, Timis R, Muniz LS, et al. Safety and immunologic activity of anakinra in HER2-negative metastatic breast cancer. J Clin Oncol 34, 2016 (suppl; abstr e14565) 2016;34 Suppl):e14565.Google Scholar
  128. 128.
    Wang Y, Wang Y, Li L. Note of clarification regarding data about the association between the interleukin-1beta -31T>C polymorphism and breast cancer risk. Breast Cancer Res Treat. 2016;155(3):415–7.PubMedCrossRefGoogle Scholar
  129. 129.
    Hong DS, Hui D, Bruera E, Janku F, Naing A, Falchook GS, et al. MABp1, a first-in-class true human antibody targeting interleukin-1alpha in refractory cancers: an open-label, phase 1 dose-escalation and expansion study. Lancet Oncol. 2014;15(6):656–66.PubMedCrossRefGoogle Scholar
  130. 130.
    Kim B, Lee Y, Kim E, Kwak A, Ryoo S, Bae SH, et al. The interleukin-1alpha precursor is biologically active and is likely a key alarmin in the IL-1 family of cytokines. Front Immunol. 2013;4:391.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Balkwill FR, Mantovani A. Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol. 2012;22(1):33–40.PubMedCrossRefGoogle Scholar
  132. 132.
    Baracos V, Rodemann HP, Dinarello CA, Goldberg AL. Stimulation of muscle protein degradation and prostaglandin E2 release by leukocytic pyrogen (interleukin-1). A mechanism for the increased degradation of muscle proteins during fever. N Engl J Med. 1983;308(10):553–8.PubMedCrossRefGoogle Scholar
  133. 133.
    Smith JW 2nd, Longo DL, Alvord WG, Janik JE, Sharfman WH, Gause BL, et al. The effects of treatment with interleukin-1 alpha on platelet recovery after high-dose carboplatin. N Engl J Med. 1993;328(11):756–61.PubMedCrossRefGoogle Scholar
  134. 134.
    Kaplanski G, Porat R, Aiura K, Erban JK, Gelfand JA, Dinarello CA. Activated platelets induce endothelial secretion of interleukin-8 in vitro via an interleukin-1-mediated event. Blood. 1993;81(10):2492–5.PubMedGoogle Scholar
  135. 135.
    Smith CJ, Emsley HC, Udeh CT, Vail A, Hoadley ME, Rothwell NJ, et al. Interleukin-1 receptor antagonist reverses stroke-associated peripheral immune suppression. Cytokine. 2012;58(3):384–9.PubMedCrossRefGoogle Scholar
  136. 136.
    •• Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ, et al. Effect of interleukin-1beta inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10105):1833–42. This study reveals that subjects at risk for a second cardiovascular event have a lower incidence of cancer and cancer deaths. Upon randomization into the CANTOS trial, the 10,061 subjects did not have evidence of cancer. A special judication committee reviewed each subject for the presence of cancer before and after the trial. Of the 196 subjects with cancer, there was a significant lower incidence of death from all cancers in subjcts receiving 300 mg of canakinumab every 3 months for 4 years. Deaths due to lung cancer dominated the data. The subjects with a diagnosis of cancer had higher levels of CRP upon randomization compared to levels in subjects without cancer suggesting a greater amount of inflammation associated with cancer. One explanation for the benefit of neutralizing IL-1β in these high-risk patients is the reduction in IL-1β driven mechanisms of cancer promotion, such as angiogenesis, myeloid-derived suppressor cells, and endothelial adhesion molecules. PubMedCrossRefGoogle Scholar
  137. 137.
    Dinarello CA, Nold-Petry C, Nold M, Fujita M, Li S, Kim S, et al. Suppression of innate inflammation and immunity by interleukin-37. Eur J Immunol. 2016;46(5):1067–81.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Towne JE, Renshaw BR, Douangpanya J, Lipsky BP, Shen M, Gabel CA, et al. Interleukin-36 (IL-36) ligands require processing for full agonist (IL-36alpha, IL-36beta, and IL-36gamma) or antagonist (IL-36Ra) activity. J Biol Chem. 2011;286(49):42594–602.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Arend WP. The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev. 2002;13(4–5):323–40.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of MedicineUniversity of Colorado DenverAuroraUSA
  2. 2.Department of MedicineRadboud University Medical CenterNijmegenThe Netherlands

Personalised recommendations