About Kineret

Kineret is a recombinant IL-1 receptor antagonist (IL-1Ra)

  • Kineret blocks the biologic activity of interleukin-1 (IL-1), a mediator of inflammation1
  • By blocking IL-1, Kineret effectively reduces signs and symptoms and slows the progression of structural damage caused by RA1
  • Kineret has over 12 years of clinical experience in RA and a well-documented safety profile2,3  
  • Kineret is the first and only FDA-approved treatment for NOMID, a severe autoinflammatory disease1-5

IL-1=interleukin-1; NOMID=Neonatal-Onset Multisystem Inflammatory Disease; RA=rheumatoid arthritis.

References

  1. Kineret [Prescribing Information]. Stockholm, Sweden: Biovitrum AB; 2013.
  2. US Food and Drug Administration Web site. Drug details (Kineret) www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed Sept. 23, 2013.
  3. Data on file. Stockholm, Sweden: Biovitrum AB; 2012.
  4. Yazdi AS, Drexler SK. Regulation of interleukin 1α secretion by inflammasomes. Ann Rheum Dis. 2013;72(suppl 2):ii96–ii99.
  5. Lauro CF, Goldbach-Mansky R, Schmidt M, et al. The anesthetic management of children with neonatal-onset multi-system inflammatory disease. Anesth Analg. 2007;105(2):351–357.

Kineret A selective IL-1 blocker

Kineret is the only IL-1 blocker approved for use in NOMID and adult RA (See full indications below).

Learn more >

Kineret mechanism of action

  • Kineret is a selective interleukin-1 (IL-1) blocker
  • Kineret, a recombinant IL-1 receptor antagonist (IL-1Ra), blocks the biologic activity of both IL-1α and IL-1β by competitively inhibiting IL-1 binding to the IL-1 type 1 receptor (IL-1R1), which is expressed in a wide variety of tissues and organs1
  • Secretion of IL-1β has an important role in the systemic inflammation and clinical and laboratory manifestations of NOMID and RA1,2

IL-R1=IL-1 receptor type 1; IL-Ra=IL-1 receptor antagonist; IL-1RAcP=IL-1 receptor accessory protein.

  • Kineret works similarly to naturally occurring endogenous IL-1Ra by blocking the IL-1 receptor without removing endogenous IL-1 from the circulation3

References

  1. Kineret [Prescribing Information]. Stockholm, Sweden: Biovitrum AB; 2013.
  2. Goldbach-Mansky R, Dailey NJ, Canna SW, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition. N Engl J Med. 2006;355:581-592.
  3. Schiff MH. Role of interleukin 1 and interleukin 1 receptor antagonist in the mediation of rheumatoid arthritis. Ann Rheum Dis. 2000;59(Suppl 1):103-108.

The role of IL-1 in autoimmune and inflammatory diseases

  • Interleukin-1 (IL-1) is a protein that is secreted by macrophages, monocytes, and other cells associated with the body’s immune system1
  • The IL-1 cytokine plays an important role in an innate immune response, the body’s first line of defense against infection and inflammation1,2
  • IL-1 production is induced in response to inflammatory stimuli and mediates various physiologic responses including inflammatory and immunological responses1
  • IL-1 is implicated in facilitating immune cell migration, increasing body temperature, and causing increased pain sensitivity3

IL-1 production

  • The cycle that leads to the production of IL-1 begins when receptors called NLRPs within the cell detect inflammatory stimuli4
    • The NLRP3 receptor in particular is directly involved with IL-1 mediated inflammation4
  • The NLRP3 inflammasome activates the protein procaspase-1, which in turn cleaves
    pro-interleukin-1β and activates it to become interleukin-1β (IL-1β)1

IL-1β binding and signaling

  • Activated IL-1β binds with the IL-1 receptor type 1 (IL-1R1) on the cell surface5
  • IL-1β binding initiates a cascade of downstream signaling that results in the production and release of a variety of cytokines from cells associated with the innate immune system, such as5:
    • Monocytes
    • Macrophages
  • Spontaneous mutations in the CIAS1/NLRP3 gene have been identified in a majority of patients with cryopyrin-associated periodic syndromes such as NOMID6
  • This mutation causes an overproduction of IL-15
    • An overproduction of IL-1 has been implicated in autoinflammatory diseases including NOMID7

NLRPs=nucleotide oligomerization domain-like receptors with pyrin domain-containing proteins; IL-1R1=IL-1 receptor type 1.

References

  1. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol Cell. 2002;10:417–426.
  2. Murphy, Kenneth, Paul Travers, Mark Walport, and Charles Janeway. Janeway's Immunobiology. 8th ed. New York: Garland Science; 2011.
  3. Contassot, Beer, French. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 3. 2012; 142:ww13590.
  4. Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–668.
  5. Moll M, Kuemmerle-Deschner JB. Inflammasome and cytokine blocking strategies in autoinflammatory disorders. Clin Immunol 2013;147:242–275.
  6. Almeida de Jesus A, Goldbach-Mansky R. Monogenic autoinflammatory diseases: concept and clinical manifestations. Clin Immunol. 2013;147:155–174.
  7. Hashkes P, Toker O. Autoinflammatory syndromes. Pediatr Clin N Am. 2012;59:447–470.

Kineret A selective IL-1 blocker

Kineret is the only IL-1 blocker approved for use in NOMID and adult RA (See full indications below).

Learn more >

Understanding the role of IL-1 in NOMID

Pathogenesis of NOMID

  • NOMID, which begins in infancy, is a lifelong and severely debilitating autoinflammatory disease characterized by chronic inflammation1,2
  • NOMID often presents in the first weeks after birth as a uticaria-like rash and fever and can progress to affect multiple organ systems1,2
    • Skin
    • Bones
    • Central nervous system (CNS)
  • Secretion of IL-1β has an important role in the systemic inflammation and clinical and laboratory manifestations of NOMID3

IL-1 drives pathogenesis of NOMID

  • NOMID is caused by autosomal dominant mutations in the CIAS1/NLRP3 gene, which encodes the protein cryopyrin (NLRP3), an important component of the NLRP3 inflammasome5
  • A mutation in cryopyrin leads to an increased rate of inflammasome assembly without the necessary inflammatory stimuli5,6
  • Increased inflammasome activity results in increased cleaving of pro-interleukin-1β and excessive production of the pro-inflammatory cytokine IL-1β6,7

References

  1. Goldbach-Mansky R, Dailey N, Canna S, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition. N Engl J Med. 2006;355:581-592.
  2. Sibley CH, Plass N, Snow J, et al. Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra. Arthritis Rheum. 2012;64(7);2375-2386.
  3. Kineret [prescribing information]. Stockholm, Sweden: Biovitrum AB; 2013.
  4. Grateau G, Hentgen V, Stojanovic K, Jéru I, Amselem S, Steichen O. How should we approach classification of autoinflammatory diseases? Nat Rev Rheumatol. 2013 Jul 9. doi: 10.1038/nrrheum.2013.101. [Epub ahead of print].
  5. Almeida de Jesus A, Goldbach-Mansky R. Monogenic autoinflammatory diseases: Concept and clinical manifestations. Clin Immunol. 2013:147:155-174.
  6. Hashkes P, Toker O. Autoinflammatory syndromes. Pediatr Clin N Am. 2012;59:447-470.
  7. Hoffman HM, Wanderer AA. Inflammasome and IL-1β -mediated disorders. Curr Allergy Asthma Rep. 2010;10:229-235.

     

Is it NOMID?

A patient presenting with fever, rash, and inflammatory symptoms is not rare, but a diagnosis of NOMID is. Will you know how to treat it?

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Understanding the role of IL-1 in RA

Pathogenesis of RA

  • RA is a chronic and progressive inflammatory disorder, characterized by synovitis and severe joint destruction1
  • The pathogenesis of RA is a complex process, involving synovial cell proliferation and fibrosis, pannus formation, and cartilage and bone erosion. This process is mediated by an interdependent network of cytokines, prostanoids, and proteolytic enzymes1
  • Cytokines, such as interleukin-1, may be an important part of the promotion and perpetuation of RA1
    • Production of IL-1 is increased beyond normal levels in the synovial fluids1

IL-1 in pathogenesis of RA

Interleukin-1 is a mediator of the inflammatory and destructive nature of RA3,4

  • Patients with RA have elevated levels of IL-1β circulating in the blood5
  • The activity of IL-1 corresponds to the severity of RA5
  • Extensive evidence from both in vivo and in vitro experiments indicate that IL-1, a prototypic proinflammatory cytokine, is involved with the mechanisms that lead to progressive joint destruction in RA5

Mean plasma analysis of IL-1 data from samples of patients with active RA vs healthy subject (control).
P=0.0001 vs control.

References

  1. De A, Bala NN. Current advances in treatment of rheumatoid arthritis. Int J Rev Life Sci. 2011;1(1):25-34.
  2. Grateau G, Hentgen V, Stojanovic K, Jéru I, Amselem S, Steichen O. How should we approach classification of autoinflammatory diseases? Nat Rev Rheumatol. 2013 Jul 9. doi: 10.1038/nrrheum.2013.101. [Epub ahead of print].
  3. Goldbach-Mansky R. Blocking interleukin-1 in rheumatic diseases: Its initial disappointments and recent successes in the treatment of autoinflammatory diseases. Ann N Y Acad Sci. 2009;1182:111-123.
  4. Schiff MH. Role of interleukin 1 and interleukin 1 receptor antagonist in the mediation of rheumatoid arthritis. Ann Rheum Dis. 2000;59 (suppl I):i103-i108.
  5. Eastgate JA, Symons JA, Wood NC, Grinlinton FM, di Giovine FS, Duff GW. Correlation of plasma interleukin-1 levels with disease activity in rheumatoid arthritis. Lancet. 1988;2:706-709.

Kineret A selective IL-1 blocker

Kineret is the only IL-1 blocker approved for use in NOMID and adult RA (See full indications below).

Learn more >

INDICATIONS

Kineret® is an interleukin-1 receptor antagonist indicated for:

Rheumatoid Arthritis (RA)

Cryopyrin-Associated Periodic Syndromes (CAPS)

IMPORTANT SAFETY INFORMATION