This is
interleukin-1 (IL-1)

interleukin-1

A potent pro-inflammatory cytokine

IL-1 is a potent pro-inflammatory cytokine that was first discovered as a fever- inducing molecule in 1974. It is produced during innate immune responses to infections and injuries. IL-1 drives inflammation by recruiting and activating immune cells, and inducing the production of various inflammatory mediators, including itself in a self-amplifying autoinflammatory loop.1-4

There are two different IL-1 proteins, IL-1α and IL-1β: IL-1α is an alarmin that is found in many different cell types and is released during cell death, ‘alarming’ the immune system to the presence of danger and triggering local (sterile) inflammation; by contrast, IL-1β is mainly produced by activated innate immune cells such as monocytes, macrophages, and neutrophils. IL-1α and IL-1β bind to the same receptor, IL-1R1, and induce the same pro-inflammatory effects.1-4

While IL-1 plays an important role in protective immune responses, abnormal or inadequately regulated IL-1 signaling may lead to excessive inflammation and tissue damage. Given the potent pro-inflammatory effects of IL-1, physiological negative regulators exist, for example the naturally-occurring IL-1 receptor antagonist that blocks IL-1 from binding to IL-1R1. However, if too much IL-1 is produced and/or regulating mechanisms are insufficient, IL-1-driven inflammation may have harmful consequences and contribute to the pathogenesis of inflammatory conditions.1-4

il-1 mediated diseases

Signs and symptoms of IL-1-mediated inflammation

Typical signs and symptoms of IL-1-mediated inflammation include fever, eleva- tion of acute phase reactants (e.g. C-reactive protein, serum amyloid A), neutrop- hilia, and tissue inflammation commonly affecting the skin and musculoskeletal system, but various other organs may also be affected.1

The effects of unopposed, excessive IL-1 signaling are exemplified by the syste- mic, potentially life-threatening, sterile inflammation seen in patients with defi- ciency of IL-1 receptor antagonist (DIRA), who present with neutrophilia, elevated inflammatory markers, and inflammation of the skin, joints, and bones.1-4

In patients with the monogenic periodic fever syndromes cryopyrin-associated periodic syndromes (CAPS) and familial Mediterranean fever (FMF), abnormal, increased production of IL-1 due gain-of-function mutations in the NLRP3 and pyrin inflammasomes lead to recurrent fever episodes, elevation of acute phase reactants, and various inflammatory manifestations involving e.g. the joints (arthritis/arthralgia), skin (rash), eyes (conjunctivitis), serosal membranes (perito- neum, pleura, leading to abdominal and chest pain), and other organs.1-3

IL-1-driven inflammation also plays an important role in Still’s disease, which is characterized by spiking fever, rash, and joint involvement (arthralgia and/or arthritis), as well as neutrophilia and elevated CRP and ferritin.1-3

In patients with rheumatoid arthritis, IL-1 contributes to joint inflammation and tissue damage by stimulating the production of pro-inflammatory mediators and cartilage-degrading enzymes, and activating bone-resorbing osteoclasts.2,3

IL-1 has also been implicated in the hyperinflammatory response observed in se- vere cases of COVID-19. Blocking IL-1 activity has been shown to mitigate the risk of developing severe respiratory failure in COVID-19 patients hospitalised with pneumonia and plasma suPAR ≥6 ng/ml.4-7

Abbreviations
IL-1, interleukin-1; IL-1R1, Interleukin-1 receptor type 1; CRP, C-reactive protein; NLRP3, NOD-like receptor family pyrin domain-containing 3.

Kineret Q&A

How is Kineret administered?
  • Kineret is given in a pre-filled syringe containing 100 mg of anakinra per 0.67 ml (150 mg/ml).1
  • Kineret is given as a subcutaneous injection.1
  • Dosage depends on indication. In children, the dose is determined depending on body weight. Please refer to current SmPC.
How should Kineret be stored?
  • Kineret should be stored in a refrigerator between 2°C and 8°C.1
  • Kineret should not be frozen or shaken.1
  • Kineret should be kept in its original carton and away from light.1

References

  • Broderick L and Hoffman HM. IL-1 and autoinflammatory disease: biology, pathogenesis and therapeutic targeting. Nat Rev Rheumatol 2022;18(8):448–463.
  • Schett G, Dayer J-M, and Manger B. Interleukin-1 function and role in rheumatic disease. Nat Rev Rheumatol 2016; 12 (1): 14–24.
  • Dinarello CA, Simon A, van der Meer JWM. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633–52.
  • Cavalli G, Colafrancesco S, Emmi G, Imazio M, Lopalco G, Maggio MC, et al. Interleukin 1α: a comprehensive review on the role of IL-1α in the pathogenesis and treatment of autoimmune and inflammatory diseases. Autoimmun Rev. 2021;20(3):102763.
  • van de Veerdonk, F.L., Netea, M.G. Blocking IL-1 to prevent respiratory failure in COVID-19. Crit Care 24, 445 (2020).
  • Kyriazopoulou E, Panagopoulos P, Metallidis S, Dalekos GN, Poulakou G, Gatselis N, et al. An open label trial of anakinra to prevent respiratory failure in COVID-19. Elife. 2021 Mar;10:e66125–e66125.
  • Kyriazopoulou E, Poulakou G, Milionis H, Metallidis S, Adamis G, Tsiakos K, et al. Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial. NatMed. 2021;27(10):1752-1760.
  • Swedish Orphan Biovitrum AB (publ). Kineret summary of product characteristics [SmPC]. Latest version available from: https:// www.ema.europa.eu/en/documents/product-information/kineret-epar-product-information_en.pdf