Anakinra Therapy for Non-cancer Inflammatory Diseases

Abstract

Interleukin-1 (IL-1) is the prototypical inflammatory cytokine: two distinct ligands (IL-1α and IL-1β) bind the IL-1 type 1 receptor (IL-1R1) and induce a myriad of secondary inflammatory mediators, including prostaglandins, cytokines, and chemokines. IL-1α is constitutively present in endothelial and epithelial cells, whereas IL-1β is inducible in myeloid cells and released following cleavage by caspase-1. Over the past 30 years, IL-1-mediated inflammation has been established in a broad spectrum of diseases, ranging from rare autoinflammatory diseases to common conditions such as gout and rheumatoid arthritis (RA), type 2 diabetes, atherosclerosis, and acute myocardial infarction. Blocking IL-1 entered the clinical arena with anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra); IL-1Ra prevents the binding of IL-1α as well as IL-1β to IL-1R1. Quenching IL-1-mediated inflammation prevents the detrimental consequences of tissue damage and organ dysfunction. Although anakinra is presently approved for the treatment of RA and cryopyrin-associated periodic syndromes, off-label use of anakinra far exceeds its approved indications. Dosing of 100 mg of anakinra subcutaneously provides clinically evident benefits within days and for some diseases, anakinra has been used daily for over 12 years. Compared to other biologics, anakinra has an unparalleled record of safety: opportunistic infections, particularly Mycobacterium tuberculosis, are rare even in populations at risk for reactivation of latent infections. Because of this excellent safety profile and relative short duration of action, anakinra can also be used as a diagnostic tool for undefined diseases mediated by IL-1. Although anakinra is presently in clinical trials to treat cancer, this review focuses on anakinra treatment of acute as well as chronic inflammatory diseases.

Inflammasomes in the pathophysiology of autoinflammatory syndromes

“…The efficacy of anakinra treatment in RA has been evaluated in several controlled studies . Although no direct comparison is available between the efficacy of IL‐1 blockade and the overwhelming number of competing biologic agents, including TNF‐α blockers, based upon indirect comparisons, anakinra seem to be modestly efficacious biologic therapy for RA . Similar to anakinra, the anti‐IL‐1β monoclonal antibody canakinumab led to reduced disease severity in patients with RA, including those who were unresponsive to anti‐TNF‐α therapies; however, unlike anakinra, long‐term preservation of joint function with canakinumab remains unstudied.…”

“…99 Although no direct comparison is available between the efficacy of IL-1 blockade and the overwhelming number of competing biologic agents, including TNF-blockers, based upon indirect comparisons, anakinra seem to be modestly efficacious biologic therapy for RA. 100 Similar to anakinra, the anti-IL-1 monoclonal antibody canakinumab led to reduced disease severity in patients with RA, including those who were unresponsive to anti-TNF-therapies 101 ;…”

New therapies in development for the management of non‐infectious uveitis: A review

“…Anakinra has been previously evaluated and demonstrated positive outcomes in combination with methotrexate for the management of rheumatoid arthritis . Anakinra has been shown to have an excellent safety profile and a short half‐life, which makes it a good option for rapid control of inflammation in young patients, those with latent infections, and even those with underlying chronic kidney disease . Because of these factors, anakinra is the only FDA approved treatment for neonatal onset multisystem inflammatory disease, a severe hereditary inflammatory disorder that can affect the brain, joints, ears and eyes at birth…”

“…131 Anakinra has been shown to have an excellent safety profile and a short half-life, which makes it a good option for rapid control of inflammation in young patients, those with latent infections, and even those with underlying chronic kidney disease. 132 Because of these factors, anakinra is the only FDA approved treatment for neonatal onset multisystem inflammatory disease, a severe hereditary inflammatory disorder that can affect the brain, joints, ears and eyes at birth. 133 Lim et al and Tsai et al were the first to demonstrate the efficacy of anakinra in animal models of uveitis.…”

Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor

“…This is best exemplified for the case of clinical inhibition of interleukin-1(IL-1), for which three different approved biologics exist, namely the IL-1 receptor antagonist anakinra, the soluble decoy receptor rilonacept, and the neutralizing monoclonal antibody canakinumab [5]. These are successfully used for the treatment of several inflammatory conditions including rheumatoid arthritis (RA), ankylosing spondylitis, Cryopyrin-associated periodic syndromes, or Familial Mediterranenan fever, among many others [6]. Other cytokines targeted include IL5, IL6, or receptor activator of nuclear factor κ B ligand (RANKL), while new ones are under study and development [7][8][9][10][11].…”