Anakinra and related drugs targeting interleukin-1 in the treatment of cryopyrin-associated periodic syndromes

Abstract

Anakinra is an interleukin (IL) receptor antagonist that works by blocking the biological activity of IL-1 by competitively inhibiting binding of IL-1 to the type 1 interleukin receptor. IL-1 production is induced in response to inflammatory stimuli and mediates various physiological mechanisms, including inflammation and immunological reactions. Patients with neonatal onset multisystem inflammatory disease (NOMID) produce excess IL-1β, a major proinflammatory cytokine that regulates innate immune responses. Anakinra binds competitively and this results in a rapid reduction in disease severity. NOMID, also known as chronic infantile neurologic, cutaneous, articular syndrome, is the most severe clinical phenotype in the spectrum of cryopyrin-associated periodic syndromes. It is characterized by cutaneous symptoms, arthropathy, and central nervous system involvement. Extensive studies in patients with NOMID have led to advances in characterizing the extent of organ-specific involvement and damage that occurs with chronic overproduction of IL-1β. NOMID is caused predominantly by mutations in the NLRP3/CIAS1 gene that encodes for the protein cryopyrin, leading to activation of the "NLRP3 inflammasome complex". This in turn regulates the maturation and secretion of the inflammatory cytokine, IL-1β. The clinical value of IL-1β has been demonstrated by the positive response of patients after treatment with anakinra, with rapid improvement in clinical symptoms, markers of inflammation, and a significant decrease in major organ manifestations.

Keywords: CIAS1; NLRP3; arthritis syndrome; chronic infantile neurologic; cutaneous; interleukin-1β; neonatal onset multisystem inflammatory disease.

Figure 1

Pathophysiology of CAPS. Activation of the NLRP3 inflammasome is triggered by exposure of immune cells to a variety of danger-associated molecular patterns and pathogen-associated molecular patterns. The leucine-rich repeat domain of the NLRP3 is thought to serve as an autoinhibitor by self-folding. The molecule spreads out, dimerizes, and associates through homotypic interaction with the ASC adaptor protein to mediate the proteolytic processing of pro-caspase 1 to caspase-1. The ASC protein also interacts with cryopyrin. When cryopyrin binds to ASC it can result in NFκB and caspase-1 activation. Once caspase-1 is activated, it results in cleavage of pro-IL-1β and pro-IL-18 into their mature forms IL-1β and IL-18, respectively, which is secreted by the immune cell. Thus, activated cryopyrin induces release of the active form, IL-1β. Abbreviations: DAMPs, danger-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; IL, interleukin; ASC, apoptosis-associated speck-like protein; CAPS, cryopyrin-associated periodic syndromes; UVB, ultraviolet B; LRR, leucine-rich repeat; ATP, adenosine triphosphate.

Figure 2

Timeline highlighting use of anakinra in various disease states. Abbreviations: CAPS, cryopyrin-associated periodic syndromes; DMARDs, disease-modifying antirheumatic drugs; US FDA, US Food and Drug Administration; FMF, familial Mediterranean fever; HIDS, hyper-IgD syndrome; STEMI, ST elevation myocardial infarction; NOMID, neonatal onset multisystem inflammatory disease; MWS, Muckle–Wells syndrome.