Interleukin-1 Blockade in Polygenic Autoinflammatory Disorders: Where Are We now?

Abstract

Polygenic autoinflammatory diseases (AIDs), such as systemic juvenile idiopathic arthritis (sJIA), adult-onset Still's disease, Kawasaki disease, idiopathic recurrent pericarditis (IRP), Behçet’s Syndrome, Crystal-induced arthropatihes such as gout or Calcium pyrophosphate deposition disease are characterized by the overexpression of inflammasome-associated genes, leading to a dysregulation of the innate immune response. The IL-1 cytokine family (IL-1α, IL-1β, IL-1Ra, IL-18, IL-36Ra, IL-36α, IL-37, IL-36β, IL-36g, IL-38, IL-33) was defined to be principally responsible for the inflammatory nature of polygenic AIDs. Several clinical trials were initiated, and IL-1 blockade has been proven to cause a rapid reduction of clinical symptoms and normalization of laboratory parameters in the majority of cases. Randomized, placebo-controlled, clinical trials, together with registry-based clinical trials and open-label, retrospective and prospective observational studies, supported the efficacy and safety of IL-1 inhibitors in the treatment of polygenic AIDs. Most of the current data are focused on the therapeutic use of anakinra, an IL-1 receptor antagonist, canakinumab, an anti-IL-1β monoclonal antibody, and rilonacept, a soluble decoy receptor. However, other promising agents, such as gevokizumab, IL-1β blocking monoclonal antibody, tadekinig alfa, a human recombinant IL-18-binding protein, and tranilast, an analog of a tryptophan metabolite, are currently being tested. Anakinra, canakinumab and rilonacept caused impressive improvements in both systemic and musculoskeletal symptoms. Furthermore, the anti-IL-1 therapy allowed corticosteroid tapering and, in some cases, even withdrawal. This article reviews the current IL-1 inhibitors and the results of all clinical trials in which they have been tested for the management of broad spectrum of polygenic AIDs.

Non-Coding RNAs: Master Regulators of Inflammasomes in Inflammatory Diseases

“…About sJIA, a kind of polygenic AIDs, is characterized by the overexpression of inflammasome-associated genes, leading to a dysregulation of the innate immune response, with a severe complication of macrophage activation syndrome (MAS). 128 Notably, sJIA and recurrent MAS were found due to a CASP1 variant causing inflammasomes hyperactivation. 116 Notably, two studies showed the correlation between miRNAs and sJIA.…”

“…What’s more, other disease entities, such as Kawasaki disease and idiopathic recurrent pericarditis disease, gout or calcium pyrophosphate deposition disease are also believed to be related to polygenic AIDs. 128 AIDs are an expanding spectrum of diseases, and more effort is needed to understand the pathogenesis.…”

Regulation of T Cell Responses by Ionic Salt Signals

“…The crosstalk of cytokines with the ionic salt micromilieu has implications for therapeutic strategies. IL-1β- or IL-1R-blocking agents are already in use in the clinic for the treatment of autoinflammatory and other chronic inflammatory diseases [ 63 ]. Therapeutic abrogation of the IL-1 signaling pathway might, in accordance with its switch factor function, promote the anti-inflammatory activities of sodium chloride in hypersalinic tissue microenvironments.…”

Anti-inflammatory Treatment of Kawasaki Disease: Comparison of Current Guidelines and Perspectives

“…Recently, biologic agents that specifically inhibit the cytokines interleukin (IL)-1 and IL-6 have demonstrated remarkable clinical effectiveness and confirmed the importance of these cytokines in the process of so-JIA (126). The three IL-1 blockers that have been tested so far (anakinra, canakinumab, and rilonacept) have all been proven effective and safe, although only canakinumab is currently approved for use in so-JIA (127)(128)(129)(130). IL-18 is another proinflammatory cytokine elevated in so-JIA and may represent a pathogenic link between so-JIA and MAS (131).…”