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Review
. 2009 Dec;124(6):1129-38; quiz 1139-40.
doi: 10.1016/j.jaci.2009.11.001.

Therapy of autoinflammatory syndromes

Hal M Hoffman  1
Affiliations
Review

Therapy of autoinflammatory syndromes

Hal M Hoffman. J Allergy Clin Immunol. 2009 Dec.

Abstract

The therapy of autoinflammatory syndromes is an excellent example of the power of translational research. Recent advances in our understanding of the molecular and immunologic basis of this newly identified classification of disease have allowed for the application of novel, effective, targeted treatments with life-changing effects on patients. Although colchicine and TNF-alpha inhibitors are important therapies for specific autoinflammatory syndromes, the novel IL-1-targeted drugs are particularly effective for many of these diseases. Recently, the pharmaceutical industry has adopted a strategy of confirming the efficacy of new targeted drugs in often-ignored patients with orphan diseases, and US Food and Drug Administration policies have allowed for accelerated approval of these drugs, creating a win-win situation for patients and industry. This article reviews the general approach to the therapy of autoinflammatory diseases, focusing on current approved therapies and novel approaches that might be used in the future.

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Figures

FIG. 1
FIG. 1
The clinical continuum of CAPS, including NOMID, MWS, and FCAS.
FIG. 2
FIG. 2
Targeting the multistepped pathways of IL-1β–mediated inflammation. The inflammasome is an intracellular protein complex that is activated by numerous pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). This activation involves several hypothesized mechanisms, including potassium efflux secondary to ATP-gated channels, reactive oxygen species (ROS), and membrane perturbation. Activation of the inflammasome leads to the cleavage and activation of caspase 1, which cleaves pro–IL-1β to its mature active form, which is subsequently released from the cell. Once released, IL-1β binds to the IL-1 receptor, leading to downstream signaling and a cascade of inflammation involving other proinflammatory cytokines. Pro–IL-1β expression is driven by Toll-like receptor (TLR) activation and autocrine IL-1 receptor activation. There are several points along this pathway that can be targeted to inhibit IL-1–mediated inflammation, including specific inflammasome triggers, common activation mechanisms, specific components of the inflammasome, inflammasome stability, caspase 1, IL-1β release, binding of IL-1β to the IL-1 receptor, IL-1 receptor (IL-1R) signaling transduction, and downstream proinflammatory cytokines. ASC, apoptosis associated speck-like protein including a caspase 1 activation and recruitment domain (CARD); Cardinal, CARD inhibitor of NF-κB activation ligand; HSP90, heat shock protein 90; NF-κB, nuclear factor κ-light chain enhancer of activated B cells; SGT1, suppressor of G2 allele of skp1.
FIG. 3
FIG. 3
Mechanisms of IL-1–targeted therapy. Current therapy is directed at IL-1B, including rilonacept and canakinumab or the IL-1 receptor (IL-1R) with anakinra, a recombinant form of IL-1 receptor antagonist (IL-1Ra).
FIG. 4
FIG. 4
Protein domain structure of NLRs, including pyrin domains (PYD), nucleotide-binding domains (NBD), leucine-rich repeat (LRR) domains, caspase activation and recruitment domains (CARD), and a domain with function to find (FIIND). ASC, apoptosis associated speck-like protein containing a caspase 1 activation and recruitment domain (CARD); Cardinal, CARD inhibitor of NF-κB activation ligand; NLRP, nucleotide binding domain, leucine rich repeat domain, pyrin domain; NOD, nucleotide oligomerization domain.
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