IL-1 blockade in autoinflammatory syndromes

Abstract

Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. Pathogenic variants in two interleukin-1 (IL-1)-regulating genes, NLRP3 and IL1RN, cause two severe and early-onset autoinflammatory syndromes, CAPS (cryopyrin associated periodic syndromes) and DIRA (deficiency of IL-1 receptor antagonist). The discovery of the mutations that cause CAPS and DIRA led to clinical and basic research that uncovered the key role of IL-1 in an extended spectrum of immune dysregulatory conditions. NLRP3 encodes cryopyrin, an intracellular "molecular sensor" that forms a multimolecular platform, the NLRP3 inflammasome, which links "danger recognition" to the activation of the proinflammatory cytokine IL-1β. The success and safety profile of drugs targeting IL -1 in the treatment of CAPS and DIRA have encouraged their wider use in other autoinflammatory syndromes including the classic hereditary periodic fever syndromes (familial Mediterranean fever, TNF receptor-associated periodic syndrome, and hyperimmunoglobulinemia D with periodic fever syndrome) and additional immune dysregulatory conditions that are not genetically well defined, including Still's, Behcet's, and Schnitzler diseases. The fact that the accumulation of metabolic substrates such as monosodium urate, ceramide, cholesterol, and glucose can trigger the NLRP3 inflammasome connects metabolic stress to IL-1β-mediated inflammation and provides a rationale for therapeutically targeting IL-1 in prevalent diseases such as gout, diabetes mellitus, and coronary artery disease.

Figure 1

Comparison and intersection between autoinflammation and autoimmunity concepts. SLE, systemic lupus erythematosus; ALPS, autoimmune lymphoproliferative syndrome.

Figure 2

Inflammatory clinical manifestations and organ damage in the IL-1-mediated diseases; in neonatal-onset multisystem inflammatory disease (NOMID), which is the severe form of cryopyrin-associated periodic syndromes (CAPS); and deficiency of interleukin-1 receptor antagonist (DIRA).

Figure 3

(a) Mechanism of IL-1 secretion and signaling. (b) Mechanism of IL-1 inhibition with the three currently approved treatments for CAPS. See text for explanation. CPPD, calcium pyrophosphate dehydrate crystals; DAMPs, danger-associated molecular patterns; FFA, free fatty acids; IAPP, islet amyloid polypeptide; LPS, lipopolysaccharide; MDP, muramyl dipeptide; MSU, monosodium urate; oxLDL, oxidized low-density lipoprotein; PAMPs, pathogen associated molecular patterns.

Figure 4

Diseases with established or proposed IL-1-mediated pathology. FCAS, familial cold autoinflammatory syndrome; MWS, Muckle-Wells syndrome; NOMID, neonatal-onset multisystem inflammatory disease; DIRA, deficiency of interleukin-1 receptor antagonist; FMF, familial Mediterranean fever; TRAPS, TNF receptor-associated periodic syndrome; HIDS, hyperimmunoglobulinemia D with periodic fever syndrome; PAPA, pyogenic arthritis, pyoderma gangrenosum, and acne syndrome; PGA, pediatric granulomatous arthritis; SoJIA, systemic-onset juvenile idiopathic arthritis; AOSD, adult-onset Still’s disease; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome; CRMO, chronic recurrent multifocal osteomyelitis; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome; DM, diabetes mellitus; CAD, coronary artery disease.