Blocking interleukin-1 in rheumatic diseases

Abstract

The role of the potent proinflammatory cytokine IL-1 in disease could clinically be investigated with the development of the IL-1 blocking agent anakinra (Kineret), a recombinant IL-1 receptor antagonist. It was first tested in patients with sepsis without much benefit but was later FDA approved for the treatment of patients with rheumatoid arthritis. More recently IL-1 blocking therapies are used successfully to treat a new group of immune-mediated inflammatory conditions, autoinflammatory diseases. These conditions include rare hereditary fever syndromes and pediatric and adult conditions of Still's disease. Recently the FDA approved two additional longer acting IL-1 blocking agents, for the treatment of cryopyrin-associated periodic syndromes (CAPS), an IL-1 dependent autoinflammatory syndrome. The study of autoinflammatory diseases revealed mechanisms of IL-1 mediated organ damage and provided concepts to a better understanding of the pathogenesis of more common diseases such as gout and Type 2 diabetes which show initial promising results with IL-1 blocking therapy.

Figure 1

IL-1 receptor signaling. IL-1α and IL-1β can bind to the IL-1R1 receptor which recruits the accessory receptor. This receptor complex forms a signaling unit (ACP). However binding of the IL-1 receptor antagonist to the IL-1R1 receptor inhibits IL-1 binding and does not allow for association with the ACP and therefore no signaling through the receptor occurs.

Figure 2

The Inflammasome, an IL-1 activating platform. Cryopyrin (NLRP3, NALP3, CIAS1) is a key molecule in regulating an inflammatory cytokine processing platform. Cryopyrin, ASC, Cardinal and two procaspase-1 molecules assemble to form, the cryopyrin inflammasome that activates caspase-1. Active caspase-1, enzymatically cleaves inactive IL-1β into its active form.

Figure 3

Clinical manifestations of NOMID/CINCA and DIRA. (A) to (D) depict characteristic clinical manifestations of patients with NOMID; (E) to (G) depict characteristic clinical manifestations of DIRA. (A) NOMID presents with an urticaria like rash, however the cellular infiltrate is neutrophilic consistent with neutrophilic dermatitis. (B) Radiographic findings of the knee show tumor like hyperostotic lesions originating in the growth plate. Once ossification is completed, the bone of these lesions is histologically normal. (C) Postcontrast FLAIR MRI of the inner ears shows abnormal cochlear enhancement suggestive of cochlear inflammation. (D) Postcontrast FLAIR MRI of brain show leptomeningeal enhancement. (E) Shows generalized pustulosis seen in a 3-month-old infant. (F) A hip X-ray shows heterotrophic ossification or periosteal cloaking of the proximal femoral metaphysic and periosteal elevation of the diaphysis. (G) Typical radiographic manifestations on a chest X-ray include widening of multiple anterior ribs (arrows).