Anti-inflammatory panacea? The expanding therapeutics of interleukin-1 blockade

Abstract

Purpose of review: Blockade of interleukin (IL)-1 signaling is one of the oldest biologic therapies, yet the use of these agents is on the rise as the role of IL-1 activation is being recognized in a wide spectrum of inflammatory disorders. This review will cover established and emerging uses of IL-1 antagonism in rheumatic diseases.

Recent findings: Expanding off-label indications for IL-1 blockade include neutrophil-dominant skin diseases, including pyoderma gangrenosum, hidradenitis supperativa, and pustular psoriasis. There is also increasing evidence for the use of IL-1 blockade in heart failure associated with rheumatic diseases. Somatic mosaicism in NLRP3 may explain the onset of later-in-life presentations of periodic fevers which are responsive to IL-1 blockade. Of importance, clinical response to anti-IL-1 therapy does not always denote protection from autoinflammatory disease complications such as macrophage activation syndrome or amyloidosis.

Summary: Indications for IL-1 blocking therapies will likely continue to broaden, but given the rarity of many rheumatic diseases which respond to such treatment, rigorous, large clinical trials for each indication are unlikely to occur. Thus, recommended use of these medications will often fall to the discretion of the astute physician. However, medication cost and hurdles of insurance approval, rather than drug efficacy, may be the primary limitation for more widespread use.

Figure 1. Drugs that antagonize IL-1 signaling utilize various approaches to block activation of the IL-1R by IL-1α and IL-1β

Anakinra binds to the IL-1R1 thus preventing recruitment of IL-1R accessory protein (IL-1RaP), a step which is required for activation of downstream signaling cascades. Because it interacts with the receptor, anakinra inhibits both IL-1α and IL-1β signaling. Canakinumab and gevokizumab are both monoclonal antibodies which recognize IL-1β and prevent its binding to the receptor. These drugs have no effect on IL-1α signaling. Rilonacept is a fusion protein between the IL1R1 and IL1Rap linked to the Fc portion of human IgG1. This medication has a much higher affinity for IL-1β than IL-1α and thus antagonizes IL-1β-mediated signaling more effectively.