Regulatory immune responses induced by IL-1 receptor antagonist in rheumatoid arthritis

Abstract

Anakinra, a human recombinant IL-1 receptor antagonist, is approved for the treatment of RA. In this study, 12 patients received the placebo plus MTX treatment, 38 patients received Anakinra combined with MTX treatment. Compared with the placebo plus MTX group, serum levels of IL-17, IFN-γ, IL-21 and IL-1β significantly decreased, the percentages of Th17 cells and Th1 cells were lower and the percentage of Treg cells was higher after receiving Anakinra combined with MTX treatment. The observed regulatory immune responses collectively correlated with clinical improvement in treated patients. A substantial response, ACR 20 at 24 w were consistent with those at 12 w, 16 w and 20 w, and was accompanied by a marked improvement in RA related laboratory parameters. The study reveals that the combination of Anakinra and MTX is safe and well tolerated, which induces regulatory immune responses and significantly provides greater clinical benefit than the placebo plus MTX group.

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disorder of unknown etiology characterized by symmetric, erosive and disabling polyarthritis and a wide array of extraarticular complications (Scott et al., 2010). The inflammatory process leads to cartilage and bone destruction. Long-term studies have demonstrated that significant disability occurs in 50–70% of patients after 10–15 years of disease (Schuna, 1998). Although the etiology and pathogenesis of RA remain unknown, it is generally considered an autoimmune pathology in which autoreactive T cells of pathogenic potential, such as Th1 and Th17 cells, are thought to play an important role (Park et al., 2005, Chen et al., 2007, Afzali et al., 2007, Gaston, 2008). There is evidence that these T cells are activated during the disease process and accumulate in the inflamed synovium, leading to perpetuation of the joint inflammation and tissue destruction (Gaston, 2008, Sato, 2008, Lubberts, 2008, Singh et al., 2007). On the other hand, regulatory T cells (Treg) are deficient in patients with RA, further unbalancing the immune system toward a pro-inflammatory state (Gaston, 2008, Sato, 2008, Lubberts, 2008, Singh et al., 2007, Boissier et al., 2008). Importantly, the cytokine milieu built progressively in inflamed synovium over the course of RA is particularly critical to maintain inflammatory process in the joint. The cytokine milieu carries the inflammatory signature of RA and is crucial in the differentiation and maintenance of pathogenic T cells, and in the dysfunction of regulatory T cells (Boissier et al., 2008, Lipsky et al., 2000, Wang et al., 2008).

IL-1 is produced by a variety of cells that are part of the innate immune system. There is increasing evidence that constant activation of the innate immune system occurs in several chronic inflammatory processes, including RA (Schiff, 2000). IL-1 has effects on cartilage degradation leading to damage as well as inhibiting repair and is a potent stimulus to osteoclasts, leading to bone erosion. The IL-1β-NF-κB axis is a key pathway in the pathogenesis of RA and is central in the production of proinflammatory mediators in the inflamed synovium. NF-κB activation in fibroblast-like synoviocytes contributes to the pathogenesis of RA by activating the transcription of a family of MMPs (Vincenti et al., 1998, Lee et al., 2009). These MMPs are major products of cytokine-stimulated FLS and efficiently degrade the collagenous components of cartilage and bone, which leads to joint deformity and a great deal of pain in RA patients. Thus, reducing the synthesis of IL-1 or blocking the effects of an overabundance of IL-1 may offer a therapeutic option for RA. IL-1 receptor antagonist (IL-1ra) is an endogenous blocker of the cytokine (Kay and Calabrese, 2004). Evidence supporting an anti-inflammatory role of IL-1ra in vivo is demonstrated by the observation that IL-1ra-deficient mice spontaneously develop autoimmune diseases similar to RA as well as vasculitis (Nicklin et al., 2000, Horai et al., 2000, Horai et al., 2004). Anakinra, a human recombinant IL-1ra, is approved for the treatment of RA. Anakinra differs from native IL-1ra by the addition of an N-terminal methionine. Anakinra blocks the biologic activity of IL-1 by binding to IL-1R type I with the same affinity as IL-1β. A randomized double-blind placebo controlled trial showed long-term safety and maintenance of clinical improvement following treatment with Anakinra in patients with RA (Nuki et al., 2002, Chen, 2010).

Increased levels of Th17 cells can be detected in IL-1Ra−/− mice even preceding the onset of arthritis. In addition, the results of cytokine-blocking studies demonstrated that IL-17 contributes to the inflammation and bone erosion in this model (Koenders et al., 2008). Gabay et al. suggested that myeloid cell-derived IL-1Ra plays a critical role in the control of the development and the severity of CIA by modulating Th1 and Th17 responses in lymphoid organs (Lamacchia et al., 2010). Some studies have found that proinflammatory cytokines, such as IL-1beta and IL-6, were all essential for human Th17 differentiation (Chung et al., 2009, Volpe et al., 2008; Acostoa-Rodriguez et al., 2007). But the developmental regulation of Anakinra on T cell subsets balance on RA patient is unclear.

Methotrexate (MTX) is the most commonly used conventional disease-modifying antirheumatic drug. Combination regimens that employ MTX plus other biological agents, such as etanercept or infliximab have been used successfully to combat disease that remains active or progressive despite treatment with MTX alone. In order to further support the use of combination therapy with MTX and a biological agent, we observed the immunological changes and evaluated the efficacy of Anakinra in combination with methorexate in patients with active rheumatoid arthritis. In this study, we evaluated the regulatory effect of IL-1 receptor Antagonist on restoring the Treg/Th17, Th1 balance. The finding described here has important implication in the understanding of the role of IL-1 receptor Antagonist in treatment of RA and suggests IL-1 as a good target for treating this autoimmune disease.