Spotlight on tocilizumab and its potential in the treatment of systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a multisystem disease characterized by extensive collagen deposition in skin and internal organs, fibrointimal microvasculopathy, and activation of the immune system. T cells and B cells can promote fibrosis in SSc. Interleukin (IL)-6 is implicated in the pathogenesis of SSc. IL-6 is increased in the peripheral blood and lesional skin from patients with SSc, and induces fibroblast collagen production directly and indirectly by inducing profibrotic M2 macrophages. IL-6 also induces Th17 differentiation and promotes B cell differentiation toward Ig-producing plasma cells. IL-6 is also implicated in the pathogenesis of SSc in animal models as it is increased in mice with bleomycin-induced fibrosis, whereas neutralization of IL-6 in these mice prevents skin fibrosis. IL-6 acts on cells by binding to IL-6 receptor (IL-6R) which is transmembrane or soluble, and then recruits the signal-transducing glycoprotein 130 which is ubiquitously expressed. Tocilizumab is an anti-IL-6R humanized monoclonal antibody that blocks IL-6-mediated signaling. Tocilizumab has been approved for the treatment of moderate-to-severe rheumatoid arthritis, for polyarticular and systemic juvenile idiopathic arthritis, and for Castleman’s disease, and is well tolerated. Case reports and a Phase II, randomized trial in SSc have shown some improvement of skin tightness and delayed deterioration of lung function. A Phase III randomized trial in SSc is anticipated.

Systemic Sclerosis Associated Interstitial Lung Disease: A Comprehensive Overview

“…119 Tocilizumab IL-6 is a pleiotropic cytokine with multiple biological effects that has been implicated in SSc-ILD pathogenesis and progression. [120][121][122] In a multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial, treatment with tocilizumab (anti-IL-6 receptor) was associated with a reduced decline in FVC at 48 weeks compared with placebo, although this was an exploratory analysis. 123 A phase III study of tocilizumab versus placebo in patients with SSc has recently been completed and confirmed apparent benefit by preventing decline in FVC over 48 weeks (NCT02453256) (►Table 1).…”

TGF-β pathway activation by idiopathic pulmonary fibrosis (IPF) fibroblast derived soluble factors is mediated by IL-6 trans-signaling

“…This process also results in Jak/signal transducer and activator of transcription (STAT) signaling pathway activation [14] and is termed IL-6 trans-signaling [15]. This signaling pathway was already implicated in a variety of inflammatory processes, including rheumatoid arthritis (RA) [16], systemic sclerosis (SS) [17], cancer [18], as well as IPF [19,20]. Importantly, unlike other soluble cytokine receptors, sIL-6R does not act antagonistically by limiting the IL-6 cytokine activity, but rather agonistically.…”

“…Tocilizumab (TCZ), an anti-human IL-6R neutralizing antibody, which prevents binding of IL-6 to IL-6R, thus inhibiting both classic and trans-signaling pathways, is approved for the treatment of RA [21]. This drug was also implicated in other inflammatory conditions that involve a fibrotic phenotype, such as SS [17]. Results from the phase II randomized controlled trial (faSScinate) of SS patients showed forced vital capacity (FVC) stabilization within the TCZ receiving SS patients in comparison to placebo controls [22], as well as in placebo-treated patients who later transitioned to TCZ in the open label period [23].…”

Characterizing Disease Manifestations and Treatment Patterns Among Adults with Systemic Sclerosis: A Retrospective Analysis of a US Healthcare Claims Population

“…SSc presents unique challenges in managing a chronic multisystem autoimmune disease because it is a complex disease with devastating manifestations, and treatment is suboptimal [23]. The clinical heterogeneity of SSc determines variations in the degree of disease expression and prognosis, and, as a result, patients may experience a highly variable treatment course [24].…”