Role of antifibrotics in the management of idiopathic inflammatory myopathy associated interstitial lung disease

Abstract

The antifibrotic therapies nintedanib and pirfenidone were first approved by the United States for the treatment of idiopathic pulmonary fibrosis in 2014. In 2020, nintedanib received U.S. Food and Drug Administration (FDA) approval for the treatment of all progressive fibrosing interstitial lung disease (ILD). Given that a major cause of mortality and morbidity in the idiopathic inflammatory myopathies (IIM) is progressive interstitial lung disease and respiratory failure, antifibrotic therapies may be useful as adjuvant to traditional immunosuppression. However, randomized controlled trials of antifibrotic therapies in IIM are lacking. The purpose of this review is to (1) summarize the mechanism of action of nintedanib and pirfenidone in ILD with possible role in IIM-ILD, (2) review the clinical data supporting their use in interstitial lung disease in general, and more specifically in connective tissue disease associated ILD, and (3) discuss the evidence and remaining challenges for using antifibrotic therapies in IIM-ILD.

Keywords: antifibrotic therapies; antisynthetase syndrome; dermatomyositis; idiopathic inflammatory myopathies; interstitial lung disease; polymyositis.

Figure 1.

Proposed mechanisms of action for pirfenidone. Pirfenidone’s most recognized mechanism of action is the reduction of transforming growth factor (TGF)-β1, which leads to a subsequent reduction in TGF-β1-mediated fibroblast proliferation, myofibroblast differentiation, TGFβR1 signaling/SMAD3 phosphorylation, and extracellular matrix production. Pirfenidone has also been proposed to (1) reduce platelet derived growth factor (PDGF) and fibroblast growth factor (FGF) thereby decreasing PDGF/FGF signaling; (2) inhibit redox reactions to relieve oxidative stress from hydroxyl radicals and mitochondrial dysfunction; (3) reduce expression of cytokines tumor necrosis factor alpha (TNF-α), interleukin-6, interleukin-8 (IL-8), interleukin 10 (IL-10), interleukin 12 subunit p40 (IL12p40), interferon gamma (IFN-γ), and monocyte chemoattractant protein-1 (MCP1); and (4) modulate the cellular immune system by reducing macrophage cytokine secretion, reducing dendritic cell mediated T cell activation, and inhibiting Th1/Th2 polarization.

Figure 2.

Possible immunomodulatory effects of nintedanib. (a) Nintedanib inhibits Lyn, which is involved in both activation and inhibition of B cell signaling after B cell receptor (BCR) ligation. (b) Nintedanib inhibits Lck, which phosphorylates ZAP70 and leads to T cell activation.

Figure 3.

Nintedanib inhibits platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR)-2 to impair pulmonary fibrosis. (a) Nintedanib directly antagonizes PDGFR signaling, which is triggered by binding of PDGF or possibly to a lesser extent FGF. Nintedanib inhibits FGFR directly and inhibits its signaling molecule, Src. Inhibition of PDGFR and FGFR decreases proliferation and migration of fibroblasts and myofibroblasts and subsequent extracellular matrix (ECM) deposition. (b) Nintedanib inhibits both VEGFR2 directly and its signaling molecule, Src, to mitigate alveolar hypervascularization and angiogenesis.

Figure 4.

Possible role of antifibrotics in the management of IIM-ILD. Schematic of how antifibrotics might be employed in the management of IIM-ILD. Key outstanding questions are (1) efficacy of upfront antifibrotic therapy in all patients both in the mild-moderate category to improve outcomes, (2) efficacy of early initiation of antifibrotics to prevent ILD in high-risk patients (e.g. +MDA5 or Ro52), (3) efficacy in severe/rapidly progressing ILD to improve survival, and (4) at failure of induction or maintenance therapy for additive benefit and to slow progression. *Tacrolimus could be considered as a first-line agent for the management of MDA5 + dermatomyositis with ILD in the outpatient setting; tofacitinib could be considered as early therapy in life-threatening MDA5+ disease.