Scanning for Therapeutic Targets within the Cytokine Network of Idiopathic Inflammatory Myopathies

Abstract

The idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of chronic disorders that include dermatomyositis (DM), polymyositis (PM), sporadic inclusion body myositis (IBM) and necrotizing autoimmune myopathy (NAM). They represent distinct pathological entities that, most often, share predominant inflammation in muscle tissue. Many of the immunopathogenic processes behind the IIM remain poorly understood, but the crucial role of cytokines as essential regulators of the intramuscular build-up of inflammation is undisputed. This review describes the extensive cytokine network within IIM muscle, characterized by strong expression of Tumor Necrosis Factors (TNFα, LTβ, BAFF), Interferons (IFNα/β/γ), Interleukins (IL-1/6/12/15/18/23) and Chemokines (CXCL9/10/11/13, CCL2/3/4/8/19/21). Current therapeutic strategies and the exploration of potential disease modifying agents based on manipulation of the cytokine network are provided. Reported responses to anti-TNFα treatment in IIM are conflicting and new onset DM/PM has been described after administration of anti-TNFα agents to treat other diseases, pointing to the complex effects of TNFα neutralization. Treatment with anti-IFNα has been shown to suppress the IFN type 1 gene signature in DM/PM patients and improve muscle strength. Beneficial effects of anti-IL-1 and anti-IL-6 therapy have also been reported. Cytokine profiling in IIM aids the development of therapeutic strategies and provides approaches to subtype patients for treatment outcome prediction.

Current pharmacological treatment of idiopathic inflammatory myopathies

“…The production of Interleukin-1 (IL-1) by activated macrophages, endothelial cells and muscle fibres is increased in IIM and can mediate the muscle damage [87].…”

Investigation on Serum Levels of Interleukin-18 and Interleukin-6 in Patients With Dermatomyositis and Polymyositis

“…The invasion of T cells may induce direct and indirect harmful effects on muscle tissues, causing necrosis and weakness of muscle tissues, but the target of the immune response is not well known. The immune cells that enter the muscle fibers may not only have direct harmful effects on muscle fibers, but may also affect molecules like cytokines that are produced and secreted in the area and in the blood circulation (14)(15)(16). Therefore, it was necessary to investigate the role of cytokines in DM and PM disorders.…”

Idiopathic Inflammatory Myopathies: A Review of the Classification and Impact of Pathogenesis

“…Reports of TNF-α blockade as a treatment for IIMs have not panned out at this time and new cases of dermatomyositis/polymyositis have been reported after administration of TNF-α therapy [28]. …”