Novel Therapeutic Approaches for Inclusion Body Myositis

Thomas E. Lloyd

Disclosures

Curr Opin Rheumatol. 2010;22(6):658-664. 

In This Article

Abstract and Introduction

Abstract

Purpose of review This review will highlight recent advances in developing strategies to accelerate muscle regeneration and to slow muscle degeneration in myositis, focusing primarily on inclusion body myositis (IBM).
Recent findings Therapies for accelerating muscle regeneration, primarily through inhibition of myostatin, have shown promise in the laboratory and are now entering clinical trials. Recent studies have implicated autophagy, a key cellular process involved in clearance of ubiquitinated aggregates, in the pathogenesis of familial and sporadic inclusion body myositis (sIBM). IBM has joined a growing list of diseases known as TDP-43 proteinopathies, in which this protein becomes mislocalized to the cytoplasm; however, it is unclear whether these protein aggregates or others are pathogenic in this disease.
Summary New discoveries of biomarkers in sIBM and new insights into the pathogenesis of familial IBM are opening novel therapeutic pathways for these disorders. In particular, drugs that stimulate autophagy, already in development for cancer and neurodegenerative diseases, are candidates for clinical trials. These disease-specific therapies combined with novel therapies to accelerate muscle regeneration hold promise for future therapy for this devastating disease.

Introduction

For most myositis patients, prognosis depends upon premorbid health and the ability of the disease to respond to immunosuppressive therapy. Skeletal muscle has an incredible ability to regenerate following an acute injury, and patients with immunotherapy-responsive idiopathic inflammatory myopathies have an excellent prognosis. In contrast, patients with immunotherapy-resistant myositis often have a relentlessly progressive course. Although newer immunotherapies may have improved efficacy in refractory cases, for patients with sporadic inclusion body myositis (sIBM), novel treatment strategies are desperately needed.

Muscle strength in disease can be thought of as a balance between regeneration and degeneration, and this balance is strongly influenced by the immune system in myositis. For example, cytokines released from inflammatory cells may stimulate satellite cells to proliferate and thus enhance regeneration. Therefore, a better understanding of the complex interplay between the inflammatory response and muscle regeneration is critical to the development of therapies designed to enhance myogenesis (reviewed in [1]). Furthermore, although the immune system is believed to directly cause muscle degeneration in most forms of myositis, there are clearly nonimmune mechanisms (reviewed in [2]), and these may be the primary culprit in sIBM. Understanding the cellular mechanisms of myofiber degeneration will likely lead to novel treatment strategies for myositis in the future. This review will focus on strategies to suppress myofiber degeneration and to enhance myofiber regeneration, and will not discuss emerging immunotherapies (recently reviewed in [3••]). These emerging therapies may be helpful in conjunction with immunosuppressive medications in many forms of myositis, and may become the primary mode of therapy for sIBM.

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