New molecular targets for the treatment of sarcoidosis

Abstract

Purpose of review: Sarcoidosis is a chronic granulomatous disease typically affecting the lung, lymph nodes, and other organ systems. Evidence suggests that the morbidity and mortality rates for sarcoidosis in the USA are rising, despite widespread use of anti-inflammatory therapies. In this review, we survey new therapies that target specific inflammatory pathways in other diseases (such as rheumatoid arthritis, Crohn's disease, and psoriasis) that are similar to pathways relevant to sarcoidosis immunopathogenesis, and therefore, represent potentially new sarcoidosis therapies.

Recent findings: Immunopathogenesis of sarcoidosis has been well elucidated over the past few years. There is abundant evidence for T-cell activation in sarcoidosis leading to activation of both Th1 and Th17 inflammatory cascades. Therapies targeting T-cell activation, Th1 pathways (such as the interleukin-6 inhibitors), Th17 pathway mediators, and others have been Food and Drug Administration approved or under investigation to treat a variety of autoimmune inflammatory diseases, but have not been studied in sarcoidosis. Targeting the p38 mitogen-activated protein kinases and the ubiquitine proteasome system with new agents may also represent a novel therapeutic option for patients with sarcoidosis.

Summary: Rising morbidity and mortality rates for patients with sarcoidosis strongly support the need to develop more effective anti-inflammatory therapies to treat chronic disease.

FIGURE 1

Numbers of deaths and age-adjusted mortality rates per 1 000 000 population [8]. Reprinted with permission of the American Thoracic Society. Copyright © 2016 American Thoracic Society [8]. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

FIGURE 2

Granuloma formation – Th1/Th17 hypothesis. Initiation: alveolar macrophages and dendritic cells are activated by a putative antigen. Dendritic cells migrate to lymph nodes and initiate Th1/Th17-cell amplification. Chemokines, produced by alveolar macrophages, attract Th1/17, Treg, B-cells as well as CD8⁺ cells and fibroblast and initiate granuloma formation (effector phase). Both dendritic cells and macrophages produce cytokines favoring Th1 and Th17 cells in sarcoidosis [54].