Advances in potential targeted therapies for Erdheim-Chester disease

Introduction: Erdheim-Chester disease (ECD) is a rare histiocytosis, characterized by infiltration of aberrant macrophages into multiple tissues and organs causing rampant inflammation and fibrosis. The clinical severity and the nuances of disease pathogenesis must be considered when pondering different treatment strategies for the individual patient. Areas covered: Interferon-α has long represented the first-line treatment for ECD, but its preeminence may be reappraised in the future as new effective medications become available. For example, alternative treatment options include cytokine-blocking agents, which dampen local and systemic inflammation. Of crucial importance, recent evidence indicates that deregulated activation of the mitogen-activated protein kinase (MAPK) pathway due to oncogenic mutations in the BRAF, NRAS, PIK3CA, and MAP2K1 genes is central to the pathogenesis of ECD. These advances in the molecular understanding of ECD as an inflammatory myeloid neoplasm translated into the therapeutic use of small-molecule RAF and MEK inhibitors, with unprecedented results in terms of clinical efficacy. Expert opinion: In the future, the development of ERK inhibitors holds tremendous promise for the treatment of ECD. Combination therapy with small-molecule plus anti-inflammatory agents may prove more beneficial than either treatment alone. New drugs against fibrosis, not amenable to treatment with currently available strategies, remain an unmet clinical need.