A Promising Target in Rheumatoid Arthritis Treatment: Granulocyte-Macrophage Colony-Stimulating Factor

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is more familiar to clinicians as a hemopoietic growth factor. However, it also modulates functions of myeloid cells such as macrophages. Experimental work has demonstrated its significant contribution to the pathogenesis of rheumatoid arthritis (RA). It was a long-time concern that targeted therapies against this cytokine could cause severe side effects such as neutropenia or pulmonary alveolar proteinosis. Nevertheless, different compounds successfully entered clinical development for RA targeting the cytokine itself or its receptor. Currently, a monoclonal antibody against its receptor has completed phase II trials with a profound and rapid onset of response, normalization of acute phase reactants, and an overall good safety profile. The development of compounds targeting the GM-CSF pathway represents a promising approach in RA. However, the obtained ACR20 and ACR50 responses were rather similar with marketed biologic agents when added to MTX. So, it is appropriate to ask the question, whether we do really need another group of agents with a similar performance? In this context, the tumor necrosis factor (TNF)-independent mode-of action of GM-CSF blockade supports the assumption that it could be a useful alternative especially in anti-TNF-resistant patients. Furthermore, a higher efficacy with concurrent blockade of IL-17 and GM-CSF, as reported from preclinical studies, also suggests that such strategies are of interest for future approaches. Therefore, comprehensive assessment of GM-CSF blockade in anti-TNF-resistant patients and combination strategies will be of major importance. Taken together, rapid onset of action, sustained effectiveness, and shown favorable safety data from phase 2 trials warrant further evaluations of anti-GM-CSF agents in different subgroups of RA patients.