Janus Kinase Inhibitors: A New Tool for the Treatment of Axial Spondyloarthritis

Abstract

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease involving the spine, peripheral joints, and entheses. This condition causes stiffness, pain, and significant limitation of movement. In recent years, several effective therapies have become available based on the use of biologics that selectively block cytokines involved in the pathogenesis of the disease, such as tumor necrosis factor-α (TNFα), interleukin (IL)-17, and IL-23. However, a significant number of patients show an inadequate response to treatment. Over 10 years ago, small synthetic molecules capable of blocking the activity of Janus kinases (JAK) were introduced in the therapy of rheumatoid arthritis. Subsequently, their indication extended to the treatment of other inflammatory rheumatic diseases. The purpose of this review is to discuss the efficacy and safety of these molecules in axSpA therapy.

Keywords: JAK inhibitors; Janus kinases; axial spondyloarthritis.

Figure 1

Several cytokines and growth factors recognize receptors that send their signals through the JAK–STAT pathway. EPO = erythropoietin; TPO = thrombopoietin; GM-CSF = granulocyte–macrophage colony-stimulating factor.

Figure 2

Immunopathology of axSpA and point of action of JAK inhibitors. Dendritic cells induce Th0 cells to differentiate into Th1 or Th17 cells. Dendritic cells also activate different cells of the innate immune system. These functions require the presence of several cytokines. In turn, differentiated/activated immune cells produce cytokines that activate monocytes, synoviocytes, osteoclasts, and osteoblasts. All these cells are responsible for the immunopathological events that cause axSpA. The cytokines depicted in the figure are those that can be inhibited by JAKinibs. The light green box includes the JAK1/JAK3-dependent cytokines that are inhibited by both the selective JAK1 inhibitors, upadacitinib and filgotinib, and the pan-JAK inhibitor, tofacitinib. The light yellow box includes the JAK2/TYK2-dependent cytokines that are inhibited by tofacitinib.

Figure 3

Flow chart showing therapeutic management of axSpA with predominant axial manifestations. The data are in accordance with ASAS-EULAR recommendations. JAK inhibitors, although included as phase II treatment along with biologics, are currently used as the second choice in clinical practice. A positive rheumatologist’s opinion is also required.