Pain in axial spondyloarthritis: role of the JAK/STAT pathway

Abstract

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that is characterized by new bone formation in the axial musculoskeletal system, with X-ray discriminating between radiographic and non-radiographic forms. Current therapeutic options include non-steroidal anti-inflammatory drugs in addition to biological disease-modifying anti-rheumatic drugs that specifically target tumor necrosis factor-alpha (TNFα) or interleukin (IL)-17. Pain is the most critical symptom for axSpA patients, significantly contributing to the burden of disease and impacting daily life. While the inflammatory process exerts a major role in determining pain in the early phases of the disease, the symptom may also result from mechanical and neuromuscular causes that require complex, multi-faceted pharmacologic and non-pharmacologic treatment, especially in the later phases. In clinical practice, pain often persists and does not respond further despite the absence of inflammatory disease activity. Cytokines involved in axSpA pathogenesis interact directly/indirectly with the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling cascade, a fundamental component in the origin and development of spondyloarthropathies. The JAK/STAT pathway also plays an important role in nociception, and new-generation JAK inhibitors have demonstrated rapid pain relief. We provide a comprehensive review of the different pain types observed in axSpA and the potential role of JAK/STAT signaling in this context, with specific focus on data from preclinical studies and data from clinical trials with JAK inhibitors.

Keywords: JAK/STAT signaling pathway; axial spondyloarthritis; pain; residual disease; small molecule inhibitor.

Figure 1

Mechanisms of pain in axSpA. Pain in axSpA is the result of the combination of three main types of pain: nociceptive, neuropathic, and nociplastic (–68). Chronic inflammation in axSpA is driven by several pro-inflammatory cytokines (directly or indirectly mediated by the JAK/STAT pathway), which act on nociceptors, lowering the activation thresholds of transducers for evoked stimuli leading to increased pain and peripheral sensitization. Peripheral inflammatory mediators can alter pain-processing regions of the brain, leading to sensory hypersensitivity and central sensitization. Central sensitization is the main pathophysiological mechanism for developing nociplastic pain and is due to different mechanisms including over-activated glial cell-derived signals, potentiation of excitatory signaling of N-methyl-d-aspartate (NMDA) receptors, and decrease in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). IL, interleukin; TNF, tumor necrosis factor; CS, central sensitization; NMDAR, N-methyl-d-aspartate receptor; axSpA, axial spondyloarthritis. The figure was created using BioRender.com.