Development Of Spondyloarthropathy Research Articles

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

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.

Interleukin 23 is critical in the pathogenesis of spondyloarthropathy and acts on a novel population of interleukin 23R+ entheseal resident cells

Spondyloarthropathy is characterised by inflammation, bone erosion, and new bone formation at the entheseal insertions of tendons and ligaments to bone. Lack of understanding of the underlying mechanisms that drive entheseal disease has seriously inhibited design of therapeutics. Although anti-tumour necrosis factor (TNF) therapy reduces signs and symptoms of inflammation, residual inflammation continues and bone growth is not inhibited. This suggests that TNF is not the optimum target to modify entheseal disease.We previously demonstrated that interleukin (IL) 23 is pivotal in autoimmune inflammation. Recently, genetic variants in the IL-23 receptor (IL23R) have been associated with development of spondyloarthropathy. Moreover, HLA-B27 (present in 90% of patients with ankylosing spondylitis) as well as associated bowel inflammation have been shown to induce IL-23 expression. However, the site and mechanism of action of IL23 are unknown and the reason why such dysregulation of IL23 is associated with inflammation specifically at the enthesis has been inexplicable. We now demonstrate that the entheses and aortic root contain a novel population of resident IL23R+ T cells, which allow the tissue to rapidly respond to IL23. Intravital microscopy reveals that these cells display an extremely restricted entheseal localisation and are absent from synovium and tendon proper. The cells express the molecule PLZF, which allows them to respond to cytokines extremely rapidly, and indeed entheses respond within hours to IL23 in vitro. Moreover, IL-23 expression in vivo in mice is sufficient by itself to rapidly induce the hallmark features of spondyloarthropathy with development of exceedingly specific enthesitis, aortitis, and typical bone erosion and new bone formation.The highly restricted distribution of IL23R+ cells provides the fundamental basis for the anatomical localisation of inflammation observed in spondyloarthropathy, as well as allowing a unified understanding of the genetic associations. These findings suggest that neutralisation of IL23 may be a truly disease modifying therapeutic approach. FundingMerck.

A possible case of spondyloarthropathy in a prehistoric Japanese skeleton

Palaeopathology helps to define the migration of past diseases. Genetic and environmental factors play a role in the development of spondyloarthropathy (SpA). We report skeletal remains with SpA from the Jomon period in Japan. The skeleton is of a female who died at a young adult age. The skeleton had characteristic features seen in SpA as follows: (1) polyarticular arthritis; (2) erosions accompanying some bone formation; (3) enthesial ossification; and (4) periostitis in lower long bones. The findings suggest that SpA was present in prehistoric Japan before contact with European civilisation, and the present example of SpA is the oldest in Asia and the Old World. Copyright © 2004 John Wiley & Sons, Ltd.

HLA-B27 and pathogenesis of spondyloarthropathies.

Although the influence of HLA-B27 on the development of spondyloarthropathies is undisputed, its role in pathogenesis remains unclear. New ideas have focused on abnormal characteristics of HLA-B27 resulting from aberrant folding, disulfide bond formation, or both, rather than a predilection for selecting arthritogenic peptides. This reflects, in part, unanswered questions about whether immunologic recognition of HLA-B27 is required for disease. Recent studies suggest that CD4+ T cells, immunomodulatory killer cell Ig receptors, and Ig-like transcript receptors may recognize aberrant forms of HLA-B27. Other reports suggest that HLA-B27 expression can alter cytokine production from monocytes and T cells-effects that appear unrelated to antigen presentation. Novel bioinformatics approaches have led to the identification of HLA-B27-restricted pathogen-derived peptides and may prove useful in determining whether HLA-B27 presents arthritogenic peptides. Elucidating the role of HLA-B27 in the pathogenesis of these conditions will require an integration of information from animal models, genome-wide screens for susceptibility alleles, and translational studies using human samples.

Immunogenetics, HLA-B27 and spondyloarthropathies.

HLA-B27 is the strongest HLA molecule associated with a disease. However, the reason only a small fraction of HLA-B27 positive individuals develop spondyloarthropathies is still unknown. Recent advances in genetics support the fact that additional genetic factors influence the disease and that the environmental factors may be ubiquitous. The mechanism of association of HLA-B27 and disease remains unknown, but recent studies reveal some peculiar properties of accessory molecules in antigen presentation of B27. Furthermore, research has focused on the analysis of HLA-B27-restricted processing and presentation of a bacteria-derived peptide as playing a key role in the development of spondyloarthropathy. Other studies support a more complex interaction between bacteria and HLA-B27 and suggest that other roles unrelated to antigen presentation might contribute to the development of SpA.

Inflammation in HLA-B27-associated Diseases

The pathogenetic mechanisms in the development of spondyloarthropathies are multifactorial. These include the possible role of infective micro-organisms which can by direct invasion lead to persistence of microbial antigens and thus trigger arthritis or by cross-reactions with the host tissue lead to inflammatory symptoms or by cross-reactions with HLA-B27 trigger cytotoxic T-cell response. After the primary event, exaggerated inflammatory response can lead to amplification of inflammation. The components in the amplification of inflammation include hyperreactive neutrophils and serum factors such as enhanced production of activation products of complement in subjects with HLA-B27. The enhanced neutrophil function seems to persist in patients with previous severe inflammatory symptoms during acute reactive arthritis or in those with late inflammatory complications. The enhancement is probably caused by priming effect by lipopolysaccharide, which seems to persist for a long period in patients with acute reactive arthritis. Enhanced production of monokines can contribute to the enhanced inflammation in patients with spondyloarthropathies. The primed phagocytes can respond vigorously when rechallenged with antigenic load during a new infection, thus leading in some patients to recurrent or chronic inflammatory symptoms. Antimicrobial therapy or sulphasalazine by modifying antigen elimination or absorption can diminish inflammatory response during acute arthritis and in chronic spondyloarthropathies. Long-term follow-up studies are needed to find out whether prolonged therapies with these agents affect the prognosis of spondyloarthropathies.