Immunopathophysiology of Juvenile Spondyloarthritis (jSpA): The “Out of the Box” View on Epigenetics, Neuroendocrine Pathways and Role of the Macrophage Migration Inhibitory Factor (MIF)

Abstract

Juvenile spondyloarthritis (jSpA) is a an umbrella term for heterogeneous group of related seronegative inflammatory disorders sharing common symptoms. Although it mainly affects children and adolescents, it often remains active during adulthood. Genetic and environmental factors are involved in its occurrence, although the exact underlying immunopathophysiology remains incompletely elucidated. Accumulated evidence suggests that, in affected patients, subclinical gut inflammation caused by intestinal dysbiosis, is pivotal to the future development of synovial–entheseal complex inflammation. While the predominant role of IL17/23 axis, TNF-α, and IL-7 in the pathophysiology of SpA, including jSpA, is firmly established, the role of the cytokine macrophage migration inhibitory factor (MIF) is generally overlooked. The purpose of this review is to discuss and emphasize the role of epigenetics, neuroendocrine pathways and the hypothalamic-pituitary (HPA) axis, and to propose a novel hypothesis of the role of decreased NLRP3 gene expression and possibly MIF in the early phases of jSpA development. The decreased NLRP3 gene expression in the latter, due to hypomethylation of promotor site, is (one of) the cause for inflammasome malfunction leading to gut dysbiosis observed in patients with early jSpA. In addition, we highlight the role of MIF in the complex innate, adaptive cellular and main effector cytokine network, Finally, since treatment of advanced bone pathology in SpA remains an unmet clinical need, I suggest possible new drug targets with the aim to ultimately improve treatment efficacy and long-term outcome of jSpA patients.

Nod-like receptors in inflammatory arthritis

“…Juvenile spondyloarthritis (JSpA) encompasses chronic and heterogenous seronegative inflammatory disorders and is associated with the HLA-B27 genotype [ 98 , 99 ]. Compared to adults, JSpA has been associated with lower HLA-B27 positivity, less peripheral arthritis and enthesitis and instead has more hip arthritis, axial involvement and acute anterior uveitis [ 99 ].…”

“…Compared to adults, JSpA has been associated with lower HLA-B27 positivity, less peripheral arthritis and enthesitis and instead has more hip arthritis, axial involvement and acute anterior uveitis [ 99 ]. Reduced expression of NLRP3 has been observed in JSpA and it is proposed that this contributes to permeability of the gut and subclinical inflammation which is seen in studies with defective NLRP3 inflammasome signaling (i.e., inflammatory bowel disease) [ 98 , 99 ]. On the other hand, it is important to note that a population study in Croatia found no association between a SNP in NLRP3 (Q705K) with JSpA or JIA [ 100 ].…”

Chronic Recurrent Multifocal Osteomyelitis (CRMO) and Juvenile Spondyloarthritis (JSpA): To What Extent Are They Related?

“…Data from animal models and studies of relatives of AS patients strongly suggest that these changes do indeed precede the onset of the disease [ 67 ]. In contrast to CRMO, where hyperactivation of the NLRP3 inflammasome and, thus, hyperproduction of IL-1β is thought to be the cause of bone inflammation, in AS, this hyperactivity was found to maintain gut homeostasis and thus protect against gut inflammation [ 68 ]. It appears that remodeling of the gut microbiota and increased induction of regulatory T cells are the main mechanisms responsible for the observed resistance [ 69 ].…”

“…There are also similarities in terms of treatment strategies. Indeed, both anti-TNF and anti-IL-17 have shown efficacy for these different diseases, which we could consider as an additional indirect argument in favor of a certain similarity [ 64 , 65 , 66 , 67 , 68 ]. It is possible, however, that TNF blockade interrupts inflammatory pathways in a nonspecific manner, whether or not the diseases have common pathophysiologic mechanisms.…”

Efficacy and safety of iguratimod in the treatment of rheumatic and autoimmune diseases: a meta-analysis and systematic review of 84 randomized controlled trials

“…Several studies have shown that IGU has good efficacy in rheumatic diseases and autoimmune diseases, such as improving RA, AS, systemic lupus erythematosus, IG4-RD, pulmonary interstitial disease, primary Sjögren's syndrome (PSS), etc. (Harjacek, 2021;Pu et al, 2021;Zeng et al, 2022a). In clinical practice, more and more rheumatologists use IGU to treat rheumatic and autoimmune diseases, but its efficacy and safety are still uncertain.…”