Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions

Abstract

Systemic juvenile idiopathic arthritis (sJIA) has long been recognized as unique among childhood arthritides, because of its distinctive clinical and epidemiological features, including an association with macrophage activation syndrome. Here, we summarize research into sJIA pathogenesis. The triggers of disease are unknown, although infections are suspects. Once initiated, sJIA seems to be driven by innate proinflammatory cytokines. Endogenous Toll-like receptor ligands, including S100 proteins, probably synergize with cytokines to perpetuate inflammation. These and other findings support the hypothesis that sJIA is an autoinflammatory condition. Indeed, IL-1 is implicated as a pivotal cytokine, but the source of excess IL-1 activity remains obscure and the role of IL-1 in chronic arthritis is less clear. Another hypothesis is that a form of hemophagocytic lymphohistiocytosis underlies sJIA, with varying degrees of its expression across the spectrum of disease. Alternatively, sJIA with MAS might be a genetically distinct subtype. Yet another hypothesis proposes that inadequate downregulation of immune activation is central to sJIA, supporting evidence for which includes ‘alternative activation’ of monocyte and macrophages and possible deficiencies in IL-10 and T regulatory cells. Some altered immune phenotypes persist during clinically inactive disease, which suggests that this stage might represent compensated inflammation. Despite much progress being made, many questions remain, providing fertile ground for future research.

HLA-DRB1*11and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

“…Many alleles of HLA-DRβ1, including HLA-DRB1*11 (16), have been reported to affect sJIA risk in studies of single populations (11)(12)(13)(14)(15)(16). However no association has reached the level of genome-wide significance and no single HLA-DRB1 allele has been found to influence sJIA risk across studies or populations (9,17), leading some to conclude that class II HLA molecules are not risk factors for sJIA (18).…”

“…Moreover, intracellular class II HLA molecules are important regulators of Toll-like receptor signaling in both monocytes and dendritic cells (24). Given that sJIA is a disease marked by systemic inflammation with enhanced production of proinflammatory cytokines (3,17), it is attractive to hypothesize that HLA-DRB1*11 molecules contribute to sJIA pathogenesis through dysregulation of innate immunity and promotion of proinflammatory cytokine production by APCs.…”

Cytokine profile in adult-onset Still's disease: Comparison with systemic juvenile idiopathic arthritis

“…Recently, the characterization of autoinflammatory diseases has led to a renewed classification of immune-mediated rheumatic diseases [27]. Recent reports suggest that s-JIA is more likely to belong to the group of autoinflammatory diseases that follow the same continuum as AOSD [12,28,29]. However, whether s-JIA and AOSD are the same disease remains controversial.…”

“…Recent studies have shown that inflammatory cytokines, including interleukin (IL)-1, IL-6, IL-18, interferon (IFN)-γ, and tissue necrosis factor (TNF)-α play pathogenic roles in the disease processes of both s-JIA and AOSD [12,13]. Furthermore, biological therapies intended to block these cytokines yield dramatic effects in patients with s-JIA and AOSD [14,15].…”

The Effect of Tocilizumab on the Condition of Bone Tissue of Patients With Systematic Juvenile Idiopatic Arthritis: Results of a Series of Cases Retrospective Study

“…До недавнего времени для лечения системного ЮИА требовалась длительная терапия глюкокортикостерои-дами (на протяжении 3 и более месяцев [4]) в высоких дозах [5,6], что является одним из факторов риска раз-вития остеопороза и вызывает серьезные побочные эффекты, в том числе остеопороз с обширными пере-DOI: 10.15690/pf.v13i6.1669 561 ломами [7,8]. С внедрением в терапию ревматических заболеваний генно-инженерных биологических препа-ратов, которые избирательно воздействуют на иммунную систему и позволяют устранить необходимое звено в патогенезе, появилась возможность уменьшить частоту и длительность применения стероидных гормонов и, тем самым, избежать развития осложнений [6].…”