Juvenile idiopathic arthritis pathophysiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dheeraj Makkar, M.D.[2] Nehal Eid, M.D.[3]
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Pathophysiology
Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of immune-mediated disorders involving dysregulation of innate and adaptive immunity.[1]
Juvenile idiopathic arthritis (JIA) comprises a group of disorders with heterogeneous pathophysiologic mechanisms involving dysregulation of the immune system. The relative contributions of innate and adaptive immunity vary by subtype.
In oligoarticular and RF-negative polyarticular JIA, disease is predominantly autoimmune in nature.
- Aberrant activation of adaptive immune responses
- Activation of Th1 and Th17 T lymphocytes and monocytes lead to the production of inflammatory cytokines, including tumor necrosis factor (TNF) and interleukin-6.
- It activates fibro blast-like synoviocytes (FLS) toward an aggressive, proinflammatory phenotype with the production of matrix metalloproteinases, pannus formation, and osteoclast activation, leading to bone erosion.
- CD8 lymphocytes are also recruited and persist in the joint as tissue-resident memory lymphocytes (Trm), which drive joint-specific memory and flares that predominantly involve previously affected joints.
- Although many patients have antinuclear antibodies (ANA), the role of B cells and autoantibodies is unknown.
RF-positive polyarticular JIA shows pathological features similar to that of seropositive rheumatoid arthritis. Activation of Th1 cells and B cells lesults in plasma cells development and autoantibodies production, including anti–citrullinated protein antibodies (ACPA) and RF, with immune complex formation. Neutrophil extracellular traps (NETosis) amplify these autoantibody responses.
Systemic JIA (Still’s disease) is predominantly autoinflammatory in nature. It is characterized by marked activation of neutrophils and monocytes, which is amplified by S100 alarmins leading to inflammasome activation and IL-1 related cytokines production, including interleukin-1β and interleukin-18.
Later in the disease course, systemic JIA can be associated with more autoimmune features, including activation of Th17 and γδ T cells.
Genetic susceptibility, environmental triggers, and immune dysregulation interact to initiate and perpetuate inflammation. The pathophysiologic spectrum of JIA overlaps with adult inflammatory arthritides, with systemic JIA forming a continuum with adult-onset Still’s disease.
Macrophage activation syndrome, a life-threatening acquired form of hemophagocytic lymphohistiocytosis (HLH), occurs in at least 10% of patients with systemic JIA.[2] Primary (e.g., familial) HLH is caused by rare defects in the perforin pathway.[3] Acquired HLH can be triggered by infection, cancer, or rheumatic disease flares. This disorder can occur at any point in the progression of systemic JIA. Affected patients present with fever, coagulopathy, cytopenias, hyperferritinemia, liver injury, and central nervous system dysfunction.[4]
Macrophage activation syndrome supposedly results from Interleukin-18 driving production of interferon-γ production.
Enthesitis-related arthritis and juvenile spondyloarthritis are associated with activation of Th1, Th17, and γδ T cells and a cytokine environment dominated by interleukin-12, interleukin-23, and interleukin-17.
Many patients carry the HLA-B27 allele, which encodes a protein that presents arthritogenic antigens to CD8 cells and drives more innate immune inflammatory responses. Inflammation occur at both entheses and the synovium.
Psoriatic JIA has an overlapping pathogenesis that resembles that of juvenile spondyloarthritis or early-onset and ANA-positive disease (oligoarthritis and RF-negative polyarthritis).
Lung disease pathophysiology is unclear. However, an association with the HLA-DRB1*15 allele may be present.[5][6][7][8] Several hypotheses involving treatment with interleukin-1 and inter leukin-6 inhibitors have been proposed, including cytokine-related lymphocyte plasticity and an unusual pulmonary complication of drug induced hypersensitivity syndrome (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]).[5][6][7][8]
References
- ↑ Sandborg CI, Schulert GS, Kimura Y. Juvenile Idiopathic Arthritis. N Engl J Med. 2025;392:XXX–XXX. doi:10.1056/NEJMra2402073.
- ↑ Minoia F, Davì S, Horne A, et al. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis Rheumatol 2014; 66: 3160-9.
- ↑ Filipovich AH. Hemophagocytic lymphohistiocytosis and related disorders. Curr Opin Allergy Clin Immunol 2006; 6:410-5.
- ↑ Ravelli A, Minoia F, Davì S, et al. 2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a Europe an League Against Rheumatism/American College of Rheumatology/Paediatric Rheu matology International Trials Organisa tion collaborative initiative. Ann Rheum Dis 2016;75:481-9.
- ↑ 5.0 5.1 Saper VE, Ombrello MJ, Tremoulet AH, et al. Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles. Ann Rheum Dis 2022;81:406-15.
- ↑ 6.0 6.1 Lerman AM, Mahmud SA, Alfath Z, et al. HLA-DRB1*15 and eosinophilia are common among patients with systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2023; 75: 2082-7.
- ↑ 7.0 7.1 Wobma H, Arvila SR, Taylor ML, et al. Incidence and risk factors for eosinophilia and lung disease in biologic-exposed children with systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2023; 75: 2063-72.
- ↑ 8.0 8.1 Saper VE, Tian L, Verstegen RHJ, et al. Interleukin (IL)-1/IL-6-inhibitor-associat ed drug reaction with eosinophilia and systemic symptoms (DReSS) in systemic inflammatory illnesses. J Allergy Clin Immunol Pract 2024; 12(11): 2996-3013.e7.