Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood [1]. It is a complex inflammatory disease with multifactorial pathogenesis including genetic predisposition and environmental factors leading to chronic inflammatory response. The resulting autoimmune disease manifests as synovial tissue inflammation, leading to chronic arthritis [2].
Clinically, JIA is defined as arthritis of unknown origin that manifests before the age of 16 years and persists for at least 6 weeks. The International League of Associations for Rheumatology (ILAR) criteria have identified classification criteria for subtypes of JIA. Oligoarticular JIA, which affects four or more joints, is the most common presentation. The ILAR classification identifies two categories of oligoarthritis: Persistent oligoarthritis, in which the disease remains in four or fewer joints, and extended oligoarthritis, in which the arthritis moves beyond four joints after the first 6 months of disease. Children presenting with five or more affected joints have polyarticular JIA, and can be further subdivided by presence or absence of rheumatoid factor. Other JIA subtypes reflect the presence of other symptoms including psoriasis (psoriatic-related arthritis), enthesitis (enthesitis-related arthritis), or quotidian fever and rash with other systemic features (systemic JIA) [3]. Identification of these subtypes of JIA is an important step toward a unified classification system, but substantial patient heterogeneity in disease presentation and response to medications remains.
Future directions in pediatric rheumatology focus on identifying biologic markers in JIA. This precision medicine approach could be used to improve classification, guide treatment options, and predict outcomes in JIA.
One potential biomarker includes the myeloid related proteins: MRP8, MRP14, and MRP6 (also known as S100A8, S100A9, and S100-A12, respectively). These are calcium-binding proteins expressed in granulocytes, monocytes, and macrophages during early differentiation stages. These proteins activate monocytes by binding to toll-like receptor 4 (TLR4) which signals tumor necrosis factor (TNF)-α production and leads to inflammation [4]. Elevated levels of MRP8/14 have been identified as biomarkers for prediction of long-term remission in oligoarticular and polyarticular JIA [5–7]. In the Childhood Arthritis Response to Medication Study (CHARMS), levels of MRP8/MRP14 were increased in serum and correlated closely with a panel of other disease activity measures in 52 children with systemic JIA [8]. Baseline levels of MRP8/MRP14 were higher in patients who achieved remission after 6 months of methotrexate therapy compared with those who did not respond. In patients with systemic JIA who were treated successfully with interleukin-1 or TNF inhibitors, levels of MRP8 and MRP14 decreased [8]. Similarly, serum levels of MRP8/MRP14 predicted response to starting and stopping anti-TNF therapy in non-systemic JIA [9].
Synovial fluid analyses can also be used to predict disease. Ratios of CD4+ T cells: CD8+ T cells in synovial fluid was reversed in a children who developed extended oligoarticular arthritis compared to children with persistent oligoarthritis [10]. In synovial fluid analyses, elevated levels of cartilage degrading enzymes were found in children with polyarticular JIA compared with those with enthesitis-related arthritis [11].
Genetic analyses of children with JIA could also be useful to help redefine JIA categories. Recent studies of 770 children with systemic JIA showed no evidence of shared genetic architecture with other forms of JIA [12]. In a study of 5043 JIA cases from around the world, rheumatoid factor-negative polyarticular JIA and oligoarticular JIA were observed to be genetically similar. The investigators were also able to correlate JIA categories to adult counterparts [13].
Identifying biomarkers, including genetic data, from serum and synovial fluid in children with JIA is helping to inform clinical decisions for more precise and personalized treatments. These studies will bring us one step closer to our goal of treating children with JIA so that they can thrive and grow into healthy adults.
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