Abstract

Introduction: Juvenile Idiopathic Arthritis (JIA) is the most common autoimmune disease in childhood. It is defined as arthritis in one or more joints in children with an age before 16 years. There are several subgroups of JIA. Aims of the study were to assess whether or not the cytokines IL-4, IL-10, IL-17, MCP-1 and TNF-α are elevated in the active stadium of the disease and whether or not there are patterns which are specific for the different subgroups of JIA.
Methods: 148 plasma and serum samples of 58 JIA patients with an average age of 11.3±5 years have been examined, as well as 118 plasma and serum samples of 118 controls or Normal Healthy Donors (NHD) with an average age of 34.9±16.8 years. The subgroups of JIA were defined as Persistent Oligoarticular JIA (PO JIA), Extended Oligoarticular JIA (EO JIA), Polyarthritis Rheuma Factor Positive JIA (RF+JIA), Enthesitis Related Arthritis (ERA JIA), Polyarthritis Rheuma Factor Negative JIA (RF-JIA) and Psoriasis Arthritis JIA (PS JIA). The serum levels of cytokines IL-4, IL-10, IL-17, MCP-1 and TNF-α were determined using ELISA technique.
Results: The levels of all measured cytokines were elevated in JIA patients compared to normal healthy donors. With an average value of 5.2±6.1pg/ml, IL-4 was significantly higher in JIA patients compared to controls, with an average value of 1.3±1.2pg/ml (p=0.0182; Mann Whitney test). However, the differences regarding the other cytokines were statistically not significant. The ROC analysis of IL-4 revealed an area under the curve of 0.7744 (p=0.0222); at a cut-off point of >1.68pg/ml IL-4 showed to have the highest sensitivity of 76.32 and a specificity of 71.43 for distinction of JIA from controls. The different cytokines were specifically elevated in different subgroups of JIA, but, however in no case statistically significant: IL-4 was elevated in PO JIA, EO JIA, RF+JIA, and RF-JIA; TNF-α was elevated in EO JIA and RF+JIA; MCP-1 was elevated in PO JIA and RF+JIA; IL-10 was elevated in PO JIA, EO JIA, RF+JIA and IL-17 was elevated in RF+JIA and RF-JIA. Interestingly, no cytokine was found to be elevated in ERA JIA or PS JIA patients. All cytokines tested were elevated in patients with active disease.
Conclusion: All parameters tested showed systemically higher values in JIA patients compared to controls: The most pronounced affect was found in IL-4. Different, specific elevation patterns were found in the subgroups of JIA. The marked elevation of IL-17 and IL-4 suggest treatment trials using specific antibodies, e. g. Ixekizumab or Dupilumab.

Keywords: Jucenile idiopathic arthritis; Cytokines; IL-4; IL-10; IL-17; MCP-1; TNF- α
List of Abbreviations: A: Active Phase; ANAs: Anti-Nuclear Antibodies; AUC: Area Under The Curve; CCL/ CXCL: Chemokine Ligand; CD8+T Cell: Cytotoxic T Cell; CHAQ: Childhood Health Assesment Questionnaire; CRP: C-Reactive Protein; DMARDs: Disease-Modifying Antirheumatic Drugs; ELISA: Enzyme-linked Immunosorbant Assay; EO JIA: Extended Oligoarticular Juvenile Idiopathic Arthritis; ERA: Enthesitis-Related Arthritis; ESR: Erythrocyte Sedimentation Rate; f: Female; HLA: Human Leukocyte Antigen; IAC: Intra-Articular Corticosteroid; Ig: Immunoglobulin; IL: Interleukin; JIA: Juvenile Idiopathic Arthritis; m: Male; Mb.: Morbus; MCP-1: Monocyte Chemoattractant Protein-1; MTX: Methotrexate; NA: Remission; NHD: Normal Healthy Donor; NK-Cells: Natural Killer-Cells; ns: Not Significant; NSAIDs: Nonsteroidal Anti-Inflammatory Drugs; PO JIA: Persistent Oligoarticular Juvenile Idiopathic Arthritis; PS JIA: Psoriatic Juvenile Idiopathic Arthritis; RANKL: Receptor Activator of NF-κB Ligand; RF+: Rheumatoid Factor Positive; RF-: Rheumatoid Factor Negative; ROC: Receiver-Operating-Characteristic-Curve; SJIA: Systemic Juvenile Idiopathic Arthritis; TH: Triamcinolone Hexacetonide; Th-Cells: T-Helper-Cells; TNF: Tumor Necrosis Factor