Increased Th17 Cell Frequency and Poor Clinical Outcome in Rheumatoid Arthritis Are Associated With a Genetic Variant in the IL4R Gene, rs1805010

Objective. The minor allele of the IL4R gene single-nucleotide polymorphism, rs1805010, confers impaired interleukin-4 (IL-4) signaling and has been associated with an aggressive destructive course of rheumatoid arthritis (RA). IL-4 inhibits the development of Th17 cells, a cell population recently identified as being prominent in RA patients and being associated with cartilage and bone destruction. The purpose of the present study was to investigate whether rs1805010 modulates Th17 cell development and, hence, subsequent clinical outcome in RA. Methods. A total of 90 patients with early, active RA (mean +/- SD Disease Activity Score in 28 joints 4.6 +/- 1.1) and 39 control subjects (24 healthy subjects and 15 patients with osteoarthritis [OA]) were genotyped. Serum levels of IL-17 and IL-22 as well as frequencies of Th17 cells were analyzed by enzyme-linked immunosorbent assay and flow cytometry. Clinical and radiographic data were collected and evaluated at baseline and 1 year after disease onset. Results. Twenty-six percent of the RA patients were homozygous for the major allele of rs1805010, 60% were heterozygous, and 14% were homozygous for the minor allele. The RA patients who were homozygous for the minor allele demonstrated significantly higher clinical activity associated with the presence of erosions after 1 year of followup as compared to the other RA patients. The inhibitory effect of IL-4 on Th17 cell development in these patients was significantly less prominent. Accordingly, the frequencies of Th17 cells and serum levels of IL-17 and IL-22 were significantly increased. Conclusion. The data indicate that the rs1805010 minor allele contributes to increased Th17 cell frequency, enhanced clinical activity, and accelerated radiographic progression in RA by rendering CD4T cells from RA patients insensitive to the attenuating effect of IL-4 on Th17 cell development.