BACKGROUND\nJoint destruction is a hallmark of autoantibody-positive rheumatoid arthritis (RA), though the severity is highly variable between patients. The processes underlying these... Show moreBACKGROUND\nJoint destruction is a hallmark of autoantibody-positive rheumatoid arthritis (RA), though the severity is highly variable between patients. The processes underlying these interindividual differences are incompletely understood.\nMETHODS\nWe performed a genome-wide association study on the radiological progression rate in 384 autoantibody-positive patients with RA. In stage-II 1557 X-rays of 301 Dutch autoantibody-positive patients with RA were studied and in stage-III 861 X-rays of 742 North American autoantibody-positive patients with RA. Sperm-Associated Antigen 16 (SPAG16) expression in RA synovium and fibroblast-like synoviocytes (FLS) was examined using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) and immunohistochemistry. FLS secrete metalloproteinases that degrade cartilage and bone. SPAG16 genotypes were related to matrix metalloproteinase (MMP)-3 and MMP-1 expression by FLS in vitro and MMP-3 production ex vivo.\nRESULTS\nA cluster of single nucleotide polymorphisms (SNPs) at 2q34, located at SPAG16, associated with the radiological progression rate; rs7607479 reached genome-wide significance. A protective role of rs7607479 was replicated in European and North American patients with RA. Per minor allele, patients had a 0.78-fold (95% CI 0.67 to 0.91) progression rate over 7 years. mRNA and protein expression of SPAG16 in RA synovium and FLS was verified. FLS carrying the minor allele secreted less MMP-3 (p=1.60×10(-2)). Furthermore, patients with RA carrying the minor allele had lower serum levels of MMP-3 (p=4.28×10(-2)). In a multivariate analysis on rs7607479 and MMP-3, only MMP-3 associated with progression (p=2.77×10(-4)), suggesting that the association between SPAG16-rs7607479 and joint damage is mediated via an effect on MMP-3 secretion.\nCONCLUSIONS\nGenetic and functional analyses indicate that SPAG16 influences MMP-3 regulation and protects against joint destruction in autoantibody-positive RA. These findings could enhance risk stratification in autoantibody-positive RA. Show less
OBJECTIVE\nUndifferentiated arthritis (UA) is a common form of arthritis. According to the Assessment of Spondyloarthritis international Society (ASAS) criteria for peripheral spondyloarthritis ... Show moreOBJECTIVE\nUndifferentiated arthritis (UA) is a common form of arthritis. According to the Assessment of Spondyloarthritis international Society (ASAS) criteria for peripheral spondyloarthritis (pSpA), HLA-B27 can be used to help classify patients with pSpA. We tested whether HLA-B27 is increased in patients diagnosed with UA.\nMETHODS\nPrevalence of HLA-B27 was compared between healthy controls and patients with UA. SpA features were compared between HLA-B27-positive and -negative UA, and SpA.\nRESULTS\nWe found 10.1% of UA (38/375) versus 7.2% (403/5584) of controls were HLA-B27-positive (OR 1.5, 95% CI 1.0-2.1; p = 0.037). HLA-B27-positive patients with UA had more SpA features than HLA-B27-negative patients (mean 1.6, SD 1.0, and 0.9 SD 0.6; p < 0.001), but patients with SpA had significantly more SpA features (mean 4.5, SD 1.5; p < 0.001). Family history and preceding infection were features more common in HLA-B27-positive than in HLA-B27-negative UA (15.8% vs 1.3%, p = 0.04 and 15.8% vs 2.6%, p = 0.04). After HLA-B27 testing, 21 additional patients (5.6%) with UA could potentially have been classified with pSpA according to the ASAS criteria.\nCONCLUSION\nHLA-B27 is more common in patients with UA than in controls. However, the yield of HLA-B27 testing in UA is low. Our results suggest that HLA-B27 testing should be reserved for patients with additional SpA features. Show less
Trouw, L.; Schonkeren, J.; Daha, N.; Levarht, N.; Roos, A.; Ernst-Kruis, M.; ... ; Toes, R. 2012
