van der Helm-van Mil Annette H M, Verpoort Kirsten N, le Cessie Saskia, Huizinga Tom W J, de Vries René R P, Toes René E M
Leiden University Medical Center, Leiden, The Netherlands.
Arthritis Rheum. 2007 Feb;56(2):425-32. doi: 10.1002/art.22373.
The HLA shared epitope (SE) alleles are primarily a risk factor for the presence of antibodies to cyclic citrullinated peptide (anti-CCP antibodies) rather than for the development of rheumatoid arthritis (RA). The SE alleles interact with the environmental risk factor tobacco exposure (TE) for predisposition to anti-CCP+ RA. The objectives of this study were to determine 1) whether different SE subtypes contribute differently to the presence of anti-CCP antibodies, 2) whether different SE subtypes all interact with TE for the development of anti-CCP antibodies, and 3) the effect of TE in relation to the SE alleles and anti-CCP antibodies on the risk of progression from undifferentiated arthritis (UA) to RA.
We assessed the effect of SE subtypes and TE on the presence and level of anti-CCP antibodies and on the risk of progression from UA to RA in 977 patients with early arthritis who were included in the Leiden Early Arthritis Clinic.
The HLA-DRB1*0401, *0404, 0405, or 0408 SE alleles conferred the highest risk of developing anti-CCP antibodies (odds ratio [OR] 5.0, compared with an OR of 2.0 for the HLA-DRB10101 or 0102 SE alleles and an OR of 1.7 for the HLA-DRB11001 SE allele). Conversely, the TE-SE allele interaction was the strongest for the HLA-DRB10101 or 0102 SE alleles and the HLA-DRB11001 SE allele. TE in SE+, anti-CCP+ patients correlated with higher levels of anti-CCP antibodies and with progression from UA to RA. In logistic regression analysis, only the presence and level of anti-CCP antibodies were associated independently with RA development.
The HLA-DRB1 SE subtypes differ in their interaction with smoking and in their predisposition to anti-CCP antibodies. TE contributes to the development of RA in SE+, anti-CCP+ patients, which is explained by its effect on the level of anti-CCP antibodies.
人类白细胞抗原共享表位（SE）等位基因主要是环状瓜氨酸肽抗体（抗CCP抗体）存在的危险因素，而非类风湿关节炎（RA）发病的危险因素。SE等位基因与环境危险因素烟草暴露（TE）相互作用，导致抗CCP阳性RA易感性增加。本研究的目的是确定：1）不同的SE亚型对抗CCP抗体存在的影响是否不同；2）不同的SE亚型是否均与TE相互作用导致抗CCP抗体产生；3）TE与SE等位基因及抗CCP抗体对未分化关节炎（UA）进展为RA风险的影响。
我们评估了SE亚型和TE对977例纳入莱顿早期关节炎诊所的早期关节炎患者抗CCP抗体的存在、水平以及UA进展为RA风险的影响。
HLA-DRB10401、0404、0405或0408 SE等位基因产生抗CCP抗体的风险最高（比值比[OR]为5.0，而HLA-DRB10101或0102 SE等位基因的OR为2.0，HLA-DRB11001 SE等位基因的OR为1.7）。相反，HLA-DRB10101或0102 SE等位基因以及HLA-DRB11001 SE等位基因的TE-SE等位基因相互作用最强。SE阳性、抗CCP阳性患者中的TE与更高水平的抗CCP抗体以及从UA进展为RA相关。在逻辑回归分析中，只有抗CCP抗体的存在和水平与RA发病独立相关。
HLA-DRB1 SE亚型在与吸烟的相互作用及其对抗CCP抗体的易感性方面存在差异。TE促成了SE阳性、抗CCP阳性患者的RA发病，这可通过其对抗CCP抗体水平的影响来解释。
