Maksymowych Walter P, Suarez-Almazor Maria E, Buenviaje Heidi, Cooper Bobbi-Lynn, Degeus Caroline, Thompson Michael, Russell Anthony S
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
J Rheumatol. 2002 Nov;29(11):2319-26.
Palindromic rheumatism (PR) is an episodic arthropathy that may precede typical rheumatoid arthritis (RA), although pathogenetic relationships between these disorders remain unclear. The predictive value for those immunogenetic risk factors implicated in RA for disease progression in PR remains to be established. A previous retrospective analysis from our group has implicated rheumatoid factor in disease progression. Our objective was to determine the contribution of HLA and cytokine gene polymorphisms implicated in RA to predisposition to PR and to progression of PR to chronic joint inflammation.
We studied 147 patients with PR seen in a tertiary referral center; 87 were selected retrospectively from the period 1986-96 using a structured selection process and 60 were selected prospectively in the period 1997-2001. Comparison groups included 149 patients with RA and 149 ethnically matched controls. Typing for HLA-DRB1 alleles and HLA-DRB1-04 subtypes was performed following polymerase chain reaction (PCR) amplification using sequence-specific primers (SSP). Cytokine genotypes were ascertained following PCR-SSP with and without digestion with restriction enzymes. Time-adjusted survival analysis (Kaplan-Meier) and multivariate logistic regression were used to assess the independent contribution of immunogenetic markers in assessing progression of PR to chronic joint inflammation.
Thirty-one percent of patients progressed to connective tissue disease after a mean of 10.6 (retrospective group) and 3.9 (prospective group) years. A significantly increased prevalence of the shared epitope (SE) allele was noted in patients with PR (65%) versus controls (39%) (OR 2.9, 95% CI 1.8-4.6, p < 0.001). This primarily reflected increased prevalence of the DRB1-0401 and 0404 and not DRB1-01 alleles. A weak contribution to disease susceptibility was also noted with carriage of the IL4 promoter -590T (OR 1.8, 95% CI 1.1-3.0, p = 0.02) and IL4 intron 3 RP1 (OR 1.7, 95% CI 1.1-2.9, p = 0.03) alleles. The TNFa +489A allele was associated with RA (OR = 2.7, 95% CI 1.5-5.1, p = 0.001) in both SE+ and SE- patients, but not with PR. Time-adjusted and multivariate Cox regression analysis revealed that only homozygosity for SE alleles was a significant independent risk factor for disease progression to chronicity in PR (hazard ratio 2.9, 95% CI 1.2-6.9, p = 0.02). However, none of 8 patients homozygous for SE- DRB1 XP4n alleles developed chronic disease after 10 years of followup (p = 0.07).
The immunogenetic risk profile for PR resembles that for RA, indicating that PR is likely not an independent entity. A significant gene dose effect for SE alleles is operative in determining risk for progression from PR to RA.
回纹型风湿症（PR）是一种发作性关节病，可能先于典型的类风湿关节炎（RA）出现，不过这些疾病之间的发病机制关系仍不明确。RA相关免疫遗传风险因素对PR疾病进展的预测价值仍有待确定。我们团队之前的一项回顾性分析表明类风湿因子与疾病进展有关。我们的目的是确定RA相关的HLA和细胞因子基因多态性对PR易感性以及PR进展为慢性关节炎症的影响。
我们研究了在一家三级转诊中心就诊的147例PR患者；其中87例是在1986 - 1996年期间通过结构化筛选过程进行回顾性选择的，60例是在1997 - 2001年期间进行前瞻性选择的。对照组包括149例RA患者和149例种族匹配的对照。使用序列特异性引物（SSP）通过聚合酶链反应（PCR）扩增后对HLA - DRB1等位基因和HLA - DRB1 - 04亚型进行分型。细胞因子基因型通过PCR - SSP并在有或没有限制性内切酶消化的情况下确定。采用时间调整生存分析（Kaplan - Meier）和多变量逻辑回归来评估免疫遗传标记在评估PR进展为慢性关节炎症中的独立作用。
31%的患者在平均10.6年（回顾性组）和3.9年（前瞻性组）后进展为结缔组织病。PR患者中共享表位（SE）等位基因的患病率显著高于对照组（65%对39%）（比值比2.9，95%置信区间1.8 - 4.6，p < 0.001）。这主要反映了DRB1 - 0401和0404而非DRB1 - 01等位基因患病率的增加。携带IL4启动子 - 590T（比值比1.8，95%置信区间1.1 - 3.0，p = 0.02）和IL4内含子3 RP1（比值比1.7，95%置信区间1.1 - 2.9，p = 0.03）等位基因对疾病易感性也有微弱影响。TNFα + 489A等位基因在SE +和SE -患者中均与RA相关（比值比 = 2.7，95%置信区间1.5 - 5.1，p = 0.001），但与PR无关。时间调整和多变量Cox回归分析显示，只有SE等位基因纯合子是PR疾病进展为慢性的显著独立风险因素（风险比2.
