背景:几种自身免疫性疾病(AIDs)常见的亚表型的存在提示了共同的病理生理学-自身免疫同义反复。多重自身免疫综合征(MAS)-一个人共存三种或更多种艾滋病-,最能说明多自身免疫不仅仅是巧合.
目的:表征和比较单自身免疫和MAS患者。了解AIDs的聚类是否导致疾病严重程度的差异,自身抗体表达或遗传多态性可能是多自身免疫的标志物。
方法:目前从单元队列中选择成年患者。当存在≥3个AIDs时,假设MAS。在排除标准后纳入343例患者:患有两种AIDs或未确定诊断。从医学档案中收集临床和免疫学数据。通过PCR-SSP方法对HLA-DRB1进行基因分型,并通过TaqManRealTimePCR对PTPN22(rs2476601)多态性进行基因分型。数据采用卡方分析,费舍尔精确检验和逻辑回归。计算赔率比(OR)和95%置信区间。
结果:与对照人群相比:升高的频率:研究队列中的HLA-DRB1×03(OR=3.68,p<0.001)和单自身免疫性SLE(OR=2.79,p<0.001)和SjS(OR=8.27,p<0.001);单自身免疫性SjS组的HLA-DRB1×15(OR=2.39,p=0.011);系统性PN
■研究队列中的HLA-DRB1×11(OR=0.57,p=0.013),MASSLE(OR=0.39,p=0.031)和单自身免疫性SjS(OR=0.10,p=0.005);研究队列中的HLA-DRB1×13(OR=0.52,p=0.001)和单自身免疫性SLE(OR=0.53,p=0.009)和SjS(OR=0.38,p=0.031);研究队列中的HLA-DRB1×14(OR=0.21MAS患者的NPSLE明显增多(OR=2.99,p<0.001),亚急性皮肤病变(OR=2.30,p=0.037),肌肉和肌腱(OR=2.00,p=0.045),和血液学(OR=3.18,p=0.006)受累和雷诺(OR=2.94,p<0.001)。SjS组:MAS患者更频繁地出现冷球蛋白(OR=2.96,p=0.030),低补体(OR=2.43,p=0.030)和雷诺(OR=4.38,p<0.001);单自身免疫性患者腮腺肿大更多(OR=0.12,p<0.001)。APS组:MAS患者的非血栓性表现较多(OR=4.69,p=0.020)和雷诺(OR=9.12,p<0.001)。三阳性系统性MAS(SLE+SjS+APS)更常出现严重肾脏受累(OR=11.67,p=0.021)和中枢神经系统血栓形成(OR=4.44,p=0.009)。抗U1RNP增加的频率横向归因于MAS。
结论:AIDs共存导致更严重的病程。我们证实了先前建立的遗传风险和保护因子,并提出了一种新的保护性因子-HLA-DRB1×14。HLA-DRB1×07和抗U1RNP可能是单一和多自身免疫的标志物,HLA-DRB1×13可能是多种AIDs患者血管风险的预测因子。PTPN22(rs2476601)多态性可能与较不严重的疾病有关。
BACKGROUND: The existence of subphenotypes common to several autoimmune diseases (AIDs) suggests a shared physiopathology - autoimmune tautology. Multiple Autoimmune Syndrome (MAS) - the coexistence of three or more AIDs in one person-, best illustrates that polyautoimmunity is more than a coincidence.
OBJECTIVE: Characterize and compare the monoautoimmune and MAS patients. Understand if clustering of AIDs leads to differences in disease severity, autoantibodies expression or genetic polymorphisms that could be markers for polyautoimmunity.
METHODS: Currently adult patients were selected from unit cohort. MAS was assumed when ≥3 AIDs were present. 343 patients were included after exclusion criteria: having two AIDs or undetermined diagnosis. Clinical and immunological data were collected from medical files. HLA-DRB1 was genotyped by PCR-SSP methodology and PTPN22(rs2476601) polymorphisms by TaqMan Real Time PCR. Data were analysed using Chi-Square, Fisher\'s exact tests and logistic regression. Odds ratios (OR) and 95% confidence intervals were calculated.
RESULTS: In comparison with control population: ELEVATED FREQUENCIES: HLA-DRB1*03 in study cohort (OR=3.68,p<0.001) and in monoautoimmune SLE (OR=2.79,p<0.001) and SjS (OR=8.27,p<0.001); HLA-DRB1*15 in monoautoimmune SjS (OR=2.39,p = 0.011); HLA-DRB1*16 in MAS SLE (OR=2.67,p = 0.031); PTPN22_T in all groups except monoautoimmune SjS and triple positive systemic MAS.
UNASSIGNED: HLA-DRB1*11 in study cohort (OR=0.57,p = 0.013), in MAS SLE (OR=0.39,p = 0.031) and monoautoimmune SjS (OR=0.10,p = 0.005); HLA-DRB1*13 in study cohort (OR=0.52,p = 0.001) and in monoautoimmune SLE (OR=0.53,p = 0.009) and SjS (OR=0.38,p = 0.031); HLA-DRB1*14 in study cohort (OR=0.32,p = 0.013) and monoautoimmune SLE (OR=0.21,p = 0.021); SLE group: HLA-DRB1*07 frequency was higher in monoautoimmune patients (OR=0.43,p = 0.023). MAS patients had significantly more NPSLE (OR=2.99,p<0.001), subacute cutaneous lesions (OR=2.30,p = 0.037), muscle&tendon (OR=2.00,p = 0.045), and haematological (OR=3.18,p = 0.006) involvement and Raynaud\'s (OR=2.94,p<0.001). SjS group: MAS patients had more frequently cryoglobulins (OR=2.96,p = 0.030), low complement (OR=2.43,p = 0.030) and Raynaud\'s (OR=4.38,p<0.001); monoautoimmune patients had more parotid enlargement (OR=0.12,p<0.001). APS group: MAS patients had more non-thrombotic manifestations (OR=4.69,p = 0.020) and Raynaud\'s (OR=9.12,p<0.001). Triple positive systemic MAS (SLE+SjS+APS) had more frequently severe kidney involvement (OR=11.67,p = 0.021) and CNS thrombosis (OR=4.44,p = 0.009). Anti-U1RNP increased frequency was transversally attributable to MAS.
CONCLUSIONS: The coexistence of AIDs contributes to a more severe disease course. We confirmed previously established genetic risk and protection factors and suggest a new protective one - HLA-DRB1*14. HLA-DRB1*07 and anti-U1RNP could be markers for mono and polyautoimmunity, respectively; HLA-DRB1*13 could be a predictor for vascular risk in patients with multiple AIDs. PTPN22(rs2476601) polymorphism could be associated with less severe disease.