Prediction of Damage Accrual in Systemic Lupus Erythematosus Using the Systemic Lupus International Collaborating Clinics Frailty Index.
- 作者列表："Legge A","Kirkland S","Rockwood K","Andreou P","Bae SC","Gordon C","Romero-Diaz J","Sanchez-Guerrero J","Wallace DJ","Bernatsky S","Clarke AE","Merrill JT","Ginzler EM","Fortin PR","Gladman DD","Urowitz MB","Bruce IN","Isenberg DA","Rahman A","Alarcón GS","Petri M","Khamashta MA","Dooley MA","Ramsey-Goldman R","Manzi S","Zoma AA","Aranow C","Mackay M","Ruiz-Irastorza G","Lim SS","Inanc M","van Vollenhoven RF","Jonsen A","Nived O","Ramos-Casals M","Kamen DL","Kalunian KC","Jacobsen S","Peschken CA","Askanase A","Hanly JG
OBJECTIVE:The Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) has been shown to predict mortality, but its association with other important outcomes is unknown. We examined the association of baseline SLICC FI values with damage accrual in the SLICC inception cohort. METHODS:The baseline visit was defined as the first visit at which both organ damage (SLICC/American College of Rheumatology Damage Index [SDI]) and health-related quality of life (Short Form 36) were assessed. Baseline SLICC FI scores were calculated. Damage accrual was measured by the increase in SDI between the baseline assessment and the last study visit. Multivariable negative binomial regression was used to estimate the association between baseline SLICC FI values and the rate of increase in the SDI during follow-up, adjusting for relevant demographic and clinical characteristics. RESULTS:The 1,549 systemic lupus erythematosus (SLE) patients eligible for this analysis were mostly female (88.7%) with a mean ± SD age of 35.7 ± 13.3 years and a median disease duration of 1.2 years (interquartile range 0.9-1.5 years) at baseline. The mean ± SD baseline SLICC FI was 0.17 ± 0.08. Over a mean ± SD follow-up of 7.2 ± 3.7 years, 653 patients (42.2%) had an increase in SDI. Higher baseline SLICC FI values (per 0.05 increase) were associated with higher rates of increase in the SDI during follow-up (incidence rate ratio [IRR] 1.19 [95% confidence interval 1.13-1.25]), after adjusting for age, sex, ethnicity/region, education, baseline SLE Disease Activity Index 2000, baseline SDI, and baseline use of glucocorticoids, antimalarials, and immunosuppressive agents. CONCLUSION:Our findings indicate that the SLICC FI predicts damage accrual in incident SLE, which further supports the SLICC FI as a valid health measure in SLE.
目的: 系统性红斑狼疮国际合作诊所 (SLICC) 虚弱指数 (FI) 已被证明可预测死亡率，但其与其他重要结局的相关性尚不清楚。我们在 SLICC 初始队列中检测了基线 SLICC FI 值与损伤累积的相关性。 方法: 基线访视定义为两个器官损害的首次访视 (SLICC/美国风湿病学会损害指数 [SDI]) 和健康相关的生活质量 (简表 36) 进行了评估。计算基线 SLICC FI 评分。通过基线评估和上次研究访视之间 SDI 的增加来测量损伤计提。采用多变量负二项回归估计基线 SLICC FI 值与随访期间 SDI 增加率之间的相关性，调整相关人口统计学和临床特征。 结果: 符合本分析条件的 1,549 例系统性红斑狼疮 (SLE) 患者多为女性 (88.7%) 基线时平均 ± SD 年龄为 35.7 ± 13.3 岁，中位病程为 1.2 年 (四分位距 0.9-1.5 年)。平均 ± SD 基线 SLICC FI 为 0.17 ± 0.08。在 7.2 ± 3.7 年的平均 ± SD 随访中，653 例患者 (42.2%) 的 SDI 增加。较高的基线 SLICC FI 值 (每增加 0.05) 在调整了年龄、性别后，随访期间与 SDI 的较高增加率相关 (发病率比 [IRR] 1.19 [95% 置信区间 1.13-1.25]) 种族/地区，教育程度，基线 SLE 疾病活动指数 2000，基线 SDI,以及糖皮质激素、抗疟药和免疫抑制剂的基线使用。 结论: 我们的研究结果表明 SLICC FI 预测 SLE 事件中的损伤累积，进一步支持 SLICC FI 作为 SLE 的有效健康措施。
METHODS:OBJECTIVE:To report the incidence of prion disease in the United States. METHODS:Prion disease decedents were retrospectively identified from the US national multiple cause-of-death data for 2003-2015 and matched with decedents in the National Prion Disease Pathology Surveillance Center (NPDPSC) database through comparison of demographic variables. NPDPSC decedents with neuropathologic or genetic test results positive for prion disease for whom no match was found in the multiple cause-of-death data were added as cases for incidence calculations; those with cause-of-death data indicating prion disease but with negative neuropathology results were removed. Age-specific and age-adjusted average annual incidence rates were then calculated. RESULTS:A total of 5,212 decedents were identified as having prion disease, for an age-adjusted average annual incidence of 1.2 cases per million population (range 1.0 per million [2004 and 2006] to 1.4 per million ). The median age at death was 67 years. Ten decedents were <30 years of age (average annual incidence of 6.2 per billion); only 2 of these very young cases were sporadic forms of prion disease. Average annual incidence among those ≥65 years of age was 5.9 per million. CONCLUSIONS:Prion disease incidence can be estimated by augmenting mortality data with the results of neuropathologic and genetic testing. Cases <30 years of age were extremely rare, and most could be attributed to exogenous factors or the presence of a genetic mutation. Continued vigilance for prion diseases in all age groups remains prudent.
METHODS::The conformational conversion of the cellular prion protein (PrPC) to the misfolded and aggregated isoform, termed scrapie prion protein (PrPSc), is key to the development of a group of neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs). Although the conversion mechanism is not fully understood, the role of gene polymorphisms in varying susceptibilities to prion diseases is well established. In ovine, specific gene polymorphisms in PrPC alter prion disease susceptibility: the Valine136-Glutamine171 variant (Susceptible structure) displays high susceptibility to classical scrapie while the Alanine136-Arginine171 variant (Resistant structure) displays reduced susceptibility. The opposite trend has been reported in atypical scrapie. Despite the differentiation between classical and atypical scrapie, a complete understanding of the effect of polymorphisms on the structural dynamics of PrPC is lacking. From our structural bioinformatics study, we propose that polymorphisms locally modulate the network of residue interactions in the globular C-terminus of the ovine recombinant prion protein while maintaining the overall fold. Although the two variants we examined exhibit a densely connected group of residues that includes both β-sheets, the β2-α2 loop and the N-terminus of α-helix 2, only in the Resistant structure do most residues of α-helix 2 belong to this group. We identify the structural role of Valine136Alanine and Glutamine171Arginine: modulation of residue interaction networks that affect the connectivity between α-helix 2 and α-helix 3. We propose blocking interactions of residue 171 as a potential target for the design of therapeutics to prevent efficient PrPC misfolding. We discuss our results in the context of initial PrPC conversion and extrapolate to recently proposed PrPSc structures.Communicated by Ramaswamy H. Sarma.
METHODS::Although experimental transmission of bovine spongiform encephalopathy (BSE) to pigs and transgenic mice expressing pig cellular prion protein (PrPC) (porcine PrP [PoPrP]-Tg001) has been described, no natural cases of prion diseases in pig were reported. This study analyzed pig-PrPC susceptibility to different prion strains using PoPrP-Tg001 mice either as animal bioassay or as substrate for protein misfolding cyclic amplification (PMCA). A panel of isolates representatives of different prion strains was selected, including classic and atypical/Nor98 scrapie, atypical-BSE, rodent scrapie, human Creutzfeldt-Jakob-disease and classic BSE from different species. Bioassay proved that PoPrP-Tg001-mice were susceptible only to the classic BSE agent, and PMCA results indicate that only classic BSE can convert pig-PrPC into scrapie-type PrP (PrPSc), independently of the species origin. Therefore, conformational flexibility constraints associated with pig-PrP would limit the number of permissible PrPSc conformations compatible with pig-PrPC, thus suggesting that pig-PrPC may constitute a paradigm of low conformational flexibility that could confer high resistance to the diversity of prion strains.