Clinical and laboratory characteristics in juvenile-onset systemic lupus erythematosus across age groups.
- 作者列表："Massias JS","Smith EMD","Al-Abadi E","Armon K","Bailey K","Ciurtin C","Davidson J","Gardner-Medwin J","Haslam K","Hawley DP","Leahy A","Leone V","McErlane F","Mewar D","Modgil G","Moots R","Pilkington C","Ramanan AV","Rangaraj S","Riley P","Sridhar A","Wilkinson N","Beresford MW","Hedrich CM
BACKGROUND:Systemic lupus erythematous (SLE) is a systemic autoimmune/inflammatory condition. Approximately 15-20% of patients develop symptoms before their 18th birthday and are diagnosed with juvenile-onset SLE (JSLE). Gender distribution, clinical presentation, disease courses and outcomes vary significantly between JSLE patients and individuals with adult-onset SLE. This study aimed to identify age-specific clinical and/or serological patterns in JSLE patients enrolled to the UK JSLE Cohort Study. METHODS:Patient records were accessed and grouped based on age at disease-onset: pre-pubertal (≤7 years), peri-pubertal (8-13 years) and adolescent (14-18 years). The presence of American College of Rheumatology (ACR) classification criteria, laboratory results, disease activity [British Isles Lupus Assessment Group (BILAG) and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K) scores] and damage [Systemic Lupus International Collaborating Clinics (SLICC) damage index] were evaluated at diagnosis and last follow up. RESULTS:A total of 418 JSLE patients were included in this study: 43 (10.3%) with pre-pubertal disease onset; 240 (57.4%) with peri-pubertal onset and 135 (32.3%) were diagnosed during adolescence. At diagnosis, adolescent JSLE patients presented with a higher number of ACR criteria when compared with pre-pubertal and peri-pubertal patients [pBILAG2004 scores: 9(4-20] vs. 7(3-13] vs. 7(3-14], respectively, p = 0.015] with increased activity in the following BILAG domains: mucocutaneous (p = 0.025), musculoskeletal (p = 0.029), renal (p = 0.027) and cardiorespiratory (p = 0.001). Furthermore, adolescent JSLE patients were more frequently ANA-positive (p = 0.034) and exhibited higher anti-dsDNA titres (p = 0.001). Pre-pubertal individuals less frequently presented with leukopenia (p = 0.002), thrombocytopenia (p = 0.004) or low complement (p = 0.002) when compared with other age groups. No differences were identified in disease activity (pBILAG2004 score), damage (SLICC damage index) and the number of ACR criteria fulfilled at last follow up. CONCLUSIONS:Disease presentations and laboratory findings vary significantly between age groups within a national cohort of JSLE patients. Patients diagnosed during adolescence exhibit greater disease activity and "classic" autoantibody, immune cell and complement patterns when compared with younger patients. This supports the hypothesis that pathomechanisms may vary between patient age groups.
背景: 系统性红斑狼疮 (SLE) 是一种全身性自身免疫/炎症性疾病。大约 15-20% 的患者在 18 岁生日前出现症状，并被诊断为青少年发病的 SLE (JSLE)。JSLE 患者与成人发病 SLE 个体之间的性别分布、临床表现、病程和结局差异显著。本研究旨在确定英国 JSLE 队列研究入组的 JSLE 患者的年龄特异性临床和/或血清学模式。 方法: 根据发病年龄对患者记录进行访问和分组: 青春期前 (≤ 7 岁)，青春期周围 (8-13 岁) 和青少年 (14-18 岁)。存在美国风湿病学会 (ACR) 分类标准、实验室结果、疾病活动性 [英伦群岛狼疮评估组 (BILAG) 和系统性红斑狼疮疾病活动指数 2000 (SLEDAI-2 k) 评分] 和损伤 [系统性红斑狼疮国际合作诊所 (SLICC) 损伤指数]在诊断和最后一次随访时进行评估。 结果: 本研究共纳入 418 例 JSLE 患者: 青春期前发病 43 例 (10.3%); 青春期周围发病 240 例 (57.4%)，135 例 (32.3%) 在青春期被诊断。诊断时，与青春期前和青春期周围患者相比，青少年 JSLE 患者表现出更高数量的 ACR 标准 [pBILAG2004 评分: 9(4-20] vs. 7(3-13] vs. 7(3-14]，分别为 p = 0.015)，在以下 BILAG 结构域中的活性增加: 皮肤粘膜 (p = 0.025) 、肌肉骨骼 (p = 0.029) 、肾脏 (p = 0.027)和心肺 (p = 0.001)。此外，青少年 JSLE 患者 ANA 阳性更常见 (p = 0.034)，抗 dsDNA 滴度更高 (p = 0.001)。与其他年龄组相比，青春期前个体出现白细胞减少 (p = 0.002) 、血小板减少 (p = 0.004) 或低补体 (p = 0.002) 的频率较低。在疾病活动性 (pBILAG2004 评分) 、损伤 (SLICC 损伤指数) 和最终随访时符合 ACR 标准的数量方面未发现差异。 结论: 在 JSLE 患者的国家队列中，疾病表现和实验室检查结果在年龄组之间存在显著差异。与年轻患者相比，青春期诊断的患者表现出更大的疾病活动性和 “经典” 自身抗体、免疫细胞和补体模式。这支持了病理机制可能因患者年龄组而异的假设。
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.