烏帕替尼和阿巴西普治療類風溼性關節炎的比較試驗
Trial of Upadacitinib or Abatacept in Rheumatoid Arthritis
背景
烏帕替尼（upadacitinib）是用於治療類風溼性關節炎的口服選擇性Janus激酶抑制劑。在生物製劑DMARD（緩解疾病的抗風溼藥）難治的類風溼性關節炎患者中，烏帕替尼與阿巴西普（T細胞共刺激調節劑）相比的療效和安全性尚不明確。Upadacitinib is an oral selective Janus kinase inhibitor to treat rheumatoid arthritis. The efficacy and safety of upadacitinib as compared with abatacept, a T-cell costimulation modulator, in patients with rheumatoid arthritis refractory to biologic disease-modifying antirheumatic drugs (DMARDs) are unclear.方法
在這項為期24周的3期、雙盲、對照試驗中，我們以1:1的比例將患者隨機分配接受烏帕替尼口服給藥（每日1次，每次15 mg）或阿巴西普靜脈給藥，且兩組均聯用穩定劑量的合成DMARD治療。主要終點是第12周時，基於C反應蛋白水平的28關節疾病活動度綜合評分（DAS28-CRP；範圍，0~9.4分，評分較高表示疾病活動度較高）相對於基線的變化，我們對主要終點進行了非劣效性評估。第12周時的關鍵次要終點是在DAS28-CRP相對於基線的變化以及在達到臨床緩解（根據DAS28-CRP<2.6分）的患者百分比方面，烏帕替尼與阿巴西普相比的優效性。In this 24-week, phase 3, double-blind, controlled trial, we randomly assigned patients in a 1:1 ratio to receive oral upadacitinib (15 mg once daily) or intravenous abatacept, each in combination with stable synthetic DMARDs. The primary end point was the change from baseline in the composite Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP; range, 0 to 9.4, with higher scores indicating more disease activity) at week 12, assessed for noninferiority. Key secondary end points at week 12 were the superiority of upadacitinib over abatacept in the change from baseline in the DAS28-CRP and the percentage of patients having clinical remission according to a DAS28-CRP of less than 2.6.結果
共計303例患者接受了烏帕替尼治療，309例患者接受了阿巴西普治療。烏帕替尼組和阿巴西普組的基線DAS28-CRP值分別為5.70分和5.88分，第12周時的平均變化分別為-2.52分和-2.00分（差異，-0.52分；95%置信區間[CI]，-0.69~-0.35；非劣效性的P<0.001；優效性的P<0.001）。在烏帕替尼組和阿巴西普組中，達到緩解的患者百分比分別為30.0%和13.3%（差異，16.8個百分點；95% CI，10.4~23.2；優效性的P<0.001）。在治療期間，烏帕替尼組發生了1例死亡、1起非致死性卒中事件和2起靜脈血栓栓塞事件，並且烏帕替尼組中肝臟轉氨酶水平升高的患者人數超過阿巴西普組。
Result
A total of 303 patients received upadacitinib, and 309 patients received abatacept. From baseline DAS28-CRP values of 5.70 in the upadacitinib group and 5.88 in the abatacept group, the mean change at week 12 was −2.52 and −2.00, respectively (difference, −0.52 points; 95% confidence interval [CI], −0.69 to −0.35; P<0.001 for noninferiority; P<0.001 for superiority). The percentage of patients having remission was 30.0% with upadacitinib and 13.3% with abatacept (difference, 16.8 percentage points; 95% CI, 10.4 to 23.2; P<0.001 for superiority). During the treatment period, one death, one nonfatal stroke, and two venous thromboembolic events occurred in the upadacitinib group, and more patients in the upadacitinib group than in the abatacept group had elevated hepatic aminotransferase levels.
結論
在生物製劑DMARD難治的類風溼性關節炎患者中，在DAS28-CRP相對於基線的變化和第12周時達到緩解的患者人數方面，烏帕替尼優於阿巴西普，但烏帕替尼與較多的嚴重不良事件相關。我們需要開展更長時間、更大規模的試驗來確定烏帕替尼治療類風溼性關節炎患者的療效和安全性。（由艾伯維公司資助；SELECT-CHOICE在ClinicalTrials.gov註冊號為NCT03086343。）
Conclusions
In patients with rheumatoid arthritis refractory to biologic DMARDs, upadacitinib was superior to abatacept in the change from baseline in the DAS28-CRP and the achievement of remission at week 12 but was associated with more serious adverse events. Longer and larger trials are required in order to determine the effect and safety of upadacitinib in patients with rheumatoid arthritis. (Funded by AbbVie; SELECT-CHOICE Clinicaltrials.gov number, NCT03086343.)
本周五 中午十二點 app和官網發布全文中譯
重症COVID-19合併呼吸衰竭的全基因組關聯研究
Genomewide Association Study of Severe Covid-19 with Respiratory Failure
背景
COVID-19致病病毒SARS-CoV-2感染患者的臨床病情大相逕庭。全基因組關聯分析有可能發現涉及COVID-19發病的潛在遺傳因素。
There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19.方法
我們在1980例重症COVID-19（定義為呼吸衰竭）患者中開展了全基因組關聯研究；這些患者來自歐洲SARS-CoV-2疫情最嚴重的義大利和西班牙的七家醫院。經過質量控制並排除人群離群值後，納入最終分析的患者包括義大利的835例患者和1255名對照，以及西班牙的775例患者和950名對照。我們總計分析了8,582,968個單核苷酸多態性，並對兩個病例-對照組進行了薈萃分析。
We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case–control panels.
結果
在兩個病例-對照組的薈萃分析中，我們檢測到與基因座3p21.31處的rs11385942以及與基因座9q34.2處的rs657152的交叉複製關聯，其在全基因組水平上具有顯著意義（P<5×10-8）（比值比，1.77；95%置信區間[CI]，1.48⁓2.11；P=1.15×10-10；比值比，1.32；95% CI，1.20⁓1.47；P=4.95×10-8）。在基因座3p21.31，關聯信號跨越了SLC6A20、LZTFL1、CCR9、FYCO1、CXCR6和XCR1基因。基因座9q34.2的關聯信號與ABO血型基因座重合；在該患者隊列中，針對血型進行的分析顯示，A型血患者的患病風險高於其他血型患者（比值比，1.45；95% CI，1.20⁓1.75；P=1.48×10-4）；而O型血與其他血型相比具有保護作用（比值比，0.65；95% CI，0.53⁓0.79；P=1.06×10-5）。
Result
We detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10−8) in the meta-analysis of the two case–control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.15×10−10; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P=4.95×10−8, respectively). At locus 3p21.31, the association signal spanned the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a blood-group–specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P=1.48×10−4) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P=1.06×10−5).結論
我們發現3p21.31基因簇是COVID-19合併呼吸衰竭患者的遺傳易感基因座，並證實ABO血型系統有可能與COVID-19相關。（由Stein Erik Hagen等資助。）
Conclusions
We identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.)David Ellinghaus, Frauke Degenhardt, Luis Bujanda, et al. Genomewide Association Study of Severe Covid-19 with Respiratory Failure. DOI: 10.1056/NEJMoa2020283
本周五 中午十二點 app和官網發布全文中譯
瑞典肥胖受試者研究中患者接受減重手術後的預期壽命
Life Expectancy after Bariatric Surgery in the Swedish Obese Subjects Study
背景
肥胖會縮短預期壽命。眾所周知，減重手術可降低死亡的遠期相對危險度，但其對預期壽命的影響尚不清楚。
Obesity shortens life expectancy. Bariatric surgery is known to reduce the long-term relative risk of death, but its effect on life expectancy is unclear.方法
我們利用Gompertz比例風險回歸模型比較了在前瞻性對照研究SOS（瑞典肥胖受試者，Swedish Obese Subjects）中接受減重手術（手術組）或肥胖常規治療（對照組）的患者以及SOS參考研究中的參與者（參考隊列，來自一般人群的隨機樣本）的死亡率和預期壽命。
We used the Gompertz proportional hazards regression model to compare mortality and life expectancy among patients treated with either bariatric surgery (surgery group) or usual obesity care (control group) in the prospective, controlled Swedish Obese Subjects (SOS) study and participants in the SOS reference study (reference cohort), a random sample from the general population.結果
分別有2007和2040例患者被納入手術組和對照組，1135例參與者被納入參考隊列。在分析時（2018年12月31日），手術組和對照組患者死亡率的中位隨訪時間分別為24年（四分位距，22~27）和22年（四分位距，21~27）；本研究獲得了99.9%患者的死亡數據。在SOS參考隊列中，中位隨訪時間為20年（四分位距，19~21），獲得了100%參與者的死亡數據。手術組457例患者（22.8%）和對照組539例患者（26.4%）死亡（風險比，0.77；95%置信區間[CI]，0.68~0.87；P<0.001）。心血管疾病死亡和癌症死亡的相應風險比分別為0.70（95% CI，0.57~0.85）和0.77（95% CI，0.61~0.96）。手術組的校正中位預期壽命比對照組長3.0年（95% CI，1.8~4.2），但比一般人群短5.5年。90日術後死亡率為0.2%，手術組2.9%的患者接受了再次手術。
Result
In total, 2007 and 2040 patients were included in the surgery group and the control group, respectively, and 1135 participants were included in the reference cohort. At the time of the analysis (December 31, 2018), the median duration of follow-up for mortality was 24 years (interquartile range, 22 to 27) in the surgery group and 22 years (interquartile range, 21 to 27) in the control group; data on mortality were available for 99.9% of patients in the study. In the SOS reference cohort, the median duration of follow-up was 20 years (interquartile range, 19 to 21), and data on mortality were available for 100% of participants. In total, 457 patients (22.8%) in the surgery group and 539 patients (26.4%) in the control group died (hazard ratio, 0.77; 95% confidence interval [CI], 0.68 to 0.87; P<0.001). The corresponding hazard ratio was 0.70 (95% CI, 0.57 to 0.85) for death from cardiovascular disease and 0.77 (95% CI, 0.61 to 0.96) for death from cancer. The adjusted median life expectancy in the surgery group was 3.0 years (95% CI, 1.8 to 4.2) longer than in the control group but 5.5 years shorter than in the general population. The 90-day postoperative mortality was 0.2%, and 2.9% of the patients in the surgery group underwent repeat surgery.
結論
在肥胖患者中，與肥胖常規治療相比，減重手術與較長的預期壽命相關。手術組和對照組的死亡率仍然高於一般人群。（由瑞典研究理事會[Swedish Research Council]等資助；SOS在ClinicalTrials.gov註冊號為NCT01479452。）
Conclusions
Among patients with obesity, bariatric surgery was associated with longer life expectancy than usual obesity care. Mortality remained higher in both groups than in the general population. (Funded by the Swedish Research Council and others; SOS ClinicalTrials.gov number, NCT01479452.)非人靈長類動物接種SARS-CoV-2疫苗mRNA-1273的評估
Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates
背景
目前亟需可預防2019冠狀病毒病（COVID-19）的疫苗。在非人靈長類動物中評估SARS-CoV-2疫苗對上呼吸道和下呼吸道內病毒複製的影響具有重要意義。
Vaccines to prevent coronavirus disease 2019 (Covid-19) are urgently needed. The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines on viral replication in both upper and lower airways is important to evaluate in nonhuman primates.方法
非人靈長類動物接種了10 μg或100 μg mRNA-1273（編碼SARS-CoV-2的融合前穩定刺突蛋白的疫苗），或者未接種疫苗。使用SARS-CoV-2激發上呼吸道和下呼吸道之前，我們評估了動物的抗體和T細胞應答。利用聚合酶鏈反應評估了支氣管肺泡灌洗（BAL）液和鼻拭子樣本中的活動性病毒複製和病毒基因組，並對肺組織樣本進行了組織病理學分析和病毒定量分析。
Nonhuman primates received 10 or 100 μg of mRNA-1273, a vaccine encoding the prefusion-stabilized spike protein of SARS-CoV-2, or no vaccine. Antibody and T-cell responses were assessed before upper- and lower-airway challenge with SARS-CoV-2. Active viral replication and viral genomes in bronchoalveolar-lavage (BAL) fluid and nasal swab specimens were assessed by polymerase chain reaction, and histopathological analysis and viral quantification were performed on lung-tissue specimens.結果
候選疫苗mRNA-1273誘導產生的抗體水平超過人類患者恢復期血清中的抗體水平，在10 μg劑量組和100 μg劑量組中，活病毒50%抑制稀釋度（ID50）的倒數（滴度）的幾何均值分別為501和3481。接種疫苗誘導產生了偏向1型輔助性T細胞（Th1）的CD4T細胞應答，以及較低或不可測的Th2或CD8 T細胞應答。接種疫苗的兩組各有8隻動物，截至激發後第2日，兩組各有7隻的BAL液內未檢測到病毒複製。在100 μg劑量組的8隻動物中，截至激發後第2日，全部動物的鼻內均未檢測到病毒複製；在接種疫苗的兩組動物的肺內觀察到有限的炎症或可檢的病毒基因組或抗原。
Result
The mRNA-1273 vaccine candidate induced antibody levels exceeding those in human convalescent-phase serum, with live-virus reciprocal 50% inhibitory dilution (ID50) geometric mean titers of 501 in the 10-μg dose group and 3481 in the 100-μg dose group. Vaccination induced type 1 helper T-cell (Th1)–biased CD4 T-cell responses and low or undetectable Th2 or CD8 T-cell responses. Viral replication was not detectable in BAL fluid by day 2 after challenge in seven of eight animals in both vaccinated groups. No viral replication was detectable in the nose of any of the eight animals in the 100-μg dose group by day 2 after challenge, and limited inflammation or detectable viral genome or antigen was noted in lungs of animals in either vaccine group.
結論
給非人靈長類動物接種疫苗mRNA-1273誘導產生了穩定的SARS-CoV-2中和活性、對上呼吸道和下呼吸道的快速保護作用，並且肺內無病變。（由美國國立衛生研究院等資助。）
Conclusions
Vaccination of nonhuman primates with mRNA-1273 induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. (Funded by the National Institutes of Health and others.)對人T細胞內致病線粒體DNA的淨化選擇
Purifying Selection against Pathogenic Mitochondrial DNA in Human T Cells
許多線粒體疾病是由線粒體DNA（mtDNA）突變引起。患者細胞內既有突變的mtDNA，也有未突變的mtDNA（該現象稱為異質性）。突變mtDNA的比例在不同患者之間和同一患者的不同組織之間存在差異。我們從患A3243G相關線粒體腦肌病、乳酸性酸中毒和卒中樣發作的3例無親緣關係患者採集了數千個血細胞，並同時檢測了單細胞異質性和細胞狀態。我們觀察到所有細胞類型之間存在廣泛的異質性，並且發現T細胞的異質性顯著減少，這一發現與該細胞系內的淨化選擇相吻合。我們在無卒中樣發作，有異質性A3243G的另外6例患者中也觀察到了這一模式。（由Marriott基金會等資助。）
Melissa A. Walker, Caleb A. Lareau, Leif S. Ludwig, et al. Purifying Selection against Pathogenic Mitochondrial DNA in Human T Cells. DOI:10.1056/NEJMoa2001265
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