Volume 133 · Issue 24 · 2020

临床实践中的医生通常不命令自身抗体测试来帮助随后的诊断或监测银屑病或银屑病关节炎(PsA)患者的疾病活动，尽管在这些患者中存在多种自身抗体。我们对银屑病和PsA中自身抗体的了解有限。

影响中国9000万人的乙型肝炎病毒（HBV）感染仍然是肝癌和肝硬化的主要原因。^[1]慢性HBV感染病程复杂，是病毒与免疫系统相互作用形成的动态过程。^[2,3]肝纤维化是肝硬化和肝癌的基础。^[4]近年来，越来越多的研究表明肠道微生物群、胆汁酸和辅助性T（Th）17/白细胞介素（IL）-17轴在HBV相关肝纤维化过程中的潜在作用。肠道微生物群与胆汁酸积极交流，在HBV相关肝纤维化的发病机制中起重要作用。在以下内容中，我们将总结目前肠道微生物群、胆汁酸和Th17/IL-17轴在HBV相关肝纤维化中的作用的证据。

Benvitimod cream, a novel synthetic small molecule, was effective in treating mild-to-moderate plaque psoriasis. We conducted a phase III clinical trial to assess the efficacy and safety of benvitimod cream in patients with mild-to-moderate plaque psoriasis.

We randomly assigned 686 patients (2:1:1) to receive 1% benvitimod cream, 0.005% calcipotriol ointment or placebo twice a day for 12 weeks. The primary efficacy end points were the percentage of patients with a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI 75) score and with a score of 0 or 1 in static physician’s global assessment (sPGA) at week 12.

The results showed that 50.4% of patients in the benvitimod group achieved PASI 75, which was significantly higher than that in the calcipotriol (38.5%, P < 0.05) and placebo (13.9%, P < 0.05) groups. The proportion of patients achieving an sPGA score 0 or 1 was 66.3% in the benvitimod group and 63.9% in the calcipotriol group, which were both significantly higher than that in the placebo group (34%, P < 0.05). In the long-term follow-up study, 50.8% of patients experienced recurrence. After retreatment with 1% benvitimod, 73.3% of patients achieved an sPGA score of 0 or 1 again at week 52. Adverse events included application site irritation, follicular papules, and contact dermatitis. No systemic adverse reactions were reported.

During this 12-week study, benvitimod cream was demonstrated with high effectiveness and safety in patients with mild-to-moderate plaque psoriasis.

Chinese Clinical Trial Registry (ChiCTR), ChiCTR-TRC-13003259; http://www.chictr.org.cn/showprojen. aspx?proj=6300.

Psoriasis is a common chronic inflammatory skin disease with 2% to 3% prevalence worldwide and a heavy social-psychological burden for patients and their families. As the exact pathogenesis of psoriasis is still unknown, the current treatment is far from satisfactory. Thus, there is an urgent need to find a more effective therapy for this disease. Keratin 17 (K17), a type I intermediate filament, is overexpressed in the psoriatic epidermis and plays a critical pathogenic role by stimulating T cells in psoriasis. Therefore, we hypothesized that inhibiting K17 may be a potential therapeutic approach for psoriasis. This study aimed to investigate the therapeutic effect of K17-specific small interfering RNA (siRNA) on mice with imiquimod (IMQ)-induced psoriasis-like dermatitis.

Eight-week-old female BALB/c mice were administered a 5% IMQ cream on both ears to produce psoriatic dermatitis. On day 3, K17 siRNA was mixed with an emulsion matrix and applied topically to the left ears of the mice after IMQ application every day for 7 days. The right ears of the mice were treated in parallel with negative control (NC) siRNA. Inflammation was evaluated by gross ear thickness, histopathology, the infiltration of inflammatory cells (CD3⁺ T cells and neutrophils) using immunofluorescence, and the expression of cytokine production using real-time quantitative polymerase chain reaction. The obtained data were statistically evaluated by unpaired t-tests and a one-way analysis of variance.

The severity of IMQ-induced dermatitis on K17 siRNA-treated mice ears was significantly lower than that on NC siRNA-treated mice ears, as evidenced by the alleviated ear inflammation phenotype, including decreased ear thickness, infiltration of inflammatory cells (CD3⁺ T cells and neutrophils), and inflammatory cytokine/chemokine expression levels (interleukin 17 [IL-17], IL-22, IL-23, C-X-C motif chemokine ligand 1, and C-C motif chemokine ligand 20) (P < 0.05 vs. the Blank or NC siRNA groups). Compared to the NC siRNA treatment, the K17 siRNA treatment resulted in increased K1 and K10 expression, which are characteristic of keratinocyte differentiation (vs. NC siRNA, K17 siRNA1 group: K1, t= 4.782, P= 0.0050; K10, t= 3.365, P= 0.0120; K17 siRNA2 group: K1, t= 4.104, P= 0.0093; K10, t= 4.168, P= 0.0042; siRNA Mix group: K1, t= 3.065, P = 0.0221; K10, t = 10.83, P < 0.0001), and decreased K16 expression, which is characteristic of keratinocyte proliferation (vs. NC siRNA, K17 siRNA1 group: t= 4.156, P= 0.0043; K17 siRNA2 group: t= 2.834, P= 0.0253; siRNA Mix group: t= 2.734, P = 0.0250).

Inhibition of K17 expression by its specific siRNA significantly alleviated inflammation in mice with IMQ-induced psoriasis-like dermatitis. Thus, gene therapy targeting K17 may be a potential treatment approach for psoriasis.

Albuvirtide is a once-weekly injectable human immunodeficiency virus (HIV)-1 fusion inhibitor. We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus lopinavir-ritonavir in HIV-1-infected adults already treated with antiretroviral drugs.

We carried out a 48-week, randomized, controlled, open-label non-inferiority trial at 12 sites in China. Adults on the World Health Organization (WHO)-recommended first-line treatment for >6 months with a plasma viral load >1000 copies/mL were enrolled and randomly assigned (1:1) to receive albuvirtide (once weekly) plus ritonavir-boosted lopinavir (ABT group) or the WHO-recommended second-line treatment (NRTI group). The primary endpoint was the proportion of patients with a plasma viral load below 50 copies/mL at 48 weeks. Non-inferiority was prespecified with a margin of 12%.

At the time of analysis, week 24 data were available for 83 and 92 patients, and week 48 data were available for 46 and 50 patients in the albuvirtide and NRTI groups, respectively. At 48 weeks, 80.4% of patients in the ABT group and 66.0% of those in the NRTI group had HIV-1 RNA levels below 50 copies/mL, meeting the criteria for non-inferiority. For the per-protocol population, the superiority of albuvirtide over NRTI was demonstrated. The frequency of grade 3 to 4 adverse events was similar in the two groups; the most common adverse events were diarrhea, upper respiratory tract infections, and grade 3 to 4 increases in triglyceride concentration. Renal function was significantly more impaired at 12 weeks in the patients of the NRTI group who received tenofovir disoproxil fumarate than in those of the ABT group.

The TALENT study is the first phase 3 trial of an injectable long-acting HIV drug. This interim analysis indicates that once-weekly albuvirtide in combination with ritonavir-boosted lopinavir is well tolerated and non-inferior to the WHO-recommended second-line regimen in patients with first-line treatment failure.

ClinicalTrials.gov Identifier: NCT02369965; https://www.clinicaltrials.gov.

Chinese Clinical Trial Registry No. ChiCTR-TRC-14004276; http://www.chictr.org.cn/enindex.aspx

Natural killer (NK) cells play a critical role in suppressing human immunodeficiency virus-1 (HIV-1) infection, but knowledge on whether and how NK cells affect immune reconstitution in HIV-1-infected individuals who receive antiretroviral therapy (ART) is limited.

We performed a case-control study with 35 healthy individuals and 66 HIV-1-infected patients including 32 immunological non-responders (INRs) with poor CD4⁺ T-cell recovery (<500 cells/μL after 4 years of ART) and 34 immunological responders (IRs) with improved CD4⁺ T-cell recovery (>500 cells/μL after 4 years of ART). NK cell phenotype, receptor repertoire, and early activation in INRs and IRs were investigated by flow cytometry.

A significantly higher proportion of CD56^dimCD16^dim/- NK cells was observed in INRs than IRs before ART and after 4 years of ART. The number of CD56^dimCD16^dim/- NK cells was inversely correlated with CD4⁺ T-cell counts in INRs before ART (r = -0.344, P = 0.050). The more CD69-expressing NK cells there were, the lower the CD4⁺ T-cell counts and ΔCD4, and these correlations were observed in INRs after ART (r = -0.416, P = 0.019; r = -0.509, P = 0.003, respectively). Additionally, CD69-expressing CD56^dimCD16^dim/- NK cells were more abundant in INRs than those in IRs (P = 0.018) after ART, both of which had an inverse association trend towards significance with CD4⁺ T-cell counts. The expression of the activating receptors NKG2C, NKG2D, and NKp46 on CD56^dimCD16^dim/- NK cell subsets were higher in IRs than that in INRs after 4 years of ART (all P < 0.01). Strong inverse correlations were observed between CD69 expression and NKG2C, NKG2A^-NKG2C⁺, NKG2D, and NKp46 expression on CD56^dimCD16^dim/- NK cells in INRs after ART (NKG2C: r = -0.491, P = 0.004; NKG2A^-NKG2C⁺: r = -0.434, P = 0.013; NKG2D: r = -0.405, P = 0.021; NKp46: r = -0.457, P = 0.008, respectively).

INRs had a larger number of CD56^dimCD16^{dim/ -} NK cells characterized by higher activation levels than did IRs after ART. The increase in the CD56^dimCD16^dim/- NK cell subset may play an adverse role in immune reconstitution. Further functional studies of CD56^dimCD16^dim/- NK cells in INRs are urgently needed to inform targeted interventions to optimize immune recovery.

Studies have reported that low bone mineral density (BMD) is prevalent in human immunodeficiency virus (HIV)-infected patients; however, the factors that contribute to HIV-related BMD changes are yet to be fully understood. Due to the application of dual X-ray absorptiometry (DXA) among a select group of hospitals only, the prevalence and risk factors of low BMD in HIV-infected populations have not been intensively investigated in China. Thus, the aim of our study was to investigate the prevalence of and risk factors associated with BMD changes among antiretroviral therapy (ART)-naive HIV-positive patients in China.

The assessment of the prevalence of and risk factors associated with BMD changes was conducted among 156 ART-naive HIV-infected patients. Demographic and clinical data, as well as results of fasting blood tests were obtained from patients. Further, all patients underwent DXA scans to determine BMD, which was then used to classify patients with osteopenia/osteoporosis. The risk factors of reduced BMD were then evaluated using binary logistic regression.

Among the 156 ART-naive HIV-infected participants, osteopenia and osteoporosis were diagnosed in 48.7% (76/156) and 4.5% (7/156) of patients, respectively. The lumbar spine was most likely to have reduced BMD (49.4% [77/156]), and the proportion of osteopenia in the left hip (32.7% [51/156]) was higher than in the right hip (24.4% [38/156]). In the lumbar spine, bone loss rate in the L1 section (60.9% [95/156]) was the most significant (L2, 53.2% [83/156]; L3, 45.5% [71/156]; L4, 52.6% [82/156]). Further analysis showed that, compared with the neck (26.9% [42/156] in the left, 18.6% [29/156] in the right) and the interior (15.4% [24/156] in the left, 13.5% [21/156] in the right), the trochanter had the greatest probability of reduced BMD (46.2% [72/156] in the left, 28.8% [45/156] in the right). In the risk factor analysis, low body mass index (BMI: <18.5 kg/m²) was positively associated with reduced BMD (Exp (B) = 39.743, 95 % confidence interval: 3.234-488.399, P = 0.004), and was specifically positively correlated with BMD values at three sites (r = 0.335 at right hip, r = 0.327 at left hip, r = 0.311 at lumbar spine).

Reduced BMD was found in the majority of ART-naive HIV-infected patients and BMI was identified as an additional risk factor for reduced BMD. Our results show that BMD reduction was simultaneously present in the left hip, right hip, and lumbar spine among nearly one fifth of patients. Our work highlights the importance of closely monitoring BMD in ART-naive patients and provides a foundation for the clinical intervention of bone demineralization in them.

Hospital-acquired pneumonia (HAP) is the most common hospital-acquired infection in China with substantial morbidity and mortality. But no specific risk assessment model has been well validated in patients with HAP. The aim of this study was to investigate the published risk assessment models that could potentially be used to predict 30-day mortality in HAP patients in non-surgical departments.

This study was a single-center, retrospective study. In total, 223 patients diagnosed with HAP from 2012 to 2017 were included in this study. Clinical and laboratory data during the initial 24 hours after HAP diagnosis were collected to calculate the pneumonia severity index (PSI); consciousness, urea nitrogen, respiratory rate, blood pressure, and age ≥65 years (CURB-65); Acute Physiology and Chronic Health Evaluation II (APACHE II); Sequential Organ Failure Assessment (SOFA); and Quick Sequential Organ Failure Assessment (qSOFA) scores. The discriminatory power was tested by constructing receiver operating characteristic (ROC) curves, and the areas under the curve (AUCs) were calculated.

The all-cause 30-day mortality rate was 18.4% (41/223). The PSI, CURB-65, SOFA, APACHE II, and qSOFA scores were significantly higher in non-survivors than in survivors (all P < 0.001). The discriminatory abilities of the APACHE II and SOFA scores were better than those of the CURB-65 and qSOFA scores (ROC AUC: APACHE II vs. CURB-65, 0.863 vs. 0.744, Z = 3.055, P= 0.002; APACHE II vs. qSOFA, 0.863 vs. 0.767, Z= 3.017, P= 0.003; SOFA vs. CURB-65, 0.856 vs. 0.744, Z= 2.589, P = 0.010; SOFA vs. qSOFA, 0.856 vs. 0.767, Z = 2.170, P = 0.030). The cut-off values we defined for the SOFA, APACHE II, and qSOFA scores were 4, 14, and 1.

These results suggest that the APACHE II and SOFA scores determined during the initial 24 h after HAP diagnosis may be useful for the prediction of 30-day mortality in HAP patients in non-surgical departments. The qSOFA score may be a simple tool that can be used to quickly identify severe infections.

Myocardial infarction occurs due to insufficient (ischemia) blood supply to heart for long time; plasmacytoma variant translocation 1 (PVT1) is a long non-coding RNAs (lncRNAs) involved in the pathogenesis of various diseases, including heart disease; However, few studies have explored its role. The present study evaluated the effects of lncRNA PVT1 on hypoxic rat H9c2 cells.

Hypoxic injury was examined by measuring cell viability and apoptosis by using cell counting kit-8 activity and flow cytometry assays. Gene expressions after hypoxia were estimated by quantitative real time polymerase chain reaction and the signaling pathway were explored by Western blot analysis. RNA immunoprecipitation and luciferase reporter assays were applied to examine the interactions among genes. Data were analyzed using t-test with one-way or two-way analysis of variance.

The lncRNA PVT1 is up-regulated in hypoxia-stressed H9c2 cells and knockdown of PVT1 mitigates hypoxia-induced injury in H9c2 cells. PVT1 acts as a sponge for miR-135a-5p and knockdown of PVT1 attenuated the increased hypoxia-induced injury by up-regulating miR-135a-5p. Forkhead box O1 (FOXO1) was identified as a target of miR-135a-5p, and the expression was negatively regulated by miR-135a-5p. The exploration of the underlying mechanism demonstrated that knockdown of FOXO1 reversed PVT1/miR-135a-5p mediated hypoxia-induced injury in H9c2 cells.

PVT1 plays a crucial role in hypoxia-injured H9c2 cells through sponging miR-135a-5p and then positively regulating FOXO1.

冠状病毒疾病2019（新冠肺炎）威胁着全球人类的健康，在撰写本文时，还没有专门针对新冠肺炎的有效药物。新冠肺炎患者的主要初始症状是发热、干咳和疲劳，尽管一些患者主要出现呕吐、腹泻和其他胃肠道症状。其他严重症状，即胸闷、呼吸困难和呼吸窘迫，通常在一周后出现，部分患者迅速发展为急性呼吸窘迫综合征（ARDS）、感染性休克，甚至可能死亡。最近一项对新冠肺炎危重患者的回顾性研究报告称，67.3%的患者出现ARDS，28.9%出现急性肾损伤，23.1%出现心脏损伤，28.9%出现肝功能异常。此外，28天死亡率高达61.5%。^[1]

银屑病是一种常见的慢性复发性炎症性疾病。斑块型银屑病占银屑病患者的90%以上。目前，没有治愈的疗法。与常规治疗相比，生物制剂大大提高了临床疗效，并且在对主要器官的毒性方面可能提供更好的长期安全性；然而，停止治疗后的复发仍然是一个重要问题。尽管大多数指南推荐维持治疗，但在现实世界的临床实践中，停药的情况相当频繁。因此，在选择不同疗法时，复发时间是一个重要的考虑因素。

致编辑：银屑病关节炎（Psoriatic arthritis，PsA）是一种与银屑病相关的慢性炎症性肌肉骨骼疾病，主要表现为外周关节炎、附着点炎、手指或脚趾炎症、脊柱关节炎。^[1]PsA可在任何年龄发生，在30至50岁达到高峰，无显著性别差异，但脊柱受累在男性中更常见。我国PsA患病率约为1.23‰。约75%的PsA患者在关节炎发作前出现皮疹，而10%在关节炎发作后出现皮疹。

银屑病是一种慢性炎症性皮肤病，免疫紊乱在银屑病的发病机制中起着至关重要的作用。抗菌肽（AMPs），包括凯萨林菌素（LL-37）和人β-防御素（HBD）-3，不仅是先天免疫的基础，也是激活适应性免疫的桥梁。在免疫应答中，包括肿瘤坏死因子-α、白细胞介素(IL)-6、IL-10、IL-17、IL-22和IL-23在内的几种炎性细胞因子参与银屑病的发生和发展。^[1]已知点滴型银屑病比其他类型的银屑病预后更好，消退快，缓解期更长。然而，在至少1年或10年的随访期间，33.0%至68.3%的点滴型银屑病随后发展为慢性斑块型银屑病。^[2]然而，点滴型和斑块型银屑病之间的发病机制联系尚不清楚，大多数研究仅关注斑块型银屑病中炎性细胞因子的变化，而不是点滴型银屑病。本研究旨在比较变异体（斑块）的血清炎性细胞因子和AMP水平vs.点滴）寻常型银屑病的一些潜在治疗靶点，并揭示不同临床表现中的发病机制。

先天性心脏病（CHD）已经成为先天性异常婴儿死亡的主要原因。肺动脉高压（PAH）是冠心病的并发症之一。^[1]也有报道称microRNA-98（miR-98）的上调可以介导心肌肥厚的抑制，这意味着miR-98可能在CHD中起重要作用。^[2]在这项研究中，回顾性分析了住院患者的临床数据，以确定是否有任何证据诊断患有PAH的CHD患者循环miR-98。

致编辑：银屑病是一种慢性炎症性疾病，通常根据典型的临床特征进行诊断。然而，有时会存在模棱两可的病例，有时会被误认为是其他红斑鳞状疾病。尽管组织病理学诊断仍然是此类病例的金标准，但它经常被绕过以避免损伤病变区域并减少患者的不适。因为活检不能提供实时监测，所以在过去几年中，具有成本效益的非侵入性技术，例如皮肤镜检查和反射共聚焦显微镜(RCM)，已经越来越多地用于临床实践。

致编辑：掌跖脓疱病（PPP）是一种慢性顽固性疾病。各种生物制剂已用于成功治疗斑块型银屑病，但其用于治疗PPP的用途有限。尽管具有有希望的作用，但生物制剂如肿瘤坏死因子-α(TNF-α)抑制剂可能加重或诱导PPP。在此，我们报告了一例对TNF-α抑制剂阿达木单抗难治但成功接受白细胞介素-17A（IL-17A）抑制剂司库奇尤单抗治疗的PPP患者。

致编辑：全身性脓疱型银屑病（GPP）是一种罕见且严重的银屑病，传统治疗方法可能无效。传统的方法是用阿维A、甲氨蝶呤和环孢素进行全身治疗；但在给药过程中常出现明显的副作用，限制了其临床应用。司库奇尤单抗是一种全人抗白细胞介素（IL）-17A单克隆抗体，显示出治疗中度至重度斑块型银屑病的疗效。尽管如此，关于司库奇尤单抗治疗GPP的循证真实世界数据有限。北京大学第三医院近期成功应用司库奇尤单抗治疗2例GPP。本研究经我院伦理委员会批准（编号：328-01）。

致编辑：银屑病是一种慢性、复发性、全身性、免疫介导的炎症性疾病，主要影响皮肤、指甲和关节。斑块型银屑病是银屑病中最常见的类型，占所有病例的80%~90%以上。司库奇尤单抗是一种拮抗白细胞介素17A（IL-17A）的人IgG单克隆抗体，2015年获美国食品药品监督管理局批准用于治疗中重度斑块型银屑病。一项中国多中心、双盲、安慰剂对照的III期随机临床试验（RCT）证明了优异的疗效和安全性。^[1]司库奇尤单抗自2019年5月起在中国市场上市，推荐剂量为300 mg。众所周知，随机对照试验由于其严格、标准化的设计方案，不能完全反映临床实践环境中发生的情况。还引入了“功效-有效性差距”的概念，^[2]这支持了现实世界研究的重要性。在此，我们回顾性总结了2019年6月至12月在北京大学第三医院接受司库奇尤单抗治疗的所有斑块型银屑病住院患者。一般信息（性别、年龄、体重、体重指数等。）和临床特征（病程、家族史、合并症、实验室检查、既往治疗、伴随治疗等。）从临床记录中收集。还记录银屑病面积严重指数（PASI）、体表面积（BSA）、皮肤病生活质量指数（DLQI）、银屑病头皮严重指数（PSSI）、指甲银屑病严重指数（NAPSI）和掌跖银屑病面积和严重指数（ppPASI）。通过不良事件评估安全性，对符合临床试验排除标准的特殊病例进行相应监测。使用SPSS 26.0软件（IBM Corp，Armonk，NY，USA）进行统计分析。本研究由北京大学第三医院伦理委员会批准（编号：329-01）。

致编辑：银屑病是一种慢性自身免疫性炎症性疾病，对生活质量有显著的负面影响。白细胞介素（IL）-17A是T辅助17途径中的关键分子，在银屑病的发病机制中很重要。司库奇尤单抗是一种靶向IL-17A的全人源免疫球蛋白G1 κ单克隆抗体，是2015年美国食品药品监督管理局批准的首个抗IL-17A抗体。在中国，它于2019年3月被批准用于治疗中度至重度寻常型银屑病（PsV），而在日本，它不仅用于PsV，还用于银屑病关节炎和泛发性脓疱型银屑病（GPP）。已在四项随机对照试验（RCT）（ERASURE、FEATURE、JUNCTURE和FIXTURE）中评估了司库奇尤单抗的安全性和有效性，这些试验显示司库奇尤单抗与安慰剂、依那西普和乌司奴单抗相比具有优越性，清除率具有长期持久性。然而，临床实践的真实世界设置不同于RCT的严格监管设置，RCT仅在符合严格纳入和排除标准的选定患者中进行，以最大限度地提高内部有效性。迄今为止，中国还没有发表过真实世界研究的官方英文报告。

致编辑：一名39岁男性表现为进行性肢体萎缩和无力。患者出生时有全身性肌张力减退；他在小学跑得不好。神经系统检查显示面部肌肉萎缩和左眼内收受限。在上肢，患者表现为近端肌肉萎缩和无力[图1A]，而在下肢，远端的无力比近端更突出。未观察到自发性或叩击性肌强直或肌肉肥大。