2020年 · 第133卷第24期

A physician in clinical practice does not usually order autoantibody testing to aid subsequent diagnosis or for monitoring disease activity in patients with psoriasis or psoriatic arthritis (PsA), although a variety of autoantibodies are present in these patients. Our understanding of autoantibodies in psoriasis and PsA is limited.

Hepatitis B virus (HBV) infection, which affects 90 million people in China, remains a prominent cause of liver cancer and liver cirrhosis.^[1]Chronic HBV infection has a complicated course, which is a dynamic process formed by the interaction between the virus and the immune system.^[2,3]Hepatic fibrosis is the basis of liver cirrhosis and liver cancer.^[4]In recent years, accumulating studies have indicated potential roles of intestinal microbiota, bile acids, and T helper (Th)17/ interleukin (IL)-17 axis in the process of HBV-related liver fibrosis. Gut microbiota actively communicates with bile acids and plays an important role in the pathogenesis of HBV-related liver fibrosis. In the following content, we are going to summarize current evidence of the role of intestinal microbiota, bile acids, and Th17/IL-17 axis in HBV-related liver fibrosis.

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.

The coronavirus disease 2019 (COVID-19) threatens the health of humans worldwide, and at the time of this writing, there is no specifically targeted effective drug for COVID-19. The major initial symptoms of patients with COVID-19 are fever, dry cough, and fatigue, although some patients mainly experience vomiting, diarrhea, and other gastrointestinal symptoms. Other severe symptoms, namely chest tightness, dyspnea, and respiratory distress, usually appear one week later, with some patients rapidly developing acute respiratory distress syndrome (ARDS), septic shock, and possibly even death. A retrospective study of critically ill patients with COVID-19 has recently reported that 67.3% of patients presented with ARDS, 28.9% with acute kidney injury, 23.1% with heart injury, and 28.9% with abnormality in liver function. In addition, the 28-day mortality rate was up to 61.5%.^[1]

Psoriasis is a common chronic recurrent inflammatory disease. Plaque psoriasis accounts for more than 90% of psoriasis patients. Currently, no therapies are curative. Biologics have greatly improved the clinical efficacy and potentially provide a better long-term safety profile, with respect to toxicity to major organs, than conventional treatments; however, relapse after treatment withdrawal is still an important issue. Although maintenance treatment is recommended in most guidelines, treatment withdrawal occurs quite frequently in real-world clinical practice. Thus, the time to relapse is an important consideration when choosing among the different therapies.

To the Editor: Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease associated with psoriasis, mainly manifested as peripheral arthritis, enthesitis, finger or toe inflammation, and spinal arthritis.^[1]PsA may develop at any age, peaking at age of 30 to 50 years with no significant gender difference, but the spinal involvement is more frequent in men. The prevalence of PsA in China is about 1.23‰. About 75% of patients with PsA develop rash before arthritic onset whereas 10% after arthritis development.

Psoriasis is a chronic inflammatory skin disease, and immunological disorder plays a crucial role in the pathogenesis of psoriasis. Antimicrobial peptides (AMPs), including cathelicidin (LL-37) and human beta-defensin (HBD)-3, are not only the basis of innate immunity but also a bridge to activate adaptive immunity. In the immune response, several inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-6, IL-10, IL-17, IL-22, and IL-23, are involved in the occurrence and development of psoriasis.^[1]Guttate psoriasis was known to have a better prognosis than other types of psoriasis with a rapid regression and a longer remission period. However, 33.0% to 68.3% of guttate psoriasis subsequently develops into chronic plaque psoriasis during the follow-up period of at least 1 or 10 years.^[2]However, the association of pathogenesis between guttate and plaque psoriasis is not clear, and most studies only focus on inflammatory cytokine changes in plaque psoriasis rather than in guttate psoriasis. This study aimed to compare the levels of serum inflammatory cytokines and AMPs of the variants (plaquevs.guttate) of psoriasis vulgaris, specifically some potential treatment targets, and to reveal the pathogenesis in different clinical manifestations.

Congenital heart disease (CHD) has become the leading mortal cause for an infant from congenital abnormalities. Pulmonary artery hypertension (PAH) is one of the complications of CHD.^[1]It has also been reported that upregulation of microRNA-98 (miR-98) could mediate the suppression of cardiac hypertrophy, which implies that miR-98 might play an important role in CHD.^[2]In this study, the clinical data from hospitalized patients were retrospectively analyzed to identify if there is any evidence of diagnosis of circulating miR-98 on CHD patients with PAH.

To the Editor:Psoriasis is a chronic inflammatory disease that is usually diagnosed on the basis of typical clinical features. However, ambiguous cases can exist at times and are sometimes mistaken for other erythematosquamous diseases. Although histopathologic diagnosis remains the gold standard in such cases, it is frequently bypassed to avoid damage to the lesion areas and reduce discomfort for patients. Because a biopsy cannot provide real-time monitoring, non-invasive techniques that are cost-effective, such as dermoscopy and reflectance confocal microscopy (RCM), have increasingly been used in clinical practice during the past few years.

To the Editor: Palmoplantar pustulosis (PPP) is a chronic recalcitrant disease. Various biologics have been used to successfully treat plaque psoriasis, but their use to treat PPP is limited. Despite their promising effects, biologics such as tumor necrosis factor-α (TNF-α) inhibitors may aggravate or induce PPP. Herein, we report a patient with PPP refractory to the TNF-α inhibitor adalimumab, but successfully treated with the interleukin-17A (IL-17A) inhibitor secukinumab.

To the Editor:Generalized pustular psoriasis (GPP) is a rare and severe form of psoriasis for which traditional treatment approaches may not be effective. The traditional approach is systemic treatment with acitretin, methotrexate, and cyclosporin; however, obvious side effects often occur during drug administration, limiting their clinical application. Secukinumab, a fully human anti-interleukin (IL)-17A monoclonal antibody, demonstrates efficacy in treating moderate to severe plaque-type psoriasis. Nonetheless, there are limited evidence-based real-world data on GPP treatment with secukinumab. Two cases of GPP were successfully treated with secukinumab in Peking University Third Hospital recently. This study was approved by the Ethics Committee of our hospital (No. 328-01).

To the Editor:Psoriasis is a chronic, recurrent, systemic, immune-mediated inflammatory disease that mainly affects the skin, nails, and joints. Plaque psoriasis is the most common type of psoriasis, accounting for more than 80% to 90% of all cases. Secukinumab, a human IgG monoclonal antibody that antagonizes interleukin 17A (IL-17A), was approved by the US Food and Drug Administration in 2015 to treat moderate-to-severe plaque psoriasis. A Chinese multicenter, double-blind, placebo-controlled phase III randomized clinical trial (RCT) demonstrated excellent efficacy and safety.^[1]Secukinumab has been available on the Chinese market since May 2019, with a recommended dose of 300 mg. It is well-known that RCTs, due to their rigorous, normalized design schemes, cannot fully reflect what happens in clinical practice settings. The concept of the "efficacy-effectiveness gap" was also introduced,^[2]which supports the importance of real-world study. Here, we retrospectively summarized all the inpatients with plaque psoriasis who were treated with secukinumab at Peking University Third Hospital from June to December 2019. General information (sex, age, weight, body mass index, etc.) and clinical features (disease duration, family history, comorbidities, laboratory tests, previous treatments, concomitant treatments, etc.) were collected from clinical records. The psoriasis area severity index (PASI), body surface area (BSA), dermatology life quality index (DLQI), psoriasis scalp severity index (PSSI), nail psoriasis severity index (NAPSI), and palmoplantar psoriasis area and severity index (ppPASI) were also recorded. Safety was assessed by adverse events, and special cases that met the exclusion criteria of clinical trials were monitored accordingly. Statistical analysis was performed with SPSS 26.0 software (IBM Corp, Armonk, NY, USA). This study was approved by the Ethical Committee of Peking University Third Hospital (No. 329-01).

To the Editor:Psoriasis is a chronic autoimmune inflammatory disease that has a significant negative impact on quality of life. Interleukin (IL)-17A, a key molecule in the T helper 17 pathway, is important in the pathogenesis of psoriasis. Secukinumab, a fully human immunoglobulin G1 kappa monoclonal antibody that targets IL-17A, was the first anti-IL-17A antibody approved by the US Food and Drug Administration in 2015. In China, it was approved in March 2019 for the treatment of moderate to severe psoriasis vulgaris (PsV), whereas in Japan, it is not only used for PsV but also psoriatic arthritis and generalized pustular psoriasis (GPP). The safety and efficacy of secukinumab have been assessed in four randomized controlled trials (RCTs) (ERASURE, FEATURE, JUNCTURE, and FIXTURE), which showed the superiority of secukinumab compared with placebo, etanercept, and ustekinumab, with long-term persistence of the clearance rate. However, the real-world setting of clinical practice is different from the strictly regulated setting of RCTs, which are conducted in only selected patients that fulfill strict inclusion and exclusion criteria to maximize internal validity. To date, there have been no official English reports of real-world studies published in China.

To the Editor:A 39-year-old man presented with progressive limb atrophy and weakness. The patient had generalized muscular hypotonia at birth; he could not run well in elementary school. Neurologic examination revealed atrophy of the facial muscles and limited left eye adduction. In the upper limbs, the patients showed proximal muscle atrophy and weakness [Figure 1A], while in the lower extremities, the weakness was more prominent distally than proximally. Neither spontaneous or percussion myotonia nor muscle hypertrophy was observed.