A Conscious Resting State fMRI Study in SLE Patients Without Major Neuropsychiatric Manifestations

Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the main causes of death in patients with systemic lupus erythematosus (SLE). Signs and symptoms of NPSLE are heterogeneous, and it is hard to diagnose, and treat NPSLE patients in the early stage. We conducted this study to explore the possible brain activity changes using resting state functional magnetic resonance imaging (rs-fMRI) in SLE patients without major neuropsychiatric manifestations (non-NPSLE patients). We also tried to investigate the possible associations among brain activity, disease activity, depression, and anxiety. In our study, 118 non-NPSLE patients and 81 healthy controls (HC) were recruited. Rs-fMRI data were used to calculate the regional homogeneity (ReHo) in all participants. We found decreased ReHo values in the fusiform gyrus and thalamus and increased ReHo values in the parahippocampal gyrus and uncus. The disease activity was positively correlated with ReHo values of the cerebellum and negatively correlated with values in the frontal gyrus. Several brain areas showed correlations with depressive and anxiety statuses. These results suggested that abnormal brain activities might occur before NPSLE and might be the foundation of anxiety and depression symptoms. Early detection and proper treatment of brain dysfunction might prevent the progression to NPSLE. More studies are needed to understand the complicated underlying mechanisms

Depressive and Anxiety Disorders in Systemic Lupus Erythematosus Patients without Major Neuropsychiatric Manifestations

Depressive and anxiety disorders are frequently observed in patients with Systemic Lupus Erythematosus (SLE). However, the underlying mechanisms are still unknown. We conducted this survey to understand the prevalence of depression and anxiety in SLE patients without major neuropsychiatric manifestations (non-NPSLE) and to explore the relationship between emotional disorders, symptoms, autoantibodies, disease activity, and treatments in SLE. 176 SLE patients were included, and SLE disease activity index (SLEDAI), Hamilton Depression Rating Scale (HAMD), and Hamilton Anxiety Rating Scale (HAMA) were recorded to evaluate their disease activity and emotional status. We found that depressive and anxiety disorders were common among SLE patients: 121 (68.8%) patients were in depression status while 14 (8.0%) patients could be diagnosed with depression. Accordingly, 101 (57.4%) were in anxiety status and 21 (11.9%) could be diagnosed with anxiety. Depression was associated with disease activity, and anxiety was associated with anti-P0 antibody, while both of them were associated with proteinuria. HAMA and HAMD scores were in strong positive correlation and they were independent risk factors of each other. We concluded that the high prevalence of depression and anxiety and the association between depression and SLE disease activity might reveal the covert damage of central nervous system in SLE. The role of anti-P0 antibody in SLE patients with emotional disorders warrants more researches

Clinical Factors Associated with Brain Volume Reduction in Systemic Lupus Erythematosus Patients without Major Neuropsychiatric Manifestations

The aim of the study was to find structural brain changes in systemic lupus erythematosus patients without major neuropsychiatric manifestations [non-neuropsychiatric systemic lupus erythematosus (non-NPSLE)] using quantitative magnetic resonance imaging (MRI) and possible associations with clinical characteristics. 89 non-NPSLE patients with normal conventional MRI and 84 healthy controls (HCs) were recruited. The whole brain gray matter volume (GMV) and white matter volume (WMV) were calculated for each individual. We found obvious GMV and WMV reduction in the systemic lupus erythematosus (SLE) group compared with HCs. Female patients showed significant reduction of GMV and WMV compared with male patients. Patients treated with immunosuppressive agents (ISA) showed less WMV reduction than those without. Cognitive impairment was the most common subclinical neuropsychiatric manifestation and had a prevalence of 46.1%. Association between WMV reduction with cognitive impairment was found. Thus, we concluded that structural brain atrophy could happen even before occurrence of obvious neuropsychiatric signs and symptoms and was associated with subclinical symptoms such as cognitive impairment. ISA treatment might have a protective effect on the brain atrophy. Early treatment might prevent the progressive damage to the brain. More studies are needed to fully understand the complicated underlying mechanisms of brain atrophy in SLE

Hippocampal Atrophy in Systemic Lupus Erythematosus Patients without Major Neuropsychiatric Manifestations

This study was conducted to explore hippocampal structural changes and their possible associations with clinical characteristics, emotional status, and treatment regimens in patients with systemic lupus erythematosus (SLE) without major neuropsychiatric manifestations (non-NPSLE). Eighty-five non-NPSLE patients with normal conventional magnetic resonance imaging (MRI) and seventy-seven matched healthy control (HC) subjects were recruited. All participants underwent the standard high-resolution volumetric MRI. The bilateral hippocampal volume (HIPV) and hippocampal density (HIPD) were calculated, respectively, for each participant. We found that the bilateral HIPV and HIPD of the SLE patient group were significantly less than those of the HC group. The bilateral HIPV of female patients were significantly less than those of male patients. The SLE disease activity index (SLEDAI) was negatively correlated with the bilateral HIPV and the right HIPD. Urine protein quantity was negatively correlated with the bilateral HIPV and HIPD. Hydroxychloroquine (HCQ) showed a protective effect on right HIPV. In conclusion, we found that the early hippocampal atrophy could occur before obvious neuropsychiatric manifestations and might be associated with SLE disease activity and organ damages. Early detection and intervention of hippocampal damage might prevent the progression to NPSLE. More studies are needed to fully understand the underlying mechanisms of hippocampal atrophy in SLE

Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer.Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636.Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7-30·4). Median overall survival was 12·7 months (95% CI 11·5-13·6) in the pembrolizumab group versus 10·9 months (9·9-11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72-0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events.Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer