OBJECTIVE: This study proposes a comprehensive quantitative evaluation of the efficacy of drugs and placebo in clinical trials for primary progressive multiple sclerosis (PPMS).
METHODS: A literature search was conducted using the PubMed, EMBASE, and Cochrane library databases and the clinical studies reporting drug efficacy in the treatment of PPMS were included in the analyses. The cumulative proportion of patients without confirmed disability progression (wCDP%) was used as the main efficacy endpoint. The model-based meta-analysis method was used to describe the time course of each drug (as well as placebo) in order to rank the drug efficacy for the treatment of PPMS.
RESULTS: Fifteen studies involving 3779 patients were included, of which, nine were placebo-controlled and six were single-arm trials. Twelve drugs were included in the study. The results showed that, except for biotin, interferon β-1a, and interferon β-1b, whose efficacy was comparable to the placebo, the efficacy of the other 9 drugs were significantly better than placebo. Among these, ocrelizumab showed outstanding performance, with wCDP% of 72.6 at 96 weeks, while the proportions of rest of the drugs ranged between approximately 55-70%.
CONCLUSIONS: The results of this study provide the necessary quantitative information for both the rational clinical use of drugs and future clinical trials in primary progressive multiple sclerosis.

Ocrelizumab is a humanised anti-CD20 monoclonal antibody developed for the treatment of multiple sclerosis (MS). It was approved by the Food and Drug Administration (FDA) in March 2017 for using in adults with relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS). Ocrelizumab is the only disease-modifying therapy (DMT) approved for PPMS. In November 2017, the European Medicines Agency (EMA) also approved ocrelizumab as the first drug for people with early PPMS. Therefore, it is important to evaluate the benefits, harms, and tolerability of ocrelizumab in people with MS.
To assess the benefits, harms, and tolerability of ocrelizumab in people with RRMS and PPMS.
We searched MEDLINE, Embase, CENTRAL, and two trials registers on 8 October 2021. We screened reference lists, contacted experts, and contacted the main authors of studies.
All randomised controlled trials (RCTs) involving adults diagnosed with RRMS or PPMS according to the McDonald criteria, comparing ocrelizumab alone or associated with other medications, at the approved dose of 600 mg every 24 weeks for any duration, versus placebo or any other active drug therapy.
We used standard methodological procedures expected by Cochrane.
Four RCTs met our selection criteria. The overall population included 2551 participants; 1370 treated with ocrelizumab 600 mg and 1181 controls. Among the controls, 298 participants received placebo and 883 received interferon beta-1a. The treatment duration was 24 weeks in one study, 96 weeks in two studies, and at least 120 weeks in one study. One study was at high risk of allocation concealment and blinding of participants and personnel; all four studies were at high risk of bias for incomplete outcome data. For RRMS, compared with interferon beta-1a, ocrelizumab was associated with: 1. lower relapse rate (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.52 to 0.73; 2 studies, 1656 participants; moderate-certainty evidence); 2. a lower number of participants with disability progression (hazard ratio (HR) 0.60, 95% CI 0.43 to 0.84; 2 studies, 1656 participants; low-certainty evidence); 3. little to no difference in the number of participants with any adverse event (RR 1.00, 95% CI 0.96 to 1.04; 2 studies, 1651 participants; moderate-certainty evidence); 4. little to no difference in the number of participants with any serious adverse event (RR 0.79, 95% CI 0.57 to 1.11; 2 studies, 1651 participants; low-certainty evidence); 5. a lower number of participants experiencing treatment discontinuation caused by adverse events (RR 0.58, 95% CI 0.37 to 0.91; 2 studies, 1651 participants; low-certainty evidence); 6. a lower number of participants with gadolinium-enhancing T1 lesions on magnetic resonance imaging (MRI) (RR 0.27, 95% CI 0.22 to 0.35; 2 studies, 1656 participants; low-certainty evidence); 7. a lower number of participants with new or enlarging T2-hyperintense lesions on MRI (RR 0.63, 95% CI 0.57 to 0.69; 2 studies, 1656 participants; low-certainty evidence) at 96 weeks. For PPMS, compared with placebo, ocrelizumab was associated with: 1. a lower number of participants with disability progression (HR 0.75, 95% CI 0.58 to 0.98; 1 study, 731 participants; low-certainty evidence); 2. a higher number of participants with any adverse events (RR 1.06, 95% CI 1.01 to 1.11; 1 study, 725 participants; moderate-certainty evidence); 3. little to no difference in the number of participants with any serious adverse event (RR 0.92, 95% CI 0.68 to 1.23; 1 study, 725 participants; low-certainty evidence); 4. little to no difference in the number of participants experiencing treatment discontinuation caused by adverse events (RR 1.23, 95% CI 0.55 to 2.75; 1 study, 725 participants; low-certainty evidence) for at least 120 weeks. There were no data for number of participants with gadolinium-enhancing T1 lesions on MRI and number of participants with new or enlarging T2-hyperintense lesions on MRI.
For people with RRMS, ocrelizumab probably results in a large reduction in relapse rate and little to no difference in adverse events when compared with interferon beta-1a at 96 weeks (moderate-certainty evidence). Ocrelizumab may result in a large reduction in disability progression, treatment discontinuation caused by adverse events, number of participants with gadolinium-enhancing T1 lesions on MRI, and number of participants with new or enlarging T2-hyperintense lesions on MRI, and may result in little to no difference in serious adverse events (low-certainty evidence). For people with PPMS, ocrelizumab probably results in a higher rate of adverse events when compared with placebo for at least 120 weeks (moderate-certainty evidence). Ocrelizumab may result in a reduction in disability progression and little to no difference in serious adverse events and treatment discontinuation caused by adverse events (low-certainty evidence). Ocrelizumab was well tolerated clinically; the most common adverse events were infusion-related reactions and nasopharyngitis, and urinary tract and upper respiratory tract infections.

BACKGROUND: As one kind of disease-modifying therapies, sphingosine-1-phosphate receptor (S1PR) modulators such as fingolimod, ozanimod, and siponimod have been approved or are being developed to treat multiple sclerosis (MS). Several randomized controlled trials (RCT) have been implemented to compare the efficacy and safety of S1PR modulators versus interferon beta in the treatment of people with relapsing-remitting multiple sclerosis (RRMS).
METHODS: We searched RCTs which were implemented from January 2010 to June 2020 by searching PubMed, Embase, Cochrane Library databases, and the Central Register of Controlled Trials. Finally, five RCTs were included in our study after carefully choosing.
RESULTS: We pooled 4304 patients from 5 RCTs. The primary outcome was the annualized relapse rate. We found that the annualized relapse rate in the S1PR modulator group is 20% less than that in the interferon beta group (95%CI, - 0.32 to - 0.07, P = 0.002). S1PR modulators led to a significant reduction in number of new or enlarging T2 lesions per scan and number of gadolinium-enhancing lesions compared with interferon beta. Moreover, S1PR modulators can also improve 54-item multiple sclerosis quality of life (MSQOL-54) physical health composite score (P = 0.0005).
CONCLUSIONS: S1PR modulators exhibited good efficacy and safety for the treatment of RRMS compared with interferon beta. According to follow-up trials, S1PR modulators can improve MSQOL-54 physical health composite score so that it may be beneficial to neurological recovery which need more research to confirm.

UNASSIGNED: Coronavirus disease 2019 (COVID-19) is rapidly spreading worldwide. Drug therapy is one of the major treatments, but contradictory results of clinical trials have been reported among different individuals. Furthermore, comprehensive analysis of personalized pharmacotherapy is still lacking. In this study, analyses were performed on 47 well-characterized COVID-19 drugs used in the personalized treatment of COVID-19.
UNASSIGNED: Clinical trials with published results of drugs use for COVID-19 treatment were collected to evaluate drug efficacy. Drug-to-Drug Interactions (DDIs) were summarized and classified. Functional variations in actionable pharmacogenes were collected and systematically analysed. \"Gene Score\" and \"Drug Score\" were defined and calculated to systematically analyse ethnicity-based genetic differences, which are important for the safer use of COVID-19 drugs.
UNASSIGNED: Our results indicated that four antiviral agents (ritonavir, darunavir, daclatasvir and sofosbuvir) and three immune regulators (budesonide, colchicine and prednisone) as well as heparin and enalapril could generate the highest number of DDIs with common concomitantly utilized drugs. Eight drugs (ritonavir, daclatasvir, sofosbuvir, ribavirin, interferon alpha-2b, chloroquine, hydroxychloroquine (HCQ) and ceftriaxone had actionable pharmacogenomics (PGx) biomarkers among all ethnic groups. Fourteen drugs (ritonavir, daclatasvir, prednisone, dexamethasone, ribavirin, HCQ, ceftriaxone, zinc, interferon beta-1a, remdesivir, levofloxacin, lopinavir, human immunoglobulin G and losartan) showed significantly different pharmacogenomic characteristics in relation to the ethnic origin of the patient.
UNASSIGNED: We recommend that particularly for patients with comorbidities to avoid serious DDIs, the predictive, preventive, and personalized medicine (PPPM, 3 PM) strategies have to be applied for COVID-19 treatment, and genetic tests should be performed for drugs with actionable pharmacogenes, especially in some ethnic groups with a higher frequency of functional variations, as our analysis showed. We also suggest that drugs associated with higher ethnic genetic differences should be given priority in future pharmacogenetic studies for COVID-19 management. To facilitate translation of our results into clinical practice, an approach conform with PPPM/3 PM principles was suggested. In summary, the proposed PPPM/3 PM attitude should be obligatory considered for the overall COVID-19 management.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s13167-021-00247-0.

暂无摘要。

The virus-induced signaling adaptor (VISA) complex plays a critical role in the innate immune response to RNA viruses. However, the mechanism of VISA complex formation remains unclear. Here, we demonstrate that thioredoxin 2 (TRX2) interacts with VISA at mitochondria both in vivo and in vitro Knockdown and knockout of TRX2 enhanced the formation of the VISA-associated complex, as well as virus-triggered activation of interferon regulatory factor 3 (IRF3) and transcription of the interferon beta 1 (IFNB1) gene. TRX2 inhibits the formation of VISA aggregates by repressing reactive oxygen species (ROS) production, thereby disrupting the assembly of the VISA complex. Furthermore, our data suggest that the C93 residue of TRX2 is essential for inhibition of VISA aggregation, whereas the C283 residue of VISA is required for VISA aggregation. Collectively, these findings uncover a novel mechanism of TRX2 that negatively regulates VISA complex formation.IMPORTANCE The VISA-associated complex plays pivotal roles in inducing type I interferons (IFNs) and eliciting the innate antiviral response. Many host proteins are identified as VISA-associated-complex proteins, but how VISA complex formation is regulated by host proteins remains enigmatic. We identified the TRX2 protein as an important regulator of VISA complex formation. Knockout of TRX2 increases virus- or poly(I·C)-triggered induction of type I IFNs at the VISA level. Mechanistically, TRX2 inhibits the production of ROS at its C93 site, which impairs VISA aggregates at its C283 site, and subsequently impedes the assembly of the VISA complex. Our findings suggest that TRX2 plays an important role in the regulation of VISA complex assembly.

暂无摘要。

BACKGROUND: Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. The treatment of MS has always been a focus of neurological research. To date, the US Food and Drug Administration has approved 15 medications for modifying the course of multiple sclerosis. In this study, we examined the effects of disease-modifying therapies (DMTs) on clinical outcomes.
METHODS: We did a systematic review and network meta-analysis based on randomized controlled trials (RCTs) comparing DMTs in patients with relapsing-remitting multiple sclerosis (RRMS). We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for RCTs published up to Oct 31, 2018. The primary outcome was efficacy (relapse rate over 24 months) and acceptability (treatment discontinuation due to adverse events over 24 months).
RESULTS: We identified 23 suitable trials encompassing 14,096 participants. During the 2 years of follow-up, all drugs were significantly more effective than were placebos. The risk ratios with 95% credible intervals were as follows: alemtuzumab, 0.49 (0.40, 0.59); ocrelizumab, 0.49 (0.40, 0.61); mitoxantrone, 0.47 (0.27, 0.80); natalizumab, 0.51 (0.43, 0.61); fingolimod, 0.57 (0.50, 0.65); peginterferon beta-1a, 0.63 (0.52, 0.77); dimethyl fumarate, 0.65 (0.56, 0.74); teriflunomide 14 mg, 0.78 (0.66, 0.92); glatiramer acetate, 0.80 (0.72, 0.89); IFN β-1a (Rebif), 0.81 (0.72, 0.90); IFN β-1b (Betaseron), 0.81 (0.72, 0.91); teriflunomide 7 mg, 0.83 (0.71, 0.98); and IFN β-1a (Avonex). 0.87 (0.77, 0.99). Risk ratios compared with placebo for discontinuation due to adverse events ranged from 1.12 for the best drug (fingolimod) to 0.10 for the worst drug (mitoxantrone); from 0.24 (alemtuzumab) to 0.89 (IFNβ-1b [Betaseron]) for sustained (3-month) disability progression; and from 0.85 (natalizumab) to 1.25 (teriflunomide 14 mg) for the number of participants with serious adverse events.
CONCLUSIONS: All DMTs were superior to placebo in reducing the relapse rate during the 2 years of follow-up. As to the comparison between drugs, alemtuzumab, ocrelizumab, natalizumab and fingolimod had a relatively higher response and lower dropout rates than did the other DMTs.

Recombinant human interferon beta (rhIFN-β) is a glycoprotein produced by genetically engineered cells and has anti-virus, anti-tumor and immunoregulation functions. Although studies have shown that other subtypes of IFN such as IFN-γ affects cell proliferation and differentiation to some extent, the effect of rhIFN-β on chondrogenic differentiation of human bone marrow mesenchymal stem cells (hMSCs) is less known. In this study we studied the effect of rhIFN-β on the chondrogenic differentiation of hMSCs by inducing hMSCs into cartilage pellet via adding IFN-β1a into regular TGF-β3 chondrogenic differentiation medium. We collected the induced pellets and then detected GAG content, assessed pellets size, observed agreecan using alcian blue staining, and analyzed the expression of Sox and CollangenⅡusing real-time PCR and Western blotting. Addition of 100 ng/mL IFN-β1a to regular TGF-β3 chondrogenic differentiation medium could improve the concentration of GAG, increase the size of pellets, promote the formation of aggrecan and up-regulate the expression of CollangenII and Sox9. IFN-β1a combined with TGF-β3 could promote chondrogenic differentiation of hMSCs.
重组人干扰素β (rhIFN-β) 是通过基因表达的一种糖蛋白，具有抗病毒、抗肿瘤和免疫调节作用，虽有研究表明其他亚型干扰素如干扰素γ 对细胞增殖和分化有一定的作用，但rhIFN-β 对人骨髓间充质干细胞(hMSCs) 诱导分化的影响尤其是成软骨细胞定向分化的研究尚少。文中采用成球法研究在常规TGF-β3 诱导分化培养基中添加重组IFN-β1a 后对诱导hMSCs 分化成软骨球的影响。hMSCs 经诱导分化后，收集软骨球，通过定量检测糖胺多糖 (GAG) 含量、软骨球形态测定、Alcian Blue 组织染色、Real-time PCR 和Western blotting 检测Sox9 和Collangen Ⅱ的表达。结果显示，在常规TGF-β3 诱导分化培养基中添加100 ng/mL IFN-β1a 能显著提高GAG 含量，增大软骨球尺寸，促进聚集蛋白聚糖形成，上调Sox9 和Collangen Ⅱ的表达。研究结果表明，重组人IFN-β1a 能够与TGF-β3 联合作用促进hMSCs 成软骨细胞定向分化。.

Alemtuzumab is a humanised monoclonal antibody that alters the circulating lymphocyte pool, causing prolonged lymphopenia, thus remoulding the immune repertoire that accompanies homeostatic lymphocyte reconstitution. It has been proved more effective than interferon (IFN) 1a for the treatment of relapsing-remitting multiple sclerosis (RRMS).
To compare the efficacy, tolerability and safety of alemtuzumab versus interferon beta 1a in the treatment of people with RRMS to prevent disease activity.
We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register (1 February 2017) which, among other sources, contains records from CENTRAL, MEDLINE, Embase, CINAHL, LILACS, PEDRO and the trial registry databases Clinical Trials.gov and WHO International Clinical Trials Registry Platform for all prospectively registered and ongoing trials.
All double-blind, randomised, controlled trials comparing intravenous alemtuzumab (12 mg per day or 24 mg per day on five consecutive days during the first month and on three consecutive days at months 12 and 24) versus subcutaneous IFN beta 1a (22 μg or 44 μg three times per week (Rebif) or intramuscular injection 30 μg once a week (Avonex)) in people of any gender and age with RRMS.
We used standard methodological procedures expected by Cochrane.
We included three trials involving 1694 participants. All trials compared alemtuzumab 12 mg per day or 24 mg per day versus IFN beta 1a for treating RRMS. In CAMMS223, participants received either subcutaneous IFN beta 1a 44 μg three times per week or annual intravenous cycles of alemtuzumab (at a dose of 12 mg per day or 24 mg per day) for 36 months. In CARE-MS I and CARE-MS II, participants received subcutaneous IFN beta 1a 44 μg three times per week or annual intravenous cycles of alemtuzumab 12 mg per day for 24 months. The methodological quality was good for all three studies.In the alemtuzumab 12 mg per day group, the results showed statistically significant difference in reducing relapses (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.52 to 0.70), preventing disease progression (RR 0.60, 95% CI 0.45 to 0.79) and developing new T2 lesions on magnetic resonance imaging (RR 0.75, 95% CI 0.61 to 0.93) after 24 and 36 months\' follow-up, but found no statistically significant difference in the changes of Expanded Disability Status Scale (EDSS) score (mean difference (MD) -0.35, 95% CI -0.73 to 0.03). In the alemtuzumab 24 mg per day group, the results showed statistically significant differences in reducing relapses (RR 0.38, 95% CI 0.23 to 0.62), preventing disease progression (RR 0.42, 95% CI 0.21 to 0.84) and the changes of EDSS score (MD -0.83, 95% CI -1.17 to -0.49) after 36 months\' follow-up.All three trials reported adverse events and serious adverse events. There was no statistically significant difference in the number of participants with at least one adverse event (RR 1.03, 95% CI 0.97 to 1.08) and the number of participants who experienced serious adverse events (RR 1.03, 95% CI 0.83 to 4.54).
There is low- to moderate-quality evidence that annual intravenous cycles of alemtuzumab at a dose of 12 mg per day or 24 mg per day reduces the proportion of participants with relapses, disease progression, change of EDSS score and developing new T2 lesions on MRI over 24 to 36 months in comparison with subcutaneous IFN beta-1a 44 μg three times per week.Alemtuzumab appeared to be relatively well tolerated. The most frequently reported adverse events were infusion-associated reactions, infections and autoimmune events. The use of alemtuzumab requires careful monitoring so that potentially serious adverse effects can be treated early and effectively.