Biologics targeting type I interferons in SLE: A meta-analysis and systematic review of randomised controlled trials

Lupus ◽  
2020 ◽  
Vol 29 (14) ◽  
pp. 1845-1853
Author(s):  
Jeffery Wei Heng Koh ◽  
Cheng Han Ng ◽  
Sen Hee Tay
Keyword(s):  
Systematic Review ◽  
Herpes Zoster ◽  
Lupus Erythematosus ◽  
Viral Infections ◽  
Meta Analysis ◽  
Type I Interferons ◽  
Type I ◽  
Upper Respiratory Tract ◽  
Type I Ifn ◽  
Tract Infections

Objective The feed-forward loop of type I interferons (IFNs) production and subsequent immunopathology of systemic lupus erythematosus (SLE) has been hypothesised to be disrupted with inhibition of IFNα or type I IFN receptor subunit 1 (IFNAR). This systematic review and meta-analysis present the treatment efficacy and safety profile of monoclonal antibodies inhibiting IFNα or IFNAR. Methods A search was done using Medline, Embase and ClinicalTrials.gov for biologics targeting IFNα or IFNAR in SLE up to 3 Jan 2020. For the meta-analysis, analyses of binary variables were pooled using odds ratio (OR) with the Mantel Haenszel model. Results Anifrolumab 300 mg (n = 3 studies, 927 patients) was more effective than placebo in achieving SRI(4) (pooled OR = 1.91, CI 1.11-3.28, P = 0.02) and BICLA response (pooled OR = 2.25, CI 1.72-2.95, P < 0.00001). In SLE patients with high type I IFN gene signature, SRI(4) response was not achieved with anifrolumab in 2 studies, 450 patients. Treatment with IFNα and IFNAR inhibitors (n = 7 studies, 1590 patients) increased the risk of herpes zoster infection (pooled OR = 3.72, CI 1.88–7.39, P = 0.0002), upper respiratory tract infections, nasopharyngitis and bronchitis. Conclusion This meta-analysis substantiates IFNAR as a therapeutic target in SLE. Inhibition of type I IFNs predisposes to herpes zoster and other viral infections.

scholarly journals Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Norzawani Buang ◽  
Lunnathaya Tapeng ◽  
Victor Gray ◽  
Alessandro Sardini ◽  
Chad Whilding ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Mitochondrial Abnormalities

AbstractThe majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

scholarly journals Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Daisy X Ji ◽  
Kristen C Witt ◽  
Dmitri I Kotov ◽  
Shally R Margolis ◽  
Alexander Louie ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Negative Regulator ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Viral Immunity ◽  
Type I Ifns ◽  
Important Negative Regulator

Type I interferons (IFNs) are essential for anti-viral immunity, but often impair protective immune responses during bacterial infections. An important question is how type I IFNs are strongly induced during viral infections, and yet are appropriately restrained during bacterial infections. The Super susceptibility to tuberculosis 1 (Sst1) locus in mice confers resistance to diverse bacterial infections. Here we provide evidence that Sp140 is a gene encoded within the Sst1 locus that represses type I IFN transcription during bacterial infections. We generated Sp140-/- mice and find they are susceptible to infection by Legionella pneumophila and Mycobacterium tuberculosis. Susceptibility of Sp140-/- mice to bacterial infection was rescued by crosses to mice lacking the type I IFN receptor (Ifnar-/-). Our results implicate Sp140 as an important negative regulator of type I IFNs that is essential for resistance to bacterial infections.

scholarly journals The Role of Genetic Variation Near Interferon-Kappa in Systemic Lupus Erythematosus

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Isaac T. W. Harley ◽  
Timothy B. Niewold ◽  
Rebecca M. Stormont ◽  
Kenneth M. Kaufman ◽  
Stuart B. Glenn ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Systemic Autoimmune Disease ◽  
Type I ◽  
Nucleotide Polymorphisms ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Genome Wide

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated theIFNKlocus in SLE susceptibility. We studiedIFNKsingle nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio=1.93,P=2.5×10−4), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific.IFNKSNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association betweenIFNKSNPs and SLE and skin phenotypes. The serum IFN association suggests thatIFNKvariants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.

scholarly journals Impact of point-of-care tests in community pharmacies: a systematic review and meta-analysis

BMJ Open ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. e034298 ◽  
Author(s):  
Ali Albasri ◽  
Ann Van den Bruel ◽  
Gail Hayward ◽  
Richard J McManus ◽  
James Peter Sheppard ◽  
...  
Keyword(s):  
Systematic Review ◽  
Point Of Care ◽  
Controlled Trial ◽  
Meta Analysis ◽  
Clinical Care ◽  
Cochrane Central Register ◽  
Upper Respiratory Tract ◽  
Review Team ◽  
Tract Infections ◽  
The Impact

ObjectivesTo summarise the literature regarding the use of point-of-care test (POCT) in pharmacies versus control/usual care.Design and settingSystematic review and random-effects meta-analysis in community pharmacy.Data sourcesMEDLINE, Cochrane Central Register of Controlled Trials, Embase, ClinicalTrial.gov and Web of Science databases were searched.Eligibility criteriaArticles were included if they: involved a POCT conducted by a community pharmacist, member of pharmacy staff or local equivalent; measured a clinically relevant outcome for example, clinical parameter monitoring. No clinical condition or language limits were set.Patient and public involvementNo patient involvement.Data extraction and synthesisData were independently extracted by two members of the review team to capture changes in clinical care that resulted from the use of the POCTs. The methodological quality of included studies was assessed, using the Cochrane Risk of Bias tool and Newcastle-Ottawa scale.ResultsThirteen of the 1584 articles found were included in the meta-analyses. Studies covered four therapeutic areas: targeted anti-malarial therapy (n=3 studies), glycated haemoglobin (HbA1c) in diabetes (n=2 studies), lipid control (n=3 studies) and international normalised ratio (INR) control in patients taking warfarin (n=5 studies). POCT in pharmacies reduced the risk of receiving antimalarial treatment when not clinically indicated (risk ratio 0.34, 95% CI 0.31 to 0.37). Lipid and HbA1c control appeared largely unaffected by pharmacy POCTs, and the impact on INR time-in-therapeutic-range was inconclusive.ConclusionsOnly 4 out of 13 included studies used a gold-standard randomised controlled trial (RCT) design, limiting our ability to conclusively determine the clinical utility of POCT conducted in pharmacies. Further RCTs are needed, particularly in areas such as upper respiratory tract infections, which have gathered momentum among service commissioners in recent years.PROSPERO registration numberCRD42017048578.

scholarly journals Effectiveness of honey for symptomatic relief in upper respiratory tract infections: a systematic review and meta-analysis

2020 ◽  
pp. bmjebm-2020-111336 ◽  
Author(s):  
Hibatullah Abuelgasim ◽  
Charlotte Albury ◽  
Joseph Lee
Keyword(s):  
Systematic Review ◽  
Antimicrobial Resistance ◽  
Respiratory Tract ◽  
Respiratory Tract Infections ◽  
Meta Analysis ◽  
Symptomatic Relief ◽  
Upper Respiratory Tract Infections ◽  
Upper Respiratory Tract ◽  
Upper Respiratory ◽  
Tract Infections

BackgroundAntibiotic over prescription for upper respiratory tract infections (URTIs) in primary care exacerbates antimicrobial resistance. There is a need for effective alternatives to antibiotic prescribing. Honey is a lay remedy for URTIs, and has an emerging evidence base for its use. Honey has antimicrobial properties, and guidelines recommended honey for acute cough in children.ObjectivesTo evaluate the effectiveness of honey for symptomatic relief in URTIs.MethodsA systematic review and meta-analysis. We searched Pubmed, Embase, Web of Science, AMED, Cab abstracts, Cochrane Library, LILACS, and CINAHL with a combination of keywords and MeSH terms.ResultsWe identified 1345 unique records, and 14 studies were included. Overall risk of bias was moderate. Compared with usual care, honey improved combined symptom score (three studies, mean difference −3.96, 95% CI −5.42 to −2.51, I2=0%), cough frequency (eight studies, standardised mean difference (SMD) −0.36, 95% CI −0.50 to −0.21, I2=0%) and cough severity (five studies, SMD −0.44, 95% CI −0.64 to −0.25, I2=20%). We combined two studies comparing honey with placebo for relieving combined symptoms (SMD −0.63, 95% CI −1.44 to 0.18, I2=91%).ConclusionsHoney was superior to usual care for the improvement of symptoms of upper respiratory tract infections. It provides a widely available and cheap alternative to antibiotics. Honey could help efforts to slow the spread of antimicrobial resistance, but further high quality, placebo controlled trials are needed.PROSPERO registration NoStudy ID, CRD42017067582 on PROSPERO: International prospective register of systematic reviews (https://www.crd.york.ac.uk/prospero/).

scholarly journals Endothelial progenitor dysfunction associates with a type I interferon signature in primary antiphospholipid syndrome

2016 ◽  
Vol 76 (2) ◽  
pp. 450-457 ◽  
Author(s):  
Robert C Grenn ◽  
Srilakshmi Yalavarthi ◽  
Alex A Gandhi ◽  
Nayef M Kazzaz ◽  
Carlos Núñez-Álvarez ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Type I Interferons ◽  
Functional Assay ◽  
Type I ◽  
Primary Antiphospholipid Syndrome ◽  
Type I Ifn ◽  
Endothelial Progenitor ◽  
Endothelial Progenitors

ObjectivesPatients with antiphospholipid syndrome (APS) are at risk for subclinical endothelial injury, as well as accelerated atherosclerosis. In the related disease systemic lupus erythematosus, there is a well-established defect in circulating endothelial progenitors, which leads to an accrual of endothelial damage over time. This defect has been at least partially attributed to exaggerated expression of type I interferons (IFNs). We sought to determine whether these pathways are important in APS.MethodsWe studied 68 patients with primary APS. Endothelial progenitors were assessed by flow cytometry and functional assay. Type I IFN activity was determined by a well-accepted bioassay, while peripheral blood mononuclear cells were scored for expression of IFN-responsive genes.ResultsEndothelial progenitors from patients with APS demonstrated a marked defect in the ability to differentiate into endothelial cells, a phenotype which could be mimicked by treating control progenitors with APS sera. Elevated type I IFN activity was detected in the circulation of patients with APS (a finding that was then replicated in an independent cohort). While IgG depletion from APS sera did not rescue endothelial progenitor function, the dysfunction was successfully reversed by a type I IFN receptor-neutralising antibody.ConclusionsWe describe, for the first time to our knowledge, an IFN signature in primary APS and show that this promotes impaired endothelial progenitor function. This work opens the door to novel approaches that may mitigate vascular damage in APS, such as anti-IFN drugs.

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