New possibilities of pharmacotherapy for systemic lupus erythematosus: Prospects for the use of anifrolumab (monoclonal antibodies to type I interferon receptor)

Systemic lupus erythematosus (SLE) is a systemic autoimmune rheumatic disease of unknown etiology, characterized by overproduction of organ-specific autoantibodies to various components of the cell nucleus and the development of immune-inflammatory damage to internal organs. According to modern concepts, one of the key mechanisms of SLE immunopathogenesis is associated with dysregulation of type I interferon (IFN) synthesis The complex of data obtained in the process of fundamental and clinical research served as the basis for the development of a new approach to the pharmacotherapy of SLE, associated with the use of monoclonal antibodies (mAbs) that block the activity of IFN type I or its receptors. Among these drugs, anifrolumab (AFM) occupies a special place, which is a human IgG1 mAbs that bind to cellular receptors for IFN-α. The article discusses the materials of the main studies concerning the efficacy and safety of AFM in SLE, and the prospects for the use of this drug in the treatment of this disease.

Dysregulation of ribosome-related genes in ankylosing spondylitis: a systems biology approach and experimental method

Background Ankylosing spondylitis (AS) is an autoimmune rheumatic disease. Few candidate gene associations have been reported for AS and the current understanding of its pathogenesis remains still poor. Thus, the exact mechanism of AS is needed to urgently be disclosed. The purpose of this study was to identify candidate genes involving in AS disease. Methods and results GSE25101 publicly available microarray and GSE117769 RNA-seq datasets of AS patients were obtained for bioinformatics analyses. Gene set enrichment analysis showed that in the microarray dataset, the ribosome pathway was significantly up-regulated in AS compared with controls. Furthermore, some ribosomal components demonstrated overexpression in patients in the RNA-seq dataset. To confirm the findings, 20 AS patients and 20 matching controls were selected from the Rheumatology Research Center clinic, Shariati Hospital. PBMCs were separated from whole blood and RNA contents were extracted. Following the results of datasets analysis, the expression level of rRNA5.8S pseudogene, rRNA18S pseudogene, RPL23, RPL7, and RPL17 genes were measured through real-time PCR. Our findings showed dysregulation of rRNA5.8S and rRNA18S pseudogenes, and also the RPL17 gene in patients. Conclusion Considering that genes involved in ribosome biogenesis contributed to some AS-associated biological processes as well as diseases that have comorbidities with AS, our results might advance our understanding of the pathological mechanisms of ankylosing spondylitis.

Polymorphic variants of proteasomal genes PSMA3 and PSMA6 in children with articular syndrome and juvenile idiopathic arthritis

A comparative analysis of three single nucleotide variations of the proteasomal genes PSMA3 (rs2348071) and PSMA6 (rs2277460 and rs1048990) was carried out in the groups of children from 1 to 16 years old with the autoimmune rheumatic disease - juvenile idiopathic arthritis (JIA; n = 199), with articular syndrome of non-autoimmune etiology (n = 229) and in the clinical control group with neither autoimmune nor chronic inflammatory diseases (n = 379). PCR, PCR–RFLP and real-time PCR were used for genotyping. It was found that the CG genotype and G allele of rs10489990 polymorphism (OR = = 1.93; 95 % CI 1.29-2.90; p = 0.002 and OR = 1.51; 95 % CI 1.11-2.04; p = 0.008 respectively), as well as the AA genotype of rs2348071 polymorphism (OR = 1.89; 95 % CI 1.02–3.49; p = 0.044) are associated with the JIA susceptibility, but not with articular syndrome. The established JIA risk genotypes may indicate the involvement of PSMA3 and PSMA6 genes in the development of an autoimmune reaction. In combination with other risk DNA markers, they can be proposed to assess a genetic predisposition to JIA. It was also revealed that the frequencies of risk genotypes and alleles for JIA in the group of patients with articular syndrome as a whole occupy an intermediate position between JIA and control group frequencies. This may indicate an increased JIA risk in some patients with articular syndrome.

Association Between Impaired Myocardial Flow Reserve on 82 Rubidium Positron Emission Tomography Imaging and Adverse Events in Patients With Autoimmune Rheumatic Disease

Background: Coronary microvascular dysfunction has been described in patients with autoimmune rheumatic disease (ARD). However, it is unknown whether positron emission tomography (PET)-derived myocardial flow reserve (MFR) can predict adverse events in this population. Methods: Patients with ARD without coronary artery disease who underwent dynamic rest-stress 82 Rubidium PET were retrospectively studied and compared with patients without ARD matched for age, sex, and comorbidities. The association between MFR and a composite end point of mortality or myocardial infarction or heart failure admission was evaluated with time to event and Cox-regression analyses. Results: In 101 patients with ARD (88% female, age: 62±10 years), when compared with matched patients without ARD (n=101), global MFR was significantly reduced (median: 1.68 [interquartile range: 1.34–2.05] versus 1.86 [interquartile range: 1.58–2.28]) and reduced MFR (<1.5) was more frequent (40% versus 22%). MFR did not differ among subtypes of ARDs. In survival analysis, patients with ARD and low MFR (MFR<1.5) had decreased event-free survival for the combined end point, when compared with patients with and without ARD and normal MFR (MFR>1.5) and when compared with patients without ARD and low MFR, after adjustment for the nonlaboratory-based Framingham risk score, rest left ventricular ejection fraction, severe coronary calcification, and the presence of medium/large perfusion defects. In Cox-regression analysis, ARD diagnosis and reduced MFR were both independent predictors of adverse events along with congestive heart failure diagnosis and presence of medium/large stress perfusion defects on PET. Further analysis with inclusion of an interaction term between ARD and impaired MFR revealed no significant interaction effects between ARD and impaired MFR. Conclusions: In our retrospective cohort analysis, patients with ARD had significantly reduced PET MFR compared with age-, sex-, and comorbidity-matched patients without ARD. Reduced PET MFR and ARD diagnosis were both independent predictors of adverse outcomes.

Anti-DFS70 Antibodies for Differentiating Systemic Autoimmune Rheumatic Disease in Patients with Positive ANA Tests: A Systematic Review and Meta-Analysis

Anti-DFS70 antibodies have been proposed as a marker to exclude systemic autoimmune rheumatic disease (SARD). We conducted this systematic diagnostic test accuracy review and meta-analysis to determine the performance of anti-DFS70 antibodies in patients with a positive anti-nuclear antibody (ANA) test result to exclude SARD. We searched PubMed, Embase, Web of Science, Scopus and the Cochrane Library up to 22 February 2021, and included studies examining the diagnostic accuracy of anti-DFS70 antibodies in patients with a positive ANA test result. The results were pooled using a hierarchical bivariate model and plotted in summary receiver operating characteristic curves. R software and Stata Statistical Software were used for the statistical analysis. Eight studies with 4168 patients were included. The summary sensitivity was 0.19 (95% confidence interval: 0.12–0.28) and the specificity was 0.93 (95% confidence interval: 0.88–0.96). The area under the curve was 0.69 (95% confidence interval: 0.64–0.72). The meta-regression analysis showed that targeting only ANA-associated rheumatic disease was associated with higher specificity. In addition, the studies with a non-SARD prevalence of <80% and using a chemiluminescence assay were associated with higher specificity. Anti-DFS70 antibodies have high specificity for the exclusion of SARD among patients presenting with a positive ANA test, but the sensitivity is low.