Impaired immunogenicity to COVID-19 vaccines in autoimmune systemic diseases. High prevalence of non-response in different patients’ subgroups

Autoimmune systemic diseases (ASD) may show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed to evaluate the seroconversion after the vaccination cycle and at 6-12-month follow-up, as well the safety and efficacy of vaccines in preventing COVID-19. The study included 478 unselected ASD patients (mean age 59 ± 15 years), namely 101 rheumatoid arthritis (RA), 38 systemic lupus erythematosus (SLE), 265 systemic sclerosis (SSc), 61 cryoglobulinemic vasculitis (CV), and a miscellanea of 13 systemic vasculitis. The control group included 502 individuals from the general population (mean age 59 ± 14SD years). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was evaluated by measuring serum IgG-neutralizing antibody (NAb) (SARS-CoV-2 IgG II Quant antibody test kit; Abbott Laboratories, Chicago, IL) on samples obtained within 3 weeks after vaccination cycle. The short-term results of our prospective study revealed significantly lower NAb levels in ASD series compared to controls [286 (53–1203) vs 825 (451–1542) BAU/mL, p < 0.0001], as well as between single ASD subgroups and controls. More interestingly, higher percentage of non-responders to vaccine was recorded in ASD patients compared to controls [13.2% (63/478), vs 2.8% (14/502); p < 0.0001]. Increased prevalence of non-response to vaccine was also observed in different ASD subgroups, in patients with ASD-related interstitial lung disease (p = 0.009), and in those treated with glucocorticoids (p = 0.002), mycophenolate-mofetil (p < 0.0001), or rituximab (p < 0.0001). Comparable percentages of vaccine-related adverse effects were recorded among responder and non-responder ASD patients. Patients with weak/absent seroconversion, believed to be immune to SARS-CoV-2 infection, are at high risk to develop COVID-19. Early determination of serum NAb after vaccination cycle may allow to identify three main groups of ASD patients: responders, subjects with suboptimal response, non-responders. Patients with suboptimal response should be prioritized for a booster-dose of vaccine, while a different type of vaccine could be administered to non-responder individuals

Role of MicroRNA Profile Modifications in Hepatitis C Virus-Related Mixed Cryoglobulinemia

Hepatitis C virus infection is closely related to lymphoproliferative disorders (LPDs), including mixed cryoglobulinemia (MC) and some lymphomas. Modification of the expression of specific microRNAs (miRNAs) has been associated with different autoimmune diseases and/or LPDs. No data exist about the modifications in miRNA expression in HCV-associated LPDs. The aim of this study was to analyze the expression levels of a panel of miRNAs previously associated with autoimmune/LPDs in a large population of HCV patients with and without MC or non-Hodgkin’s lymphoma (NHL), to identify potential markers of evolution of HCV infection. PBMC expression of miR-Let-7d, miR-16, miR-21, miR-26b, miR-146a and miR-155 was evaluated by real-time PCR in 167 HCV patients (75 with MC [MC-HCV], 11 with HCV-associated NHL [NHL-HCV], 81 without LPD [HCV]) and in 35 healthy subjects (HS). A significant increase in miR-21 (p<0.001), miR-16 (p<0.01) and miR-155 (p<0.01) expression was detected in PBMCs from only NHL patients whereas a significant decrease in miR-26b was detected in both MC and NHL subjects (p<0.01) when compared to HS and HCV groups. A restoration of miR-26b levels was observed in the post-treatment PBMCs of 35 HCV-MC patients experiencing complete virological and clinical response following antiviral therapy. This study, for the first time, shows that specific microRNAs in PBMC from HCV patients who developed MC and/or NHL are modulated differently. The specific, reversible downregulation of miR-26b strongly suggests the key role it plays in the pathogenesis of HCV-related LPDs and its usefulness as a biomarker of the evolution of HCV infection to these disorders

MIR-17/92 EXPRESSION PATTERN: A MOLECULAR SIGNATURE OF HCV-RELATED MIXED CRYOGLOBULINEMIA

Background and Aims: HCV chronic infection is closely related to the development of lymphoproliferative disorders (LPDs), mainly mixed cryoglobulinemia (MC) and some subtypes of B-cell lymphoma. The pathogenesis of HCV-LPDs is still largely unknown. Modification of the expression levels of specific microRNAs (miRNAs) has been associated with different autoimmune and/or LPDs. In particular, the endogenous miR-17/92 cluster is very often amplified in cancer and in autoimmunity. Scarce data exist about the modifications of miRNA expression levels in HCV-related LPDs. The aim of this study was to evaluate the modifications of the expression levels of the miR-17/92 cluster in a large population of HCV patients with and without MC and the effects of viral eradication. Methods: The expression levels of miR-17/92 cluster were evaluated by Real Time PCR in PBMC samples from 79 HCV patients: 34 without LPD [HCV] and 45 with MC [HCV-MC]; among the 45 MC patients were included 20 patients who experienced a sustained virological and clinical response after antiviral treatment and of which pre and post therapy sampling was available. Relative expression levels of all the members of the miR-17/92 cluster (namely, miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a) were evaluated with the 2-DDCt method, using miR-let-7d as housekeeping. Results: All the members of the miR-17/92 cluster were highly upregulated in PBMCs from HCV-MC patients (p &lt; 0.001) when compared to HCV group. A restoration of miRNAs levels was observed in the samples taken after viral eradication (miR-17, miR-18a, miR-19a, miR-19b, miR-20a, p &lt; 0.001 and miR-92a, p &lt; 0.05, when compared with pre-treatment levels). Regarding miR-20a, the levels in samples taken after HCV eradication continued to be significantly higher than in controls (HCV patients) (p &lt; 0.05), in spite of the sudden fall observed after therapy. Conclusions: This study, for the first time, shows that the expression pattern of miRNA-17/92 cluster is modified in PBMC from HCV patients with MC. The sudden restoration of these values of expression in patients achieving a sustained virological and clinical response after antiviral treatment, strongly suggests that miR-17/92 cluster plays a key role in the pathogenesis of MC

MIR-17/92 EXPRESSION PATTERN: A MOLECULAR SIGNATURE OF HCV-RELATED MIXED CRYOGLOBULINEMIA

Introduction: HCV infection is closely related to the development of lymphoproliferative disorders (LPDs), mainly mixed cryoglobulinemia (MC) and B-cell lymphoma. Modification of the expression levels of specific microRNAs (miRNAs) has been associated with different autoimmune and/or LPDs. In particular, the endogenous miR-17/92 cluster is very often amplified in cancer and in autoimmunity. Scarce data exist about the modifications of miRNA expression levels in HCV-related LPDs. Aim: To evaluate the modifications of miR-17/92 cluster levels in HCV-positive patients with and without MC. Methods: miR-17/92 cluster expression levels were evaluated by Real Time PCR in PBMC samples from 79 HCV patients: 34 without LPD [HCV] and 45 with MC [HCV-MC]; among the 45 MC patients were included 20 patients who experienced a sustained virological and clinical response after antiviral treatment and of which pre and post therapy sampling was available. Relative expression levels of all the members of the miR-17/92 cluster (namely, miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a) were evaluated with the 2−ΔΔCt method, using miR-let-7d as housekeeping. Results: All the members of the miR-17/92 cluster were highly upregulated in PBMCs from HCV-MC patients (p&nbsp;&lt;&nbsp;0.001) when compared to HCV group. A restoration of miRNAs levels was observed in the samples taken after viral eradication (miR-17, miR-18a, miR-19a, miR-19b, miR-20a, p&nbsp;&lt;&nbsp;0.001 and miR-92a, p&nbsp;&lt;&nbsp;0.05, when compared with pre-treatment levels). Regarding miR-20a, the levels in samples taken after HCV eradication continued to be significantly higher than in controls (HCV patients) (p&nbsp;&lt;&nbsp;0.05), in spite of the sudden fall observed after therapy. Conclusions: This study shows that the pattern of miRNA-17/92 cluster is modified in PBMC from HCV patients with MC. The sudden restoration of these values of expression in patients achieving a sustained virological and clinical response after antiviral treatment, strongly suggests that miR-17/92 cluster plays a key role in the pathogenesis of MC

Can microvascular invasion in hepatocellular carcinoma be predicted by diagnostic imaging? A critical review

Imaging still has a limited capacity to detect microvascular invasion (mVI). The objective of this critical review is the evaluation of the most significant predictors of mVI in hepatocellular carcinoma (HCC) detectable by computed tomography, PET/computed tomography and MRI using a mathematical model. We systematically reviewed 15 observational studies from 2008 to 2018 to analyze factors with most impact on mVI detection. The most significant predictors of mVI correlating with imaging techniques were considered. From 1902 patients considered, we individuated 30 total predictors of mVI in a multivariate analysis. The most frequent predictors related to the highest presence with mVI in HCC were: \u3b1-fetoprotein (p &lt; 0.0001), tumor size (p &lt; 0.0001) and number of HCC nodules (p = 0.0020)

Value of IL28B genotyping in patients with HCV-related mixed cryoglobulinemia: results of a large, prospective study

HCV-related mixed cryoglobulinemia (MC) is characterized by clonal expansion of B-cells producing a polyreactive natural antibody (rheumatoid factor) and interferon (IFN)-based therapy is the first therapeutic option in mild-moderate MC. Single nucleotide polymorphisms (SNPs) proximal to genes involved in the innate response (IL28B/IFN-λ gene family) are strongly associated with spontaneous and IFN-induced viral clearance in hepatitis C, but no data exist about their role in HCV-positive MC (MC-HCV). A large cohort of MC-HCV patients was studied in order to evaluate the influence of IL28B genotype on the response to treatment and/or the evolution to MC of HCV infection. The rs12979860/rs8099917 IL28B polymorphisms were analyzed in 481 consecutive HCV-positive subjects (250 with MC-HCV and 231 without MC -controls-) using Real-time PCR and direct sequencing. 115 MC-HCV patients received standard anti-HCV therapy and the results were evaluated according to the IL28B SNP distribution. Similar IL28B SNPs allele frequencies were recorded for MC-HCV patients and controls. IL28B major allele homozygosis (for both SNPs tested) was tightly correlated with virological and clinical response (p=0.002). A statistically significant association was limited to “difficult-to-treat” (G1/4) HCV genotypes. The IL28B genotype was a strong independent predictor of response (p=0.007, O.R. 6.06; C.I. 1.65-22.22). The IL28B genotype was confirmed to be a useful predictor of response to IFN-based therapy in also MC-HCV patients. The very close correlation between IL28B SNPs distribution, virological and clinical response definitively confirmed the key role played by HCV in MC. Conversely, the IL28B genotype does not seem to influence the evolution to MC