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1.
European Journal of Human Genetics ; 31(Supplement 1):627-628, 2023.
Article in English | EMBASE | ID: covidwho-20235387

ABSTRACT

Background/Objectives: COVID-19 still represents a lifethreatening disease in individuals with a specific genetic background. We successfully applied a new Machine Learning method on WES data to extract a set of coding variants relevant for COVID- 19 severity. We aim to identify personalized add-on therapy. Method(s): A subset of identified variants, "actionable" by repurposed drugs, were functionally tested by in vitro and in vivo experiments. Result(s): Males with either rare loss of function variants in the TLR7 gene or L412F polymorphism in the TLR3 gene benefit from IFN-gamma, which is specifically defective in activated PBMCs, restoring innate immunity. Females heterozygous for rare variants in the ADAMTS13 gene and males with D603N homozygous polymorphism in the SELP gene benefit from Caplacizumab, which reduces vWF aggregation and thrombus formation. Males with either the low-frequency gain of function variant T201M in CYP19A1 gene or with poly-Q repeats >=23 in the AR gene benefit from Letrozole, an aromatase inhibitor, which restores normal testosterone levels, reducing inflammation and which rescues male golden hamsters from severe COVID-19. Conclusion(s): By adding these commonly used drugs to standard of care of selected patients, the rate of intubation is expected to decrease consistently, especially in patients with high penetrance rare genetic markers, mitigating the effect of the pandemic with a significant impact on the healthcare system.

2.
Clinical and Experimental Rheumatology ; 41(2):452, 2023.
Article in English | EMBASE | ID: covidwho-2293787

ABSTRACT

Background. Rituximab (RTX) is a chimeric monoclonal antibody that binds the CD20 molecule on the surface of B cells and leads to B cell depletion. RTX is recommended by the European League Against Rheumatism (EULAR) as off-label in patients affected by idiopathic inflammatory myopathies (IIM). The real-world experience has shown that hypogammaglobulinemia occurring early after anti-CD20 treatment can be multifactorial (active disease, effect of other drugs) and usually transient, with a minimal increase in the risk of infections. The present study aimed to analyse the differences in the rate of RTX-associated hypogammaglobulinemia in a cohort of IIM patients in clinical practice, as well as the onset of major infections and its correlation with hypogammaglobulinemia. Methods. Patients followed at Rheumatology Unit of Siena University Hospital from January 2020 to September 2021 were retrospectively enrolled. Inclusion criteria were as follows: fulfilment of disease-specific classification criteria 2017 EULAR criteria and /or Peter and Bohan criteria for dermatomyositis (DM) and polymyositis (PM), positivity of anti-synthetase antibody and typical clinical features for anti-synthetase syndrome (ASS) and the measurement of serum Ig levels at the time of RTX administration (maximum 2 weeks before) (T0) and 6 (T1) to 12 (T2) months later, consistently with previous studies. Ig serum levels, measured by standard nephelometry (normal ranges: IgG 700-1600 mg/dL, IgM 40-240 mg/dL, IgA 70-400 mg/dL) were assessed as part of routine clinical care. Hypogammaglobulinemia was defined as moderate (serum IgG <600 mg/dL) and severe (IgG <400 mg/dL), as previously reported. Results. Seven patients (mean+/-SD, 57.3+/-19.7 years;7 female) were enrolled. Three of them had diagnosis of DM, three ASS and one PM. Two patients showed MDA5-positivity, two JO1-positivity, one TIF1-gamma-positivity, one PL7-positivity and the other one PM/Scl-positivity. All patients had at least two organs involved, and 4 out of 7 (57%) suffered from interstitial lung disease. Before starting RTX treatment, three and four patients underwent at least one and two synthetic immunosuppressants. All patients underwent low dosage of corticosteroids, and four patients underwent concomitant synthetic immunosuppressants (2 hydroxychloroquine and 2 MTX). IgG concentrations were statically lower at T2 compared to those at baseline (p=0.0391). None of them showed severe hypogammaglobulinemia. Similarly, IgM concentration significantly decreased at T2 compared to those at baseline (p=0.0078). Two patients showed major infections and two patients had paucisymptomatic COVID-19 (one of them had twice). Corticosteroids dosages were inversely correlated with IgG T2 concentrations (p=0.040, r=-0.919). Conclusion. Hypogammaglobulinemia following RTX is uncommon in IIM and is more likely in patients with high glucocorticoids, immunosuppressants and CYC exposure. IgG monitoring at least 6 months after RTX treatment may be useful in stratifying patients to identify those who require closer monitoring. These results shine a spotlight for increased awareness of the role of immunoglobulin measurement before maintenance doses of RTX.

3.
Annals of the Rheumatic Diseases ; 81:970, 2022.
Article in English | EMBASE | ID: covidwho-2009127

ABSTRACT

Background: Vaccinations against SARS-CoV-2 represent a fundamental tool in controlling the pandemic. To date, data on the safety of anti-SARS-CoV-2 vaccines in patients with rare rheumatic diseases, such as systemic vasculitis, are limited. Objectives: In this study we aimed at evaluating the safety of anti-SARS-CoV-2 vaccines in a multicentric cohort of patients with systemic vasculitis. Methods: Patients with systemic vasculitis from two Rheumatology centres who had received anti-SARS-CoV-2 vaccine were retrospectively examined. The primary outcome was to evaluate, in this multi-centric cohort, the occurence of a disease fare after the administration of the vaccine, defned as development of clinical manifestations related to vasculitis with a concomitant increase in serum infammatory markers. As a secondary outcome we aimed at evaluating, in a monocentric cohort of patients with vasculitis, the occurrence of adverse events (AEs) following vaccine administration compared to healthy controls (HC). Results: We examined 111 patients with systemic vasculitis (n=69 female, n=42 male), with a mean age of 64.3 (± 13) years. Sixty had ANCA-associated vas-culitis (AAV), fourty-two had Giant-Cell Arterities (GCA), five had Periarteritis Nodosa, four had Takayasu's arteritis. One-hundred and five patients received a mRNA vaccine and six a viral vector one. A disease fare occurred in only 2 patients (1.8%) after the frst dose of a mRNA vaccine: both had AAV (microscopic poliangioitis) and developed a pulmunary disease fare (respiratory failure requiring hospitalization and treatment with high-dose glucocorticoids). Of note, one of these patients had multiple previous comorbidities, including a severe COPD. Multivaried analysis, adjusted for age and sex, performed in a single monocentric cohort of patients with systemic vasculitis [n=60 (39 AAV, 21 GCA), 37 female, 23 male, mean age 71 (± 12.5) years] demonstrated a statistically sig-nifcant higher frequency of AEs in vasculitis patients compared to HC (p=0.015) after the frst dose of vaccination. No signifcant differences in the frequency of AEs in vasculitis patients compared to HC after the second dose were detected. All the AEs were mild in both groups (malaise was the most frequently reported);no serious AEs were reported. Conclusion: Our data show a very low incidence of disease fares after the administration of anti-SARS-CoV-2 vaccines in patients with systemic vasculitis. Patients with systemic vasculitis seem more prone to develop mild AEs after the frst dose of the vaccine. Taken together, this data suggest a good risk profile for anti-SARS-CoV-2 vaccine in patients with systemic vasculitis.

4.
Annals of the Rheumatic Diseases ; 81:939, 2022.
Article in English | EMBASE | ID: covidwho-2008908

ABSTRACT

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination plays a crucial role as pivotal strategies to curb the coronavirus dis-ease-19 (COVID-19) pandemic. Despite the mass-scale vaccination, literature data about the incidence of disease fares in IIM patients are still not reported as well as the immunological condition. Objectives: The present study aimed to describe the clinical status of patients affected by IIM after vaccination against COVID19 in order to assess the number of relapses or immune-mediated reactions in a cohort of Italian patients with such disease. Methods: We included all patients affected by IIM and followed by Myositis Clinic, Rheumatology and Respiratory Diseases Units, Siena University Hospital, Bari University Hospital, Policlinico Umberto I, Sapienza University, Rome, and Policlinico Paolo Giaccone, Palermo. Inclusion criteria were a recent (<3 months) clinical and serological assessment before the survey and a defnite diagnosis of dermatomyosi-tis, polymyositis and anti-synthetase syndrome. All patients underwent a telephone survey in order to establish their clinical status and potential relapses after vaccination. Results: A total of 119 IIM patients (median, IQR 58 (47-66) years;32 males) were consecutively enrolled. Fifty had a diagnosis of DM, 39 had PM and 30 had ASS. The median months of disease duration was 79.62±83.98. According to number of organs involvement, forty-two had only one, 45 had two organs involvement, 20 had three, 11 had four and one had five. The majority of them received two doses of COVID-19 vaccine, except four patients who refused the vaccination: 94 (78.9%) Cominarty, 16 (13.4%) Moderna, 5 (0.04%) AZ. Seven (0.06%) patients had fare after vaccination, the majority of them were mild except one major with three organs involved and one life-threatening with systemic involvement. In order to understand or predict the effect of demographic and clinical features on the fare development after vaccination, a logistic regression analysis was performed. The goodness-of-ft statistics showed a Chi2 associated with the Log ratio (L.R.) of 0.045. From the probability associated with the Chi-square tests, the Type II analysis showed the variable that most influences the development of fare was the number of organs involved (p=0.047). Sixty-eight patients received the third dose of COVID-19 vaccination: 51 (75%) Cominarty and 17 (25%) Moderna. Only one (0.01%) patient (the same who had life-threatening fare with systemic involvement after two doses) had fare after third dose and eventually died. Conclusion: Vaccines against SARS-CoV2 have provided, both in registratory studies and in preliminary real-life evidence, an overall good efficacy and safety. Nevertheless, only scanty data are available for rheumatic patients in general and the ones affected by IIM in particular. To the best of our knowledge, ours represent the largest cohort of IIM patients in which immunogenicity of anti-SARS-CoV2 vaccine was assessed. In line with real-life data from other diseases, we found a non-statistically signifcant risk of relapse in our patients, which occurred seldom, usually mild and in patients with a more severe and aggressive course of disease.

6.
Cytokine ; 141: 155455, 2021 05.
Article in English | MEDLINE | ID: covidwho-1051584

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome caused by novel coronavirus 2 (SARS-CoV-2) emerged in Wuhan (China) in December 2019. Here we evaluated a panel of biomarkers to phenotype patients and to define the role of immuno-inflammatory mediators as biomarkers of severity. MATERIALS AND METHODS: Serum samples were obtained from 24 COVID-19 patients on admission to hospital, before any treatment or infusion of intravenous steroids or invasive ventilation. KL-6 IL-6 and C-peptide were measured by chemiluminescent enzyme immunoassay. IL-6 assay was validated for accuracy and precision. The validity of variables used to distinguish severe from mild-to-moderate patients was assessed by areas under curves (AUC) of the receiver operating characteristic (ROC) and logistic regression was performed to combine parameters of the two groups. RESULTS: In the severe group, IL-6, CRP and KL-6 concentrations were significantly higher than in mild-to-moderate patients. KL-6, IL-6 and CRP concentrations were directly correlated with each other. ROC curve analysis of the logistic regression model including IL-6, KL-6 and CRP showed the best performance with an AUC of 0.95. CONCLUSIONS: Besides corroborating previous reports of over-expression of IL-6 in severe COVID-19 patients requiring mechanical ventilation, analytical determination of other mediators showed that IL-6 concentrations were correlated with those of KL-6 and CRP. The combination of these three prognostic bioindicators made it possible to distinguish severe COVID-19 patients with poor prognosis from mild-to-moderate patients.


Subject(s)
Biomarkers/blood , COVID-19/blood , COVID-19/immunology , Cytokines/blood , Pandemics , SARS-CoV-2 , Aged , C-Peptide/blood , C-Reactive Protein/metabolism , COVID-19/epidemiology , Case-Control Studies , Female , Humans , Inflammation Mediators/blood , Interleukin-6/blood , Italy/epidemiology , Male , Middle Aged , Mucin-1/blood , Prognosis , Severity of Illness Index
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