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MxA mRNA decrease preceding NAb detection in IFN?-treated MS patients.

ABSTRACT: BACKGROUND:Multiple sclerosis (MS) patients treated with interferon beta (IFN?) are at risk of a declining response to treatment because of the production of IFN?-neutralizing antibodies (NAbs). The expression of Myxovirus resistance protein A (MxA) mRNA is regarded as a marker of IFN? bioactivity. AIMS:The aim of this study was to analyze the kinetics of MxA mRNA expression during long-term IFN? treatment and assess its relationship to NAb production. METHODS:A prospective, observational, open-label, non-randomized study was designed in multiple sclerosis patients starting IFN? treatment. NAbs and MxA mRNA were monitored every six months. RESULTS:119 patients were consecutively enrolled and 107 were included in the final analysis. Both the presence of NAbs and a decrease in MxA mRNA below the cut off were revealed in 15 patients, however, in six patients (40%) positivity for NAbs was preceded by the decrease in MxA mRNA. In addition, a further six patients showing a decline in MxA mRNA did not have detectable NAbs. CONCLUSION:Our data indicate that quantification of MxA mRNA is a more sensitive identifier of loss of IFN? efficacy than the NAb positivity.

SUBMITTER: Libertinova J

PROVIDER: S-EPMC5346526 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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MxA mRNA decrease preceding NAb detection in IFNβ-treated MS patients.

Libertinova Jana J Meluzinova Eva E Matoska Vaclav V Zajac Miroslav M Kovarova Ivana I Havrdova Eva E Horakova Dana D Tomek Ales A Marusic Petr P Bojar Martin M

Brain and behavior 20170209 3

<h4>Background</h4>Multiple sclerosis (MS) patients treated with interferon beta (IFNβ) are at risk of a declining response to treatment because of the production of IFNβ-neutralizing antibodies (NAbs). The expression of Myxovirus resistance protein A (MxA) mRNA is regarded as a marker of IFNβ bioactivity.<h4>Aims</h4>The aim of this study was to analyze the kinetics of MxA mRNA expression during long-term IFNβ treatment and assess its relationship to NAb production.<h4>Methods</h4>A prospective ...[more]

PMID: 28293479

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Project description:Even though anti-interferon beta (IFNβ) antibodies are the main determinants of IFNβ bioactivity loss and Myxovirus-resistance protein A (MxA) is the most established marker of IFNβ biological activity in IFNβ-treated multiple sclerosis patients, their usefulness in the routine clinical practice is still debated. Therefore, 118 multiple sclerosis patients naïve for treatment were enrolled for a 3-year longitudinal observational study mimicking the conditions of a real-world setting. In order to evaluate the kinetics of bioactivity loss in blood samples obtained every 6 months after therapy initiation, MxA and interferon receptor isoform/subunit mRNA were quantified by real-time PCR, anti-IFNβ binding antibodies were detected by radioimmunoprecipitation, and neutralizing antibodies by cytopathic effect inhibition assay. Clinical measures of disease activity and disability progression were also obtained at all time points. We found that, at the individual-patient level, the response to IFNβ therapy was extremely heterogeneous, including patients with stable or transitory, early or late loss of IFNβ bioactivity, and patients with samples lacking MxA mRNA induction in spite of absence of antibodies. No interferon receptor isoform alterations that could explain these findings were found. At the group level, none of these biological features correlated with the measures of clinical disease activity or progression. However, when MxA mRNA was evaluated not at the single time point as a dichotomic marker (induced vs. non-induced), but as the mean of its values measured over the 6-to-24 month period, the increasing average MxA predicted a decreasing risk of short-term disability progression, independently from the presence of relapses. Therefore, a more bioactive treatment, even if unable to suppress relapses, reduces their severity by an amount that is proportional to MxA levels. Together with its feasibility in the routine laboratory setting, these data warrant the quantification of MxA mRNA as a primary tool for a routine monitoring of IFNβ therapy.

Project description:BackgroundIn patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) affects immune response to antigens. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response.MethodsWe designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech,Inc or mRNA-1273, Moderna Tx,Inc). A blood collection before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche-Diagnostics). The log-transform of the antibody levels was analyzed by multivariable linear regression.Findings780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariable analysis, the antibody levels of patients on ocrelizumab (201-fold decrease (95%CI=128-317), p < 0·001), fingolimod (26-fold decrease (95%CI=16-42), p < 0·001) and rituximab (20-fold decrease (95%CI=10-43), p < 0·001) were significantly reduced as compared to untreated patients. Vaccination with mRNA-1273 resulted in a systematically 3·25-fold higher antibody level (95%CI=2·46-4·27) than with the BNT162b2 vaccine (p < 0·001). The antibody levels on anti-CD20 therapies correlated to the time since last infusion, and rituximab had longer intervals (mean=386 days) than ocrelizumab patients (mean=129 days).InterpretationIn pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·25-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod. Combining our data with those on the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS.FundingFISM[2021/Special-Multi/001]; Italian Ministry of Health'Progetto Z844A 5 × 1000'.

Project description:Background: Neutralizing anti-drug antibodies (ADA) can greatly reduce the efficacy of biopharmaceuticals used to treat patients with multiple sclerosis (MS). However, the biological factors pre-disposing an individual to develop ADA are poorly characterized. Thus, there is an unmet clinical need for biomarkers to predict the development of immunogenicity, and subsequent treatment failure. Up to 35% of MS patients treated with beta interferons (IFNβ) develop ADA. Here we use machine learning to predict immunogenicity against IFNβ utilizing serum metabolomics data. Methods: Serum samples were collected from 89 MS patients as part of the ABIRISK consortium-a multi-center prospective study of ADA development. Metabolites and ADA were quantified prior to and after IFNβ treatment. Thirty patients became ADA positive during the first year of treatment (ADA+). We tested the efficacy of six binary classification models using 10-fold cross validation; k-nearest neighbors, decision tree, random forest, support vector machine and lasso (Least Absolute Shrinkage and Selection Operator) logistic regression with and without interactions. Results: We were able to predict future immunogenicity from baseline metabolomics data. Lasso logistic regression with/without interactions and support vector machines were the most successful at identifying ADA+ or ADA- cases, respectively. Furthermore, patients who become ADA+ had a distinct metabolic response to IFNβ in the first 3 months, with 29 differentially regulated metabolites. Machine learning algorithms could also predict ADA status based on metabolite concentrations at 3 months. Lasso logistic regressions had the greatest proportion of correct classifications [F1 score (accuracy measure) = 0.808, specificity = 0.913]. Finally, we hypothesized that serum lipids could contribute to ADA development by altering immune-cell lipid rafts. This was supported by experimental evidence demonstrating that, prior to IFNβ exposure, lipid raft-associated lipids were differentially expressed between MS patients who became ADA+ or remained ADA-. Conclusion: Serum metabolites are a promising biomarker for prediction of ADA development in MS patients treated with IFNβ, and could provide novel insight into mechanisms of immunogenicity.

Dataset Information

MxA mRNA decrease preceding NAb detection in IFN?-treated MS patients.

Publications

MxA mRNA decrease preceding NAb detection in IFNβ-treated MS patients.

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