Teriflunomide and Epstein–Barr virus in a Spanish multiple sclerosis cohort: in vivo antiviral activity and clinical response

Biomarker; Multiple sclerosis; TeriflunomideBiomarcador; Esclerosi múltiple; TeriflunomidaBiomarcador; Esclerosis múltiple; TeriflunomidaBackground: Epstein–Barr virus (EBV) and human herpesvirus 6 (HHV-6) have been associated with multiple sclerosis (MS). Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing forms of MS. In the preclinical Theiler’s murine encephalitis virus model of MS, the drug demonstrated an increased rate of viral clearance versus the vehicle placebo. Furthermore, teriflunomide inhibits lytic EBV infection in vitro. Objective: 1. To evaluate the humoral response against EBV and HHV-6 prior to teriflunomide treatment and 6 months later. 2. To correlate the variation in the humoral response against EBV and HHV-6 with the clinical and radiological response after 24 months of treatment with teriflunomide. 3. To analyze the utility of different demographic, clinical, radiological, and environmental data to identify early biomarkers of response to teriflunomide. Methods: A total of 101 MS patients (62 women; mean age: 43.4 years) with one serum prior to teriflunomide onset and another serum sample 6 months later were recruited. A total of 80 had been treated for at least 24 months, 13 had stopped teriflunomide before 24 months, and 8 were currently under teriflunomide therapy but with less than 24 months of follow-up. We analyzed the levels of the viral antibodies titers abovementioned in serum samples with ELISA commercial kits, and the levels of serum neurofilament light chain (Nf-L). Results: Antiviral antibody titers decreased for EBNA-1 IgG (74.3%), VCA IgG (69%), HHV-6 IgG (60.4%), and HHV-6 IgM (73.3%) after 6 months of teriflunomide. VCA IgG titers at baseline correlated with Nf-L levels measured at the same time (r = 0.221; p = 0.028) and 6 months later (r = 0.240; p = 0.017). We found that higher EBNA-1 titers (p = 0.001) and a higher age (p = 0.04) at baseline were associated with NEDA-3 conditions. Thus, 77.8% of patients with EBNA-1 >23.0 AU and >42.8 years (P50 values) were NEDA-3. Conclusion: Treatment with teriflunomide was associated with a reduction of the levels of IgG antibody titers against EBV and HHV-6. Furthermore, higher EBNA-1 IgG titers prior to teriflunomide initiation were associated with a better clinical response.AM has a technician contract from “REI: Red de Enfermedades Inflamatorias” (RD21/0002/0038). This work was financially supported by Ministerio de Ciencia e Innovación (Proyectos de generación de conocimiento)-Fondo Europeo de Desarrollo Regional (Feder) (PID2021-126041OB-I00) and “Fundación LAIR”

Anti-HHV-6A/B IgG and IgM titers in 216 serum samples collected in relapse (REL.) and in 278 serum samples collected three months before and after the relapse (n = 21 at day–84, n = 20 at day –70, n = 23 at day –56, n = 23 at day –42, n = 25 at day –28, n = 31 at day –14, n = 26 at day 14, n = 21 at day 28, n = 22 at day 42, n = 24 at day 56, n = 23 at day 70, n = 19 at day 84).

<p>A. Anti-HHV-6A/B IgG response. B. Anti-HHV-6A/B IgM response.</p

Clinical and demographic characteristics of the samples and subjects included in the study.

<p>*At least two-years of follow-up with the same disease modifying therapy (DMT) from a base line visit (serum sample extracted before starting the DMT) to a 24 months visit.</p><p>**EDSS: Expanded Disability Status Scale. MSSS: Multiple Sclerosis Severity Score.</p><p>***It was included: adverse events, pregnancy, drug withdrawal for lack of efficacy, and patient decision.</p

Association between the anti-HHV-6A/B IgG titers at the 2-years visit with the progression of the disease (A) and the activity of the disease (B) after two years of treatment with the different DMTs.

<p>A. 9/18 MS patients with titers >44 PU after 2-years of treatment were free of progression vs. 39/54 with titers between 33–44 PU vs. 74/104 with titers between 22–33 PU vs. 82/108 with titers between 11–22 PU vs. 15/17 with titers <11 PU. B. 10/18 MS patients with titers >44 PU after 2-years of treatment were free of relapses vs. 37/54 with titers between 33–44 PU vs. 74/104 with titers between 22–33 PU vs. 80/108 with titers between 11–22 PU vs. 14/17 with titers <11 PU.</p

Prevalences and mean titers of the anti-HHV-6A/B IgG and IgM antibodies before and after 2-years of treatment with the different DMTs.

<p>TOTAL: prevalence and mean titers of all the different disease modifying therapies (DMTs); IFN-beta: interferon beta; GA: glatiramer acetate; NTZ: natalizumab.</p

Predictive factors and early biomarkers of response in multiple sclerosis patients treated with natalizumab.

There are an increasing number of treatments available for multiple sclerosis (MS). The early identification of optimal responders to individual treatments is important to achieve individualized therapy. With this aim, we performed a multicenter retrospective longitudinal study including 186 MS patients treated with natalizumab who were followed for 2 years. We analyzed the following variables at recruitment: sex, current age, age at disease onset, disease duration, EDSS, number of T2 and Gd + lesions, IgG and IgM oligoclonal bands, HLA class II (DR, DRB, DQA, DQB, and DRB1*15:01), IgG and IgM antibody titers against human herpesvirus 6 (HHV-6) and the antibody response to Epstein-Barr virus (EBV) through the measurement of the anti-EBNA-1 and anti-VCA IgG titers, in relation to clinical response (no relapses or disability progression), and to NEDA-3 (no evidence of disease activity in terms of clinical response and no changes in MRI scans either) after 2-years follow-up. Baseline EDSS score, baseline EBNA-1 IgG titers and percentage change of HHV6 IgG titers between baseline and 6 month visits were significantly different in clinical responders and in NEDA-3 status (all of them remained significant in the multivariate analysis). We identified three variables for the early identification of natalizumab optimal responders in a rapid and cost-effective approach

MHC2TA mRNA levels and human herpesvirus 6 in multiple sclerosis patients treated with interferon beta along two-year follow-up

<p>Abstract</p> <p>Background</p> <p>In previous studies we found that MHC2TA +1614 genotype frequency was very different when MS patients with and without human herpesvirus 6 (HHV-6) in serum samples were compared; a different clinical behavior was also described. The purpose of the study was: 1. To evaluate if MHC2TA expression in MS patients was influenced by interferon beta (IFN-beta) treatment. 2. To study MHC2TA expression in MS patients with and without minor allele C. 3. To analyze the relation between MHC2TA mRNA levels and HHV-6 active infection in MS patients.</p> <p>Methods</p> <p>Blood and serum samples of 154 MS patients were collected in five programmed visits: basal (prior to beginning IFN-beta treatment), six, twelve, eighteen and twenty-four months later. HHV-6 in serum and MHC2TA mRNA levels were evaluated by PCR and RT-PCR, respectively. Neutralizing antibodies (NAbs) against IFN-beta were analyzed by the cytopathic effect assay.</p> <p>Results</p> <p>We found that MHC2TA mRNA levels were significantly lower among MS patients with HHV-6 active infection at the basal visit (without treatment) than in those MS patients without HHV-6 active infection at the basal visit (p = 0.012); in all the positive samples we only found variant A. Furthermore, 58/99 (58.6%) MS patients without HHV-6 along the five programmed visits and an increase of MHC2TA expression after two-years of IFN-beta treatment were clinical responders vs. 5/21 (23.8%) among those MS patients with HHV-6 and a decrease of MHC2TA mRNA levels along the two-years with IFN-beta treatment (p = 0.004); no differences were found between patients with and without NAbs.</p> <p>Conclusions</p> <p>MHC2TA mRNA levels could be decreased by the active replication of HHV-6; the absence of HHV-6 in serum and the increase of MHC2TA expression could be further studied as markers of good clinical response to IFN-beta treatment.</p