Fingolimod Use for the Treatment of Multiple Sclerosis in a Clinical Practice Setting in Madrid.

OBJECTIVE: To assess the effectiveness and safety of fingolimod use in a Spanish clinical practice setting. METHODS: Retrospective study with multiple sclerosis patients who received at least 1 fingolimod dose between January 2004 and January 2015. Effectiveness and safety data were collected during the entire treatment of each patient. Analysis was performed for the total population and stratified according to prior treatment, sex, and age at treatment initiation. RESULTS: A total of 167 patients were included, 50.9% had prior immunomodulator use, 33.5% natalizumab use, and 15.6% were naive patients. The annual relapse rate (ARR) decreased for the total population at month 12 (62%) and month 24 (84%) (P < 0.0001, in both cases); for naive patients (P < 0.05) and patients with prior immunomodulator use (P < 0.0001); for patients with prior natalizumab use, the ARR kept low after treatment initiation (0.23). After 24 months, the proportion of relapse-free patients was 70% or greater and disability progression-free patients was 80% or greater. No significant differences were observed when the results were compared by prior treatment, sex, or age. Thirty-two patients (19.2%) reported adverse drug reactions and 9.6% discontinued: 4.8% due to adverse drug reactions and 4.8% for lack of effectiveness. CONCLUSIONS: The results support fingolimod use due to clinical effectiveness, tolerability, and ease of administration.

Anti-human herpesvirus 6A/B IgG correlates with relapses and progression in multiple sclerosis.

OBJECTIVE: To analyze the titers of the IgG and IgM antibodies against human herpesvirus 6A/B (HHV-6A/B) in multiple sclerosis (MS) patients treated with different disease modified therapies (DMTs) along two-years of follow-up. METHODS: We collected 2163 serum samples from 596 MS; for 301 MS patients a 2-years follow-up was performed. Serum samples of 337 healthy controls were also analyzed. Anti-HHV-6A/B IgG and IgM were analyzed by ELISA (Panbio). RESULTS: We found that 129/187 (69.0%) MS patients with a decrease of the anti-HHV-6A/B IgG titers after 2-years with DMTs were free of relapses and progression vs. 46/113 (40.7%) of MS patients with an increase of the anti-HHV-6A/B IgG titers (p = 0.0000015); the higher significance was found for natalizumab. Furthermore, we found that anti-HHV-6A/B IgG titers reached their highest value two weeks before the relapse (p = 0.0142), while the anti-HHV-6A/B IgM titers reached their highest value one month before the relapse (p = 0.0344). CONCLUSION: The measurement of the anti-HHV-6A/B IgG titers could be a good biomarker of clinical response to the different DMTs. The increase of the anti-HHV-6A/B IgG and IgM titers predicts the upcoming clinical relapses. However, further longitudinal studies are needed to validate these results.

Anti-JCV antibodies detection and JCV DNA levels in PBMC, serum and urine in a cohort of Spanish Multiple Sclerosis patients treated with natalizumab.

One of the most effective multiple sclerosis (MS) treatment is natalizumab. Nevertheless, it has been associated with an increased risk of progressive multifocal leukoencephalopathy (PML) caused by the JC virus (JCV). Our main objective was to assess the utility of testing JCV-DNA, apart from anti-JCV antibodies, to determine which natalizumab-treated MS patients has been previously in contact with the virus. For this purpose, 138 MS natalizumab/non-natalizumab treated patients participated in several studies. Cross-sectional study (CS): association of several epidemiological variables with anti-JCV antibodies and JCV-DNA levels in PBMC/serum/urine. First longitudinal study (A): evaluation of JCV-DNA prevalence in urine throughout the treatment. Second longitudinal study (B): simultaneous assessment of antibodies and viral DNA levels in PBMC/serum/urine at two time points. CS: The seropositivity rate for anti-JCV antibodies (62.3 %) and JCV prevalence in urine (59.4 %) were similar; although 26 % of our population was positive only using one of the two techniques. A: The viral prevalence in urine seemed to increase between the baseline visit and the others (Baseline-Visit/V18months, p = 0.006). B: Our rate of positive antibody seroconversion was 36 %. Nearly all patients with detectable JCV-DNA levels in PBMC excreted the virus intermittently in urine; while our PML case, positive in PBMC and serum samples 2 month before the PML, excreted JCV permanently. In conclusion, the determination of JCV DNA levels in urine could be complementary to anti-JCV antibodies for identifying MS patients who has been infected by the JCV. Further research would be necessary to understand the different JCV excretion profiles in urine.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Herpesvirus active replication in multiple sclerosis: a genetic control?

Although the etiology of multiple sclerosis (MS) is unknown, it is generally believed that genetic, immunologic, and environmental factors are involved. The objectives of this study were: 1. to analyze if a genetic control could explain why HHV-6 would be able to actively replicate in a subset of MS patients but not in controls; 2. to study if MS patients with HHV-6 active replication are clinically different from those without HHV-6 active replication. A total of 195 MS patients and 195 controls were analyzed for two SNPs at the MHC2TA locus and two SNPs at the CD46 locus. Furthermore, the MS cohort was analyzed by PCR for the detection of HHV-6 genomes in five serum samples collected every six months along two-year follow-up. We found that 59/195 (30.2%) MS patients had at least one HHV-6 positive serum sample. No statistical significant difference was found for the two genes when the comparison was made between MS patients and controls; however, a statistical significance was found for the two polymorphisms of MHC2TA when we compared MS patients with active replication and controls (p=0.0000004 for rs4774C and p=0.011 for rs3087456G). Furthermore, increased significant differences were found for MHC2TA and CD46 when we compared interferon beta responders and non-responders within MS patients. In conclusion, we describe a gene-environment interaction in MS patients between HHV-6 and MHC2TA and CD46 that should be further studied to clarify if that interaction could be a genetic control. The results show that MS patients without HHV-6 active replication are better responders to interferon beta treatment than those with HHV-6 active replication.