Wide Cytokine Analysis in Cerebrospinal Fluid at Diagnosis Identified CCL-3 as a Possible Prognostic Factor for Multiple Sclerosis.

Background: Apart from IgG oligoclonal bands, no other biomarker has, to date, been validated for diagnostic and/or prognostic purposes in multiple sclerosis (MS). Aim: To investigate a wide panel of cytokines and chemokines in the cerebrospinal fluid (CSF) of relapsing-remitting MS (RRMS) patients and evaluate their association with clinical and magnetic resonance imaging (MRI) parameters, as well as their predictive clinical value. Methods: Fifty-one RRMS at clinical onset and 17 other not inflammatory neurological disorders (ONINDs) underwent brain MRI (including 3D-T1, 3D-FLAIR, and 3-DIR sequences) and CSF examination. Eighty-seven cytokines and chemokines were analyzed in CSF by Multiplex technology. Results: Compared to ONIND, CXCL-10, CXCL-11, CXCL-13, CCL-1, CCL-2, CCL-3, CCL-22, IL-16, and BAFF were significantly (p < 0.05) increased in RRMS CSF. However, only CCL-3 was associated with both MS diagnosis and IgGOB detection. Based on a 95%CI in ONIND (cut-off value: 0.798 pg/ml) and ROC analysis (cut-off value: 0.495 pg/ml), RRMS patients were stratified in CCL-3high (>0.736 pg/mL), CCL-3medium, and CCL-3low (<0.495 pg/ml). Survival analysis disclosed a strong association between high CCL-3 values and disease reactivation (OR = 4.9, 95%CI: 1.8-13.3, p < 0.005) in the following 2 years. Conclusions: CCL-3 deserves further investigation as a candidate prognostic biomarker for RRMS.

Peripheral imbalanced TFH/TFR ratio correlates with intrathecal IgG synthesis in multiple sclerosis at clinical onset.

BACKGROUND: Alteration of T-follicular helper (TFH) and regulatory (TFR) subpopulations may contribute to the development of auto-reactive B-cell. OBJECTIVE: To investigate whether changes in TFH and TFR subsets are associated with abnormal IgG synthesis in blood and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. METHODS: Paired blood and CSF samples were obtained from 31 untreated relapsing-remitting multiple sclerosis (RRMS) patients at diagnosis. Peripheral blood TFH (CD3+CD4+CXCR5+CD25-CD127+), TFR (CD3+CD4+CXCR5+CD25+CD127dim), conventional T-Helper (TH, CD3+CD4+CXCR5-CD25-CD127+), and regulatory T-cells (T-Reg, CD3+CD4+CXCR5-CD25+CD127dim) were analyzed in all RRMS patients and in 13 healthy controls (HCs). Qualitative and quantitative intrathecal IgG synthesis was evaluated in RRMS patients, who were then further subclassified according to the presence of IgG oligoclonal bands in blood and/or CSF. RESULTS: Compared to HC, RRMS had lower TFR percentage ( p < 0.01) and higher TFH/TFR ratio ( p < 0.001). In RRMS, TFH/TFR ratio correlated with both qualitative ( r = 0.56, p < 0.005) and quantitative intrathecal IgG synthesis (IgG Index: r = 0.78; IgGLoc: r = 0.79; IgGIF: r = 0.76, all p < 0.001). Patients with the highest TFH/TFR ratios had higher percentages of circulating B-cells (36.1 ± 35.2%, p < 0.05). CONCLUSION: In RRMS, increased TFH/TFR ratio associates with abnormal IgG production in blood and CSF, suggesting that antibody-producing cells, derived from deregulated peripheral germinal center reaction, colonize the CNS.

Multiple Sclerosis Incidence and Prevalence Trends in the Province of Padua, Northeast Italy, 1965-2018.

BACKGROUND: Previous studies, dating back to the 1960s disclosed a progressive increase in multiple sclerosis (MS) incidence and prevalence in the Province of Padua. To further analyze whether this trend is the effect of the improved diagnostic procedures or is primarily related to a real increase risk of MS, we analyzed MS incidence and prevalence of the 5-year period 2011-2015. METHODS: Patients with a diagnosis of MS or clinically isolated syndrome highly suggestive of MS were included in the study. All available sources of clinical and administrative information were evaluated. Mean annual incidence in the 5-year period 2011-2015 and the prevalence on December 31, 2015 were calculated. RESULTS: The 2011-2015 mean incidence was 6.5/100,000/year, 7.9 for females, 4.1 for males. The overall prevalence was 182/100,000, 241 for females, 116 for males. Compared to the 2000-2009 period, mean age at onset, onset-diagnosis delay and F/M ratio did not significantly change. Since the 1960s, incidence and prevalence of MS linearly increased with no interposed plateau periods. CONCLUSIONS: MS incidence and prevalence further and significantly increased in the period 2011-2015. Our 1965-2015 data indicate a real increased risk of MS and stress a role of exogenous factors in MS susceptibility.

NEDA-3 status including cortical lesions in the comparative evaluation of natalizumab versus fingolimod efficacy in multiple sclerosis.

BACKGROUND: Cortical lesions (CLs) are typical of multiple sclerosis (MS) and have been recently incorporated in MS diagnostic criteria. Thus, the 'no evidence of disease activity' (NEDA) definition should now include CLs. The aim of this study was to evaluate the NEDA3 + CL status in natalizumab- or fingolimod-treated relapsing remitting MS (RMS) patients. METHODS: Natalizumab- or fingolimod-treated RMS patients were enrolled in a 2-year longitudinal study based on clinical and magnetic resonance imaging (MRI) evaluations performed respectively biannually and annually. CLs were detected by double inversion recovery. The NEDA3 + CL condition was evaluated at baseline (T0) and at the end of the first (T1) and second (T2) year. RESULTS: Of the 137 RMS patients included in the study, 86 were propensity-matched. At T2, the annualized relapse rate was lower on natalizumab (p = 0.021), but the effect on white matter lesions (p = 0.29) and the proportion of NEDA-3 patients (p = 0.14) were similar in the two treatment arms. At T2, 11.6% natalizumab- and 62.8% fingolimod-treated patients had new CLs (p < 0.001) and a higher proportion of natalizumab-treated patients (55.8% versus 11.6%, p < 0.001) achieved the NEDA3 + CL status (hazard ratio 5.2, p < 0.001). CONCLUSION: The incorporation of CLs in the NEDA-3 definition highlighted the higher efficacy of natalizumab versus fingolimod in suppressing disease activity in RMS patients.