Multiple sclerosis, the most common cause of neurological disability in young population after trauma, represents a significant public health burden. Current challenges associated with management of multiple sclerosis (MS) patients stem from the lack of biomarkers that might enable stratification of the different clinical forms of MS and thus prompt treatment for those patients with progressive MS, for whom there is currently no therapy available. In the present work we analyzed a set of thirty different plasma cytokines, chemokines and growth factors present in circulation of 129 MS patients with different clinical forms (relapsing remitting, secondary progressive and primary progressive MS) and 53 healthy controls, across two independent cohorts. The set of plasma analytes was quantified with Luminex xMAP technology and their predictive power regarding clinical outcome was evaluated both individually using ROC curves and in combination using logistic regression analysis. Our results from two independent cohorts of MS patients demonstrate that the divergent clinical and histology-based MS forms are associated with distinct profiles of circulating plasma protein biomarkers, with distinct signatures being composed of chemokines and growth/angiogenic factors. With this work, we propose that an evaluation of a set of 4 circulating biomarkers (HGF, Eotaxin/CCL11, EGF and MIP-1β/CCL4) in MS patients might serve as an effective tool in the diagnosis and more personalized therapeutic targeting of MS patients.

IntroductionConventional or biologic disease-modifying anti-rheumatic drugs (DMARDs) are the mainstay of treatment for systemic autoimmune disease (SAD). Infectious complications are a major concern in their use.ObjectiveTo evaluate the clinical benefit of sublingual mucosal polybacterial vaccines (MV130 and MV140), used to prevent recurrent respiratory and urinary tract infections, in patients with SAD and secondary recurrent infections following conventional or biologic DMARDs.MethodsAn observational study in SAD patients with recurrent respiratory tract infections (RRTI) and/or recurrent urinary tract infections (RUTI) was carried out. All patients underwent mucosal (sublingual) vaccination with MV130 for RRTI or with MV140 for RUTI daily for 3 months. Clinical evaluation was assessed during 12 months of follow-up after the first dose, i.e., 3 months under treatment and 9 months once discontinued, and compared with the previous year.ResultsForty-one out of 55 patients completed 1-year follow-up. All patients were on either conventional or biologic DMARDs. A significant decrease in the frequency of RUTI (p<0.001), lower respiratory tract infections (LRTI) (p=0.009) and upper respiratory tract infections (URTI) (p=0.006) at 12-mo with respect to the previous year was observed. Antibiotic prescriptions and unscheduled medical visits decreased significantly (p<0.020) in all groups. Hospitalization rate also declined in patients with RRTI (p=0.019). The clinical benefit demonstrated was concomitant to a significant increase in both anti-S. pneumoniae IgA and IgG antibodies following MV130 vaccination.ConclusionsSublingual polybacterial vaccines prevent recurrent infections in patients with SAD under treatment with immunosuppressant therapies, supporting a broad non-specific anti-infectious effect in these patients.

BackgroundMultiple sclerosis (MS) is a chronic, progressive autoimmune disease of the central nervous system in which inflammation plays a key role in the induction, development, and progression. Most of the MS patients present with relapsing–remitting (RR) form, characterized by flare-ups followed by periods of recovery. Many inflammatory and anti-inflammatory cytokines have been proposed as backers in MS pathogenesis, and the balance between these differing cytokines can regulate MS severity. Interferon (IFN)-β, a current disease-modifying therapy for MS, has demonstrated beneficial effects in reducing disease severity in MS patients. However, its immunoregulatory and anti-inflammatory actions in MS are not wholly understood. The aim of the study was to define, in clinically stable patients with RR-MS, the serum concentration of several cytokines, canonical or not, and their modulation by IFN-β therapy.MethodsRelapsing–remitting-MS patients were enrolled and diagnosed according to revised Mc Donald Diagnostic Criteria. A set of cytokines [including non-canonical neurotransmitter acetylcholine (ACh) and adipokines] and B-cell differentiation molecules, as potential biomarkers, were evaluated in 30 non-treated RR-MS patients compared to 30 IFN-β-treated MS patients and 30 age, gender, and body mass index-matched healthy controls (HC).ResultsNaïve MS patients showed significantly higher levels of interleukin (IL)-1β, IL-12/IL-23p40, IL-18, high-mobility group box protein-1, and IL-18 binding protein (IL-18BP) than MS-treated patients (p < 0.001 for all) and HC (p < 0.01). IFN-β therapy has significantly downmodulated IL-1β, IL-12/IL-23p40, IL-18 to normal levels (p < 0.001), whereas it has decreased IL-18BP (p < 0.001). ACh was significantly higher in the IFN-β-treated than HC and non-treated MS patients (p < 0.001). No significant differences were observed either in adipokines concentration or in B-cell-associated molecules among the three study groups.ConclusionAlthough more experimental evidence are required, we speculate that the efficacy of treatment of MS with IFN-β is mediated, at least in part, by its ability to work on several levels to slow down the disease progression. Proposed actions include the modulation of IL-1–inflammasome axis and modulation of ACh, B-cell activating factor/a proliferation-inducing ligand system, and several adipokines.