Isoprostanes in clinically isolated syndrome and early multiple sclerosis as biomarkers of tissue damage and predictors of clinical course.

BACKGROUND: Isoprostanes (IsoP) are sensitive biomarkers of oxidative stress. Their cerebrospinal-fluid (CSF) level is increased in several neurological conditions, including multiple sclerosis (MS). In particular, in relapsing-remitting MS, IsoP have been proposed as an index of neurodegenerative processes. The mechanisms leading to neuroaxonal damage in MS are not fully understood but oxidative mechanisms play a substantial role. Although axonal loss is present in MS patients since their first clinical symptoms, IsoP levels at this early stage have not been evaluated yet. OBJECTIVES: The objectives of this study were (a) to assess IsoP levels in CSF of patients with a first clinical attack suggestive of MS; (b) to correlate IsoP levels with magnetic resonance imaging (MRI) measures of brain damage and (c) to assess IsoP value in predicting disease clinical evolution. METHODS: Thirty-nine patients with a first clinical attack suggestive of MS underwent neurological examination, lumbar puncture with IsoP levels quantification and conventional/spectroscopic-MRI. Patients were followed up for 24 months. RESULTS: CSF IsoP levels were higher in patients than controls (mean ± standard deviation (SD) 123.4 ± 185.8 vs 4.5 ± 2.9 pg/ml; p<0.0001) and inversely correlated to normalized brain volume (p=0.04) and N-acetylaspartate/choline (NAA/Cho) (p=0.01). The risk of experiencing clinical relapses differed according to IsoP level: subjects with levels higher than 95 pg/ml (a cut-off value resulting from ROC analysis) were more likely to relapse than patients with levels equal or lower than 95 pg/ml (59% vs 27% respectively; p=0.03). CONCLUSIONS: CSF IsoP might be useful biomarkers of tissue damage in MS with a predictive value of disease course.

Neutralizing antibodies explain the poor clinical response to interferon beta in a small proportion of patients with multiple sclerosis: a retrospective study.

BACKGROUND: Neutralizing antibodies (NAbs) against Interferon beta (IFNbeta) are reported to be associated with poor clinical response to therapy in multiple sclerosis (MS) patients. We aimed to quantify the contribution of NAbs to the sub-optimal response of IFNbeta treatment. METHODS: We studied the prevalence of NAbs in MS patients grouped according to their clinical response to IFNbeta during the treatment period. Patients were classified as: group A, developing >or= 1 relapse after the first 6 months of therapy; group B, exhibiting confirmed disability progression after the first 6 months of therapy, with or without superimposed relapses; group C, presenting a stable disease course during therapy. A cytopathic effect assay tested the presence of NAbs in a cohort of ambulatory MS patients treated with one of the available IFNbeta formulations for at least one year. NAbs positivity was defined as NAbs titre >or= 20 TRU. RESULTS: Seventeen patients (12.1%) were NAbs positive. NAbs positivity correlated with poorer clinical response (p < 0.04). As expected, the prevalence of NAbs was significantly lower in Group C (2.1%) than in Group A (17.0%) and Group B (17.0%). However, in the groups of patients with a poor clinical response (A, B), NAbs positivity was found only in a small proportion of patients. CONCLUSION: The majority of patients with poor clinical response are NAbs negative suggesting that NAbs explains only partially the sub-optimal response to IFNbeta.

Emerging oral drugs for multiple sclerosis.

BACKGROUND: Therapy for multiple sclerosis (MS) has changed dramatically over the past decade, yielding significant progress in the treatment of relapsing/remitting and secondary progressive MS. Disease-modifying treatments are now widely available, and their beneficial effects on relapse rates, MRI outcomes and, in some cases, relapse-related disability have been shown in several clinical studies. However, as these treatments are only partially effective in halting the MS disease process and in clinical practice are frequently associated with injection-related side effects and suboptimal patient adherence, new oral therapeutic approaches are warranted. OBJECTIVE: The aim of the present paper is to present new promising results from emerging oral drugs for multiple sclerosis. METHODS: This review focuses on advances in current and novel oral treatment approaches for MS. Nevertheless, most of the data were obtained from Phase I/II clinical trials, we need further confirmation of their safety and efficacy profile from longer Phase III clinical trials. RESULTS: Several pivotal reports have provided promising results for new oral therapies evaluating the safety and efficacy of new agents including fingolimod, fumaric acid, cladribine, teriflunomide and laquinomid. CONCLUSIONS: It is unknown whether these oral drugs could be used as first-line treatment for MS; this will depend mostly on their safety profile. Alternatively, these drugs could be used as add-on treatment for failed first-line therapy, or as an effective induction agent.