Modified Rio Score with Platform Therapy Predicts Treatment Success with Fingolimod and Natalizumab in Relapsing-Remitting Multiple Sclerosis Patients.

BACKGROUND: Reliable markers of disease outcomes in multiple sclerosis (MS) would help to predict the response to treatment in patients treated with high efficacy drugs. No evidence of disease activity (NEDA) has become a treatment goal whereas the modified Rio score (MRS) predicts future suboptimal responders to treatment. The aim of our study was to identify factors that would predict poor response to treatment with natalizumab and fingolimod. METHODS: In the multicenter prospective trial, 336 subjects were enrolled, initiating therapy with natalizumab (n = 135) or fingolimod (n = 201). Data on relapse rate, the expanded disability status scale, and MRI results were collected, and MRS was estimated. RESULTS: NEDA-3 after the first year of therapy was 73.9% for natalizumab and 54.8% for fingolimod (p < 0.0001). Patients with MRS = 0 in the last year on platform therapy had the best NEDA-3 (71%) and patients with MRS = 3 had the worst NEDA-3 (41%) in the first year of treatment with the second-line therapy. CONCLUSION: We conclude that switching to the second-line therapy should occur earlier to enable better results for patients treated with natalizumab or fingolimod. The outcome on both drugs is better with better neurological conditions and lower MRS of the patient on the platform therapy.

Evaluation of clinical prognostic factors in Polish interferon beta-1b treated multiple sclerosis patients.

INTRODUCTION: Prompt successful control of disease activity in multiple sclerosis (MS) patients improves outcomes. Therefore, tools to aid drug selection and detect non-responders are urgently needed. Although several biochemical markers for predicting response to treatment have been proposed, clinical markers involving relapses, imaging activity and disability progression in the initial years of therapy remain competitive and appear cost-effective in a real-life setting. The aim of this study was to evaluate the prognostic value of select clinical scores in interferon beta-1b (IFNß-1b) treated MS patients. MATERIALS AND METHODS: Eighty-eight relapsing-remitting MS (RRMS) patients initiating treatment with IFNß-1b in a Polish outpatient clinic were followed for a median of 5.5 years. Rio, modified Rio and BREMSO scores, as well as two-year no evidence of disease activity (NEDA), were assessed as predictors of disease activity during the observation. RESULTS: A Rio score of 1 had a Positive Predictive Value (PPV) of 83.3% and a Negative Predictive Value (NPV) of 71.4% for the occurrence of relapses in the first five years. A Rio and modified Rio score of 1 was associated with MRI activity after year 3. A loss of NEDA within the first two years was associated with a failure to maintain NEDA in the next three years. The BREMSO score was higher in patients with early relapse activity. Only baseline EDSS and total number of pre-treatment relapses were significantly associated with disability progression. CONCLUSIONS: Rio, modified Rio, early NEDA on treatment and BREMSO score are relatively specific, but insensitive, predictors of relapse activity in the first years of IFNß-1b treatment. Higher pre-treatment EDSS and relapse activity is associated with disability progression, but not overall NEDA, in subsequent observation. While none of the markers is sufficiently sensitive or specific to make a certain prognosis, they may aid treatment decisions in patients with continued early disease activity.

Early predictors of injectable disease modifying drugs suboptimal response based on clinical and radiological data assessment in Polish Multiple Sclerosis patients.

BACKGROUND: Prospective database studies can provide useful information regarding 'real-world' outcomes and drug efficacy. OBJECTIVE: To determine the early predictors of suboptimal treatment responses at two and three years under injectable Disease Modifying Therapy (DMT). METHODS: This was a multi-centre prospective database study. Adult patients who started injectable DMTs between January 2008 and June 2013 were included. The follow-up continued until July 2014. Suboptimal treatment responses were defined as: the presence of clinical relapse and/or Expanded Disability Status Score (EDSS) progression and/or newly emerging T2 lesions or/and gadolinium enhancing lesions on magnetic resonance imaging (MRI). The parameters were assessed up to 24 months prior to, and every 12 months during, the treatment. RESULTS: Analysis included 297 MS (multiple sclerosis) patients followed for a mean time of 2.3 ± 1.3 years (range 1-5). Within the three years of observation, the persistence and efficacy with injectable DMTs was high. With increased disability, defined by EDSS ≥ 3, the risk of treatment failure increased up to seven times, OR 7.33 in the second year radiological analysis (CI 95% : 1.69-29.2) p < 0.01, similar to over two times in the second year clinical analysis, with the baseline symptomatic hemiparesis OR 2.75 (CI 95% : 1.06-7.06) p 0.034. A high relapse rate one year prior to treatment adversely influenced the treatment success at three years, OR 3.04 (CI 95% : 1.49-8.43) p < 0.01. CONCLUSIONS: Injectable DMTs should not be chosen for treatment initiation in motoric disabled patients (EDSS ≥ 3) with a high grade of clinical activity. These drugs are effective in less active relapsing-remitting (RR) MS patients.

Therapeutic Targets for Multiple Sclerosis: Current Treatment Goals and Future Directions.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system, and the most common cause of nontraumatic disability in young adults. Most patients have a relapsing-remitting course, and roughly half of them will eventually enter a degenerative progressive phase, marked by gradual accrual of disability over time in the absence of relapses. Early initiation of treatment has delayed the onset of disability progression. Thus, there is increased interest in treating to target in MS, particularly targeting no evidence of disease activity. This review will describe the most common treatment goals in MS: the Rio scores, disease-free survival, and no evidence of disease activity. We will also cover how well current disease-modifying therapies achieve no evidence of disease activity, and discuss future options for improving MS treatment targets.

Hypothalamic damage in multiple sclerosis correlates with disease activity, disability, depression, and fatigue.

OBJECTIVES: Disturbances in the hypothalamo-pituitary axis are supposed to modulate activity of multiple sclerosis (MS). We hypothesised that the extent of HYP damage may determine severity of MS and may be associated with the disease evolution. We suggested fatigue and depression may depend on the degree of damage of the area. METHOD: 33 MS patients with relapsing-remitting and secondary progressive disease, and 24 age and sex-related healthy individuals (CON) underwent 1H-MR spectroscopy (1H-MRS) of the hypothalamus. Concentrations of glutamate + glutamin (Glx), cholin (Cho), myoinositol (mIns), N-acetyl aspartate (NAA) expressed as ratio with creatine (Cr) and NAA were correlated with markers of disease activity (RIO score), Multiple Sclerosis Severity Scale (MSSS), Depressive-Severity Status Scale and Simple Numerical Fatigue Scale. RESULTS: Cho/Cr and NAA/Cr ratios were decreased and Glx/NAA ratio increased in MS patients vs CON. Glx/NAA, Glx/Cr, and mIns/NAA were significantly higher in active (RIO 1-2) vs non-active MS patients (RIO 0). Glx/NAA and Glx/Cr correlated with MSSS and fatigue score, and Glx/Cr with depressive score of MS patients. In CON, relationships between Glx/Cr and age, and Glx/NAA and fatigue score were inverse. CONCLUSION: Our study provides the first evidence about significant hypothalamic alterations correlating with clinical outcomes of MS, using 1H-MRS. The combination of increased Glu or mIns with reduced NAA in HYP reflects whole-brain activity of MS. In addition, excess of Glu is linked to severe disease course, depressive mood and fatigue in MS patients, suggesting superiority of Glu over other metabolites in determining MS burden.

Study design of PANGAEA 2.0, a non-interventional study on RRMS patients to be switched to fingolimod.

BACKGROUND: The therapeutic options for patients with Multiple Sclerosis (MS) have steadily increased due to the approval of new substances that now supplement traditional first-line agents, demanding a paradigm shift in the assessment of disease activity and treatment response in clinical routine. Here, we report the study design of PANGAEA 2.0 (Post-Authorization Non-interventional GermAn treatment benefit study of GilEnyA in MS patients), a non-interventional study in patients with relapsing-remitting MS (RRMS) identify patients with disease activity and monitor their disease course after treatment switch to fingolimod (Gilenya®), an oral medication approved for patients with highly active RRMS. METHOD/DESIGN: In the first phase of the PANGAEA 2.0 study the disease activity status of patients receiving a disease-modifying therapy (DMT) is evaluated in order to identify patients at risk of disease progression. This evaluation is based on outcome parameters for both clinical disease activity and magnetic resonance imaging (MRI), and subclinical measures, describing disease activity from the physician's and the patient's perspective. In the second phase of the study, 1500 RRMS patients identified as being non-responders and switched to fingolimod (oral, 0.5 mg/daily) are followed-up for 3 years. Data on relapse activity, disability progression, MRI lesions, and brain volume loss will be assessed in accordance to 'no evidence of disease activity-4' (NEDA-4). The modified Rio score, currently validated for the evaluation of treatment response to interferons, will be used to evaluate the treatment response to fingolimod. The MS management software MSDS3D will guide physicians through the complex processes of diagnosis and treatment. A sub-study further analyzes the benefits of a standardized quantitative evaluation of routine MRI scans by a central reading facility. PANGAEA 2.0 is being conducted between June 2015 and December 2019 in 350 neurological practices and centers in Germany, including 100 centers participating in the sub-study. DISCUSSION: PANGAEA 2.0 will not only evaluate the long-term benefit of a treatment change to fingolimod but also the applicability of new concepts of data acquisition, assessment of MS disease activity and evaluation of treatment response for the in clinical routine. TRIAL REGISTRATION: BfArM6532; Trial Registration Date: 20/05/2015.

Validation of 1-year predictive score of long-term response to interferon-ß in everyday clinical practice multiple sclerosis patients.

BACKGROUND AND PURPOSE: The Rio score (RS) and the modified Rio score (MRS) are two scoring systems that can identify the early predictive factors of disability progression in relapsing-remitting multiple sclerosis (RRMS) patients treated with interferon-ß (IFN-ß). The objective of the study was to validate the usefulness of the RS and MRS in a large cohort of multiple sclerosis patients treated with IFN-ß in daily clinical practice. METHODS: The analysis included a cohort of RRMS patients treated with different formulations of IFN-ß for at least 1 year. The RS and MRS were used to classify the patients after 1 year of treatment. Multivariate analysis was performed to identify predictive variables of suboptimal response at 5 years, defined as Expanded Disability Status Scale confirmed progression or switching to a second-line therapy. RESULTS: Sixty-nine of 416 included patients were considered as suboptimal responders at 5-year evaluation. The possible score range was 0-3. A higher risk of suboptimal response was found for RS and MRS in the presence of ≥2 scores (hazard ratio 3.0, P = 0.002, and hazard ratio 5.0, P < 0.0001, respectively). CONCLUSIONS: Our study confirmed, in a daily clinical setting, that MRS had a better specificity and accuracy than RS in identifying the patients who will have a poor response to long-term IFN-ß treatment.