No Evidence Of Disease Activity Status Research Articles

Real-World Effectiveness and Safety of Cladribine in Multiple Sclerosis: Longitudinal Data From the Nationwide Registry in Argentina.

The aim was to evaluate patient profiles, effectiveness and safety of cladribine (CLAD) in patients with relapsing-remitting multiple sclerosis in Argentina. This was a substudy included in RelevarEM (MS and neuromyelitis optica registry in Argentina, NCT03375177). Patients with MS who received CLAD tablets and were followed up for at least 24 months were included. Clinical evaluations every 3 months collect information about: a) clinical relapses; b) progression of physical disability, evaluated through Expanded Disability Status Scale, and c) new lesions found in the magnetic resonance imaging. Lymphopenia was evaluated during the follow-up and defined as grade 1: absolute lymphocyte count (ALC) 800-999/μL; grade 2: ALC 500-799/μL; grade 3: ALC 200-499/μL and grade 4: ALC <200/μL. A total of 240 patients were included from 19 centers from Argentina. The mean annualized relapse rate during the 12-month pre-CLAD initiation was 1.19 ± 0.56 versus 0.22 ± 0.18 at month 12 and 0.19 ± 0.15 at month 24 (P < 0.001). A total of 142 (59.2%) fulfilled the criteria of disease activity during the 12 months before treatment initiation, whereas 27 (11.3%) fulfilled it at month 12 and 38 (15.8%) at month 24, P < 0.001. Regarding no evidence of disease activity (NEDA), 202 (84.2%) patients achieved NEDA status at month 12 and 185 (77%) at month 24. The most frequent incidence density of lymphopenia for course 2 observed was also for grade 1, 6.1 (95% confidence interval [CI] = 5.5-7.1). The overall incidence density of lymphopenia grade 4 was 0.1 (95% CI = 0.06-0.19). This information will help when choosing the best treatment option for Argentinean patients.

High frequency of circulating non-classical monocytes is associated with stable remission in relapsing-remitting multiple sclerosis

‘No evidence of disease activity (NEDA)’, judged by clinical and radiological findings, is a therapeutic goal in patients with multiple sclerosis (MS). It is, however, unclear if distinct biological mechanisms contribute to the maintenance of NEDA. To clarify the immunological background of long-term disease stability defined by NEDA, circulating immune cell subsets in patients with relapsing-remitting MS (RRMS) were analyzed using flow cytometry. Patients showing long-term NEDA (n = 31) had significantly higher frequencies of non-classical monocytes (NCMs) (6.1% vs 1.4%) and activated regulatory T cells (Tregs; 2.1% vs 1.6%) than those with evidence of disease activity (n = 8). The NCM frequency and NCMs to classical monocytes ratio (NCM/CM) positively correlated with activated Treg frequency and duration of NEDA. Co-culture assays demonstrated that NCMs could increase the frequency of activated Tregs and the expression of PD-L1, contributing to development of Tregs, was particularly high in NCMs from patients with NEDA. Collectively, NCMs contribute to stable remission in patients with RRMS, possibly by increasing activated Treg frequency. In addition, the NCM frequency and NCM/CM ratio had high predictive values for disease stability (AUC = 0.97 and 0.94, respectively), suggesting these markers are potential predictors of a long-term NEDA status in RRMS.

Prevalence of 2-year "No evidence of disease activity" (NEDA-3 and NEDA-4) in relapsing-remitting multiple sclerosis. A real-world study.

No evidence of disease activity (NEDA) is becoming a gold standard in the evaluation of disease modifying therapies (DMT) in relapsing-remitting multiple sclerosis (RRMS). NEDA-3 status is the absence of relapses, new activity on brain MRI, and disability progression. NEDA-4 meets all NEDA-3 criteria plus lack of brain atrophy. Aim of this study was to investigate the prevalence of two-year NEDA-3, NEDA-4, six-month delayed NEDA-3 (6mdNEDA-3), and six-month delayed NEDA-4 (6mdNEDA-4) in a cohort of patients with RRMS. Six-month delayed measures were introduced to consider latency of action of drugs. Observational retrospective monocentric study. All the patients with RRMS starting DMT between 2015 and 2018, and with 2-year of follow-up, were included. Annualized brain volume loss (a-BVL) was calculated by SIENA software. We included 108 patients, the majority treated with first line DMT. At 2-year follow-up, 35% of patients were NEDA-3 (50% 6mdNEDA-3), and 17% NEDA-4 (28% 6mdNEDA-4). Loss of NEDA-3 status was mainly driven by MRI activity (70%), followed by relapses (56%), and only minimally by disability progression (7%). In our cohort 2-year NEDA status, especially including lack of brain atrophy, was hard to achieve. Further studies are needed to establish the prognostic value of NEDA-3 and NEDA4 in the long-term follow-up.

Predictive value of brain atrophy, serum biomarkers and information processing speed for early disease progression in multiple sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune-mediated demyelinating disease of the central nervous system (CNS). A clinical presentation of the disease is highly differentiated even from the earliest stages of the disease. The application of stratifying tests in clinical practice would allow for improving clinical decision-making including a proper assessment of treatment benefit/risk balance. This prospective study included patients with MS diagnosed up to 1 year before recruitment. We analyzed serum biomarkers such as CXCL13, CHI3L1, OPN, IL-6, and GFAP and neurofilament light chains (NfLs); brain MRI parameters of linear atrophy such as bicaudate ratio (BCR), third ventricle width (TVW); and information processing speed were measured using the Symbol Digit Modalities Test (SDMT) during the 2 years follow-up. The study included a total of 50 patients recruited shortly after the diagnosis of MS diagnosis (median 0 months; range 0-11 months), and the mean time of observation was 28 months (SD = 4.75). We observed a statistically significant increase in the EDSS score (Wilcoxon test: Z = 3.06, p = 0.002), BCR (Wilcoxon test: Z = 4.66, p < 0.001), and TVW (Wilcoxon test: Z = 2.84, p = 0.005) after 2 years of disease. Patients who had a significantly higher baseline level of NfL suffered from a more severe disease course as per the EDSS score (Mann-Whitney U-test: U = 107, Z = -2,74, p = 0.006) and presence of relapse (Mann-Whitney U-test: U = 188, Z = -2.01, p = 0.044). In the logistic regression model, none of the parameters was a significant predictor for the achieving of no evidence of disease activity status (NEDA). In the model considering all assessed parameters, only the level of NfL had a significant impact on disease progression, measured as the increase in EDSS (logistic regression: β = 0.002, p = 0.017). We confirmed that NfL levels in serum are associated with more active disease. Moreover, we found that TVW at the time of diagnosis was associated with an impairment in cognitive function measured by information processing speed at the end of the 2-year observation. The inclusion of serum NfL and TVW assessment early in the disease may be a good predictor of disease progression independent of NEDA.

Comparison of dimethyl fumarate and interferon outcomes in an MS cohort

BackgroundTo compare the effectiveness of dimethyl fumarate (DMF) with subcutaneous interferon beta-1a (IFNβ-1a) in controlling disease activity in patients with relapsing–remitting Multiple Sclerosis (MS).MethodsClinical and imaging data from patients treated with either IFNβ-1a or DMF for at least one year were reviewed. The proportion of patients with at least one clinical relapse within 3–15 months after treatment onset, the proportion of patients with new T2 or gadolinium-enhancing lesions, and the proportion of subjects who achieved no evidence of disease activity (NEDA) status were assessed.ResultsThree hundred sixteen (98 on IFNβ-1a, 218 on DMF) subjects were included. Baseline demographics were comparable between groups except for age, disease duration, and the number of previous treatments being higher and relapse rate in the prior year being lower in the DMF-treated group. The proportion of patients having a clinical relapse (24.5% vs. 9.6%; OR = 3.04; P < 0.001) or a new MRI lesion (28.6% vs. 8.7%; OR = 4.19, P < 0.001) at 15 months were higher on IFNβ-1a. 79.9% of the patients achieved NEDA status at 15 months on DMF (vs. 51.1% for IFNβ-1a; OR = 0.26, P < 0.001). Further adjustment for demographics, disease characteristics, treatment and relapse history, and subgroup analyses confirmed these findings.ConclusionDMF was associated with less clinical and radiological disease activity compared to IFNβ-1a.

The “no evidence of disease activity” (NEDA) concept in MS: Impact of spinal cord MRI

Measures to define treatment response, such as no evidence of disease activity (NEDA), are routinely used in multiple sclerosis (MS) clinical practice. Although spinal cord involvement in MS is frequent and strongly correlated with future disability accrual, its magnetic resonance imaging (MRI) monitoring, in the absence of spinal cord symptoms, is not routinely performed. This study aimed to assess the impact of spinal cord imaging and specifically, the impact of missing asymptomatic spinal cord lesions, in the definition of NEDA status in a cohort of MS patients treated with disease-modifying therapies (DMTs).

Should I stop or should I go on? Disease modifying therapy after the first clinical episode of multiple sclerosis

IntroductionTreatment with disease-modifying therapies (DMT) in patients with clinically isolated syndrome (CIS) represents standard care in multiple sclerosis (MS) patients nowadays. Since a proportion of patients may show no evidence of disease activity (NEDA) after some time of treatment, the question might arise about the risks of stopping DMT.MethodsWe present a cohort of 49 patients who started DMT immediately after CIS and had no evidence of disease activity (NEDA-3) for at least five years before discontinuation of therapy. Thereafter, patients underwent clinical and MRI follow-up for at least five consecutive years.ResultsOf 49 patients discontinuing DMT, 53% (n = 26) had NEDA for at least further five years, while 47% (n = 23) showed either a relapse/disease progression (18.4%, n = 9), MRI activity (14.3%, n = 7) or both (14.3%, n = 7). The main predictive factor for sustained NEDA was age at DMT termination. Patients aged > 45 years had a significantly lower risk of disease reactivation (13% vs. 54% in patients aged < 45 years, p < 0.001) after DMT discontinuation.DiscussionIn CIS patients with immediate DMT after their first clinical episode, older age at the time of DMT discontinuation is the main predictive factor for sustained NEDA status.

Magnetic resonance spectroscopy of the normal appearing grey matter in the posterior cingulate gyrus in the prognosis and monitoring of disease activity in MS patients treated with interferon-β in a 3-year follow-up

Several predictors of non-response to interferon-β (IFN-β) treatment have been proposed. The aim of the study was to identify metabolite changes in the normal-appearing cortex of the posterior cingulate gyrus (PCG) using MRS (magnetic resonance spectroscopy) and to investigate their usefulness in prognosis of NEDA (no evidence of disease activity) in the 3-year follow-up and in monitoring treatment effects during IFN-β therapy in the parallel period of time in multiple sclerosis (MS) patients.Forty-one relapsing-remitting MS patients and 41 sex- and age-matched healthy subjects underwent routine MRI protocol with MRS sequence with the use of a 1.5 T magnet. A single voxel size of 2x2x2cm was inserted in the cortex of PCG region. Associations between baseline metabolic ratios, conventional MRI findings, demographic and clinical factors, and NEDA status were evaluated using logistic, Cox, and multinomial logistic regression models.MS patients in the initial scan showed a statistically significant decline in NAA/Cr ratio (p < 0.0001) and an increase in Cho/Cr ratio (p = 0.016) compared to the control group. None of the MRS parameters predicted NEDA maintenance or the time to loss of NEDA. In treatment monitoring only an improvement in the combination of NAA/Cr + Cho/Cr ratio between the 1st and 2nd year of treatment was connected with a 6.27-fold chance (p = 0.025) of having simultaneous NEDA maintenance.To conclude, metabolite alterations in the PCG region did not predict NEDA maintenance, but they seem to be useful in treatment monitoring.

The role of ADC values within the normal-appearing brain in the prognosis of multiple sclerosis activity during interferon-\u03b2 therapy in the 3-year follow-up: a preliminary report

Predictors of multiple sclerosis (MS) activity during disease-modifying treatment are being extensively investigated. The aim of this study was to assess the prognosis of NEDA (no evidence of disease activity) status during IFN-β (interferon-β) treatment, using apparent diffusion coefficient (ADC) measurements obtained at initial MRI (magnetic resonance imaging). In 87 MS patients treated with IFN-β, ADC values were calculated for 13 regions of normal-appearing white and grey matter (NAWM, NAGM) based on MRI performed with a 1.5 T magnet before (MS0, n = 45) or after one year of therapy (MS1, n = 42). Associations were evaluated between ADC, conventional MRI findings, demographic and clinical factors and NEDA status within the following 3 years using logistic, Cox and multinomial logistic regression models. NEDA rates in the MS0 group were 64.4%, 46.5% and 33.3% after the 1st, 2nd and 3rd year of treatment, respectively and in MS1 patients 71.4% and 48.7% for the periods 1st–2nd and 1st–3rd years of treatment, respectively. ADC values in the NAWM regions contributed to loss of NEDA and its clinical and radiological components, with a 1–3% increase in the risk of NEDA loss (p = 0.0001–0.0489) in both groups. ADC measurements may have an additional prognostic value with regard to NEDA status.

Natalizumab in patients with multiple sclerosis in Colombia: a case series

INTRODUCTION:Natalizumab is a humanized monoclonal antibody prescribed in the treatment of multiple sclerosis, the most prevalent chronic and inflammatory disease of the central nervous system (CNS). NEDA (no evidence of disease activity) status is the goal of multiple sclerosis treatment. METHODOLOGY:The clinical records of 22 patients with multiple sclerosis, followed for a mean of 9.2 years (range: 1.9 -18.3 years) between 2000 and 2018 were analyzed. These patients received treatment with natalizumab in a high-complexity neurological outpatient clinic in Bogotá, Colombia. RESULTS:Eighteen patients (82%) reached NEDA status within a median time of six months. Seven patients (32%) tested positive for anti-JC virus antibodies. However, none of them developed progressive multifocal leukoencephalopathy. During the evaluation period, five patients (23%) presented new lesions and 17 patients (77%) had relapses before reaching NEDA status. CONCLUSIONS:This study gave an exploratory analysis of the characteristics of a series of patients with MS in the Colombian context. In the retrospective analysis, it was observed that more than 80% of the studied sample that received treatment with natalizumab, reached NEDA status. Despite the methodological limitations inherent to this type of study and sample size, it suggests that natalizumab could be an appropriate medication for the management of multiple sclerosis in Colombia.

Impact of Gadolinium-enhancing (GD+) Lesions on No Evidence of Disease Activity (NEDA) Status in Subcutaneous Interferon Beta-1a (SC IFNβ-1a)-treated Patients

Background: SC IFNβ-1a treatment after clinically isolated syndrome (CIS) increases chances of NEDA status vs delayed treatment (DT) after clinically-definite multiple sclerosis (CDMS). The impact of baseline gd+ lesions on NEDA using data from reflex/reflexion is assessed.

Effectiveness and safety of Rituximab in demyelinating diseases spectrum: An Italian experience

BackgroundRituximab (RTX), a monoclonal antibody targeting the CD20+ B lymphocytes, deserves major attention as therapeutic option in the treatment of demyelinating disorders of the central nervous system (DDCNS). We reported our clinical experience with the use of RTX in terms of efficacy and safety in persons suffering from DDCNS. MethodsAn Italian single-center observational analysis of patients who underwent RTX treatment between 2011 and 2017 was performed at MS center of Catania, Italy. No evidence of disease activity (NEDA) was applied to evaluate the response to RTX. CD19+ and CD20+ counts were collected along therapy. RTX-related adverse events were recorded. ResultsEleven patients with MS, four with NMOSD and two with NMO were enrolled. Out of them, 4/17 were naïve to previous treatments. According to NEDA status, 11/17 got NEDA3 status at the follow-up. Six patients had relapses (two had a single relapse and four had multiple relapses). One patient with primary progressive MS and one with relapsing remitting MS stopped RTX, the last one for severe lymphopenia. ConclusionsRTX showed efficacy to impact DDCNS worsening with an acceptable safety profile.

THUR 179 Ocrelizumab effect on neda in patient subgroups of opera I and opera II

BackgroundIn a pooled analysis of patients with relapsing multiple sclerosis in the Phase III OPERA I and OPERA II (NCT01247324/NCT014112333) studies, ocrelizumab increased the proportion of patients with no evidence of disease activity (NEDA) vs interferon β−1a (IFNβ1a); post hoc subgroup analyses are reported here.MethodsNEDA (no 12 week confirmed disability progression, relapse, new/enlarging T2 lesions or T1 gadolinium enhancing lesions) rates were compared by Cochran–Mantel–Haenszel test on the pooled modified intent-to-treat (mITT) population (ocrelizumab, n=761 [600 mg intravenously every 24 weeks]; IFNβ1a, n=759 [44 μg subcutaneously three times weekly]; excludes patients with NEDA discontinuing for reasons unrelated to efficacy).ResultsTreatment benefit for NEDA in the mITT population with ocrelizumab vs IFNβ1a (47.7% vs 27.1%; p&lt;0.001) was maintained across subgroups (ocrelizumab/IFNβ1a; p&lt;0.001 unless stated): age (&lt;40 years: 44.3%/22.6%; ≥40 years: 52.8%/33.7%), gender (male: 44.0%/22.2%; female: 49.7%/29.6%), prior [last 2 years] disease-modifying therapy (yes: 42.8%/23.9%; no: 49.5%/28.3%), prior relapses [last 12 months] (≤1: 49.2%/29.2%; ≥2: 44.2%/22.6%), baseline T1 Gd-enhancing lesions (none: 59.6%/38.8%; ≥1: 30.1%/10.2%) and baseline EDSS score (EDSS &lt;2.5/&lt;4.0: ocrelizumab 50.5%/50.3%, IFNβ1a 27.5%/26.4%; EDSS ≥2.5/≥4.0: ocrelizumab 46.0%/39.6%, IFNβ1a 26.9%/29.4% [NB: EDSS score ≥4: ocrelizumab/IFNβ1a p=0.043]).ConclusionsSubgroup analyses were consistent with those of the overall pooled population on maintaining NEDA status.

Permeability of the blood-brain barrier predicts no evidence of disease activity at 2 years after natalizumab or fingolimod treatment in relapsing-remitting multiple sclerosis.

ObjectiveTo investigate whether blood–brain barrier (BBB) permeability, as measured by dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI), can provide early detection of suboptimal treatment response in relapsing–remitting multiple sclerosis (RRMS).MethodsThirty‐five RRMS patients starting on fingolimod or natalizumab, drugs with a common effect of decreasing lymphocyte influx into the central nervous system, were scanned with DCE‐MRI at 3T prior to treatment and at 3 and 6 months posttreatment. We calculated the influx constant Ki, a measure of BBB permeability, using the Patlak model. Suboptimal treatment response was defined as loss of no evidence of disease activity (NEDA) status after 2 years of treatment.ResultsSubjects with loss of NEDA status at 2 years had a 51% higher mean Ki in normal‐appearing white matter (NAWM) measured after 6 months of treatment, compared to subjects with maintained NEDA status (mean difference = 0.06ml/100g/min, 95% confidence interval [CI] = 0.02–0.09, p = 0.002). Ki in NAWM at 6 months was a good predictor of loss of NEDA status at 2 years (area under the curve = 0.84, 95% CI = 0.70–0.99, p = 0.003), and a value above 0.136ml/100/g/min yielded an odds ratio of 12.4 for suboptimal treatment response at 2 years, with a sensitivity of 73% and a specificity of 82%.InterpretationOur results suggest that BBB permeability as measured by DCE‐MRI reliably predicts suboptimal treatment response and is a surrogate marker of the state of health of the BBB. We find a predictive threshold for disease activity, which is remarkably identical in clinically isolated syndrome as previously reported and established RRMS as investigated here. Ann Neurol 2018;83:902–914

No evidence of disease activity (NEDA) analysis by epochs in patients with relapsing multiple sclerosis treated with ocrelizumab vs interferon beta-1a.

BackgroundNo evidence of disease activity (NEDA; defined as no 12-week confirmed disability progression, no protocol-defined relapses, no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions) using a fixed-study entry baseline is commonly used as a treatment outcome in multiple sclerosis (MS).ObjectiveThe objective of this paper is to assess the effect of ocrelizumab on NEDA using re-baselining analysis, and the predictive value of NEDA status.MethodsNEDA was assessed in a modified intent-to-treat population (n = 1520) from the pooled OPERA I and OPERA II studies over various epochs in patients with relapsing MS receiving ocrelizumab (600 mg) or interferon beta-1a (IFN β‐1a; 44 μg).ResultsNEDA was increased with ocrelizumab vs IFN β-1a over 96 weeks by 75% (p < 0.001), from Week 0‒24 by 33% (p < 0.001) and from Week 24‒96 by 72% (p < 0.001). Among patients with disease activity during Weeks 0‒24, 66.4% vs 24.3% achieved NEDA during Weeks 24‒96 in the ocrelizumab and IFN β-1a groups (relative increase: 177%; p < 0.001).ConclusionSuperior efficacy with ocrelizumab compared with IFN β-1a was consistently seen in maintaining NEDA status in all epochs evaluated. By contrast with IFN β-1a, the majority of patients with disease activity early in the study subsequently attained NEDA status with ocrelizumab.

Peginterferon β-1a every 2 weeks increased achievement of no evidence of disease activity over 4 years in the ADVANCE and ATTAIN studies in patients with relapsing-remitting multiple sclerosis.

Background:No evidence of disease activity (NEDA) is a composite measurement, incorporating clinical and magnetic resonance imaging (MRI) elements of disease activity to sensitively evaluate the therapeutic efficacy of treatments for relapsing–remitting multiple sclerosis (RRMS).Objective:To assess the NEDA status of patients treated with peginterferon β-1a in the ADVANCE and ATTAIN studies and explore its predictive value on longer-term clinical outcomes.Methods:ATTAIN was a 2-year extension of the pivotal 2-year ADVANCE study of peginterferon β-1a for RRMS. Achievement of clinical NEDA, MRI NEDA, or overall NEDA was calculated cumulatively and by year over 4 years. Clinical outcomes during ATTAIN were analyzed based on NEDA status at the end of ADVANCE.Results:Significantly more patients treated with peginterferon β-1a every 2 weeks than every 4 weeks achieved clinical NEDA (60.6% versus 50.6%, p = 0.0063) and MRI NEDA (28.3% versus 15.8%, p = 0.0005) through year 4 and overall NEDA through year 3 (20.9% versus 13.9%, p = 0.0160). Over 4 years, 15.8% of patients in the every 2 weeks group and 10.7% of patients in the every 4 weeks group maintained overall NEDA (p = 0.0584). Achievement of clinical NEDA, MRI NEDA, or overall NEDA in ADVANCE was predictive of annualized relapse rate in ATTAIN; achievement of clinical NEDA in ADVANCE was also predictive of NEDA achievement and confirmed disability worsening in ATTAIN.Conclusions:Peginterferon β-1a every 2 weeks is associated with higher levels of NEDA compared with placebo in year 1 or peginterferon β-1a every 4 weeks in years 2–4. Overall NEDA within the first 2 years of treatment may be prognostic of long-term clinical outcomes.Clinicaltrials.gov: NCT01332019

No evidence of disease activity is associated with reduced rate of axonal retinal atrophy in MS.

To explore, in a longitudinal study, the usefulness of optical coherence tomography (OCT) in monitoring people with multiple sclerosis (MS) by testing the association between retinal nerve fiber layer (RNFL) thinning and clinical and brain MRI criteria of no evidence of disease activity (NEDA). OCT, visual evoked potentials (VEPs), and disability, using the Expanded Disability Status Scale (EDSS), were tested at baseline and after 2 years in 72 patients, 63 with routine yearly brain MRI. Longitudinal mean binocular RNFL thinning, in absence of optic neuritis during follow-up, was correlated with EDSS worsening, also controlling for baseline EDSS, RNFL, disease duration, and MS subtype (Spearman ρ -0.462, p < 0.001; partial correlation coefficient -0.437, p < 0.001). At follow-up, patients classified as NEDA (20; 31.7%) had RNFL loss of -0.93 μm ± 1.35 SD, while patients with active disease had -2.83 μm ± 2 SD thinning (t test; p < 0.001). At logistic regression, mean RNFL reduction correctly classified 76.2% of patients as NEDA at 2 years (R2 0.355; p = 0.003). A cutoff of -1.25 μm RNFL loss classified NEDA status with specificity 81.4% and sensitivity 80% (receiver operating characteristic curve: area under the curve 0.8; p < 0.001). No significant longitudinal correlations were found between changes in RNFL and in VEP latencies or scores. NEDA is associated with a relatively preserved RNFL over 2 years. A greater neuroretinal loss was detected even in patients with clinical evidence of disease activity independently from changes in brain MRI lesions, prompting further validation of OCT as an additional tool in MS monitoring.

Blood lymphocyte subsets identify optimal responders to IFN-beta in MS.

Response to interferon-beta (IFN-beta) treatment is heterogeneous in multiple sclerosis (MS). We aimed to search for biomarkers predicting no evidence of disease activity (NEDA) status upon IFN-beta treatment in MS. 119 patients with relapsing-remitting MS (RRMS) initiating IFN-beta treatment were included in the study, and followed prospectively for 2years. Neutralizing antibodies (NAb) were explored in serum samples obtained after 6 and 12months of IFN-beta treatment. Soluble cytokines and blood lymphocytes were studied in basal samples by ELISA and flow cytometry, respectively. 9% of patients developed NAb. These antibodies were more frequent in patients receiving IFN-beta 1b than in those treated subcutaneous (p=0.008) or intramuscular (p<0.0001) IFN-beta 1a. No patient showing NAb remained NEDA during follow-up. Basal immunological variables are also associated with patient response. Percentages below 3% of CD19+CD5+cells (AUC 0.74, CI 0.63-0.84; OR 10.68, CI 3.55-32.15, p<0.0001; Likelihood ratio 4.28) or above 2.6% of CD8+perforin+T cells (AUC 0.79, CI 0.63-0.96; OR 6.11, CI 2.0-18.6, p=0.0009; Likelihood ratio 5.47) increased the probability of achieving NEDA status during treatment. Basal blood immune cell subsets contribute to identify MS patients with a high probability of showing an optimal response to IFN-beta.

NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs

The no evidence of disease activity (NEDA) composite measure has emerged as one attractive new target of therapies in relapsing–remitting multiple sclerosis (RRMS), consisting of the following features: (1) no relapses, (2) no disability progression, and (3) no magnetic resonance imaging (MRI) activity (new or enlarging T2 lesions or Gd-enhancing lesions). Achievement of NEDA status in patients receiving a disease-modifying therapy (DMT) seems to be an ambitious but ideal goal for therapies in RRMS. Recently, published post hoc analyses of clinical trials reported percentages of RRMS patients maintaining the NEDA status after 2 years of therapy ranging between 13% and 46%. Long-term assessment of NEDA patients in real-life settings showed very low probability to be NEDA in the long run. Against this scenario, immunoablative therapy followed by autologous hematopoietic stem cell transplantation (aHSCT) demonstrated the potential to maintain a much higher proportion of NEDA patients at 2 years (ranging from 78% to 83%) and also at 5 years (ranging from 60% to 68%). This is even more relevant when considering that MS patients who underwent aHSCT are much more active than patients usually enrolled in clinical trials. The emerging evidence of the efficacy of this therapeutic approach in early aggressive and treatment-resistant RRMS calls for the organization of a randomized comparative trial to fully evaluate the risk–benefit profile of aHSCT in patients with highly active MS not responding to DMTs.

Is no evidence of disease activity an achievable goal in MS patients on intramuscular interferon beta-1a treatment over long-term follow-up?

Background: No evidence of disease activity (NEDA) has been proposed as a new treatment goal in multiple sclerosis (MS). NEDA-3 status is defined as the absence of magnetic resonance imaging (MRI; new/enlarging/enhancing lesions and increased whole brain volume loss in NEDA-4) and clinical disease activity. Objectives: To investigate the persistence of NEDA status over long-term follow-up in MS patients treated with weekly intramuscular interferon beta-1a. Methods: We included 192 patients after the first demyelinating event suggestive of MS, that is, clinically isolated syndrome (CIS) and 162 relapsing-remitting MS (RRMS) patients. Results: NEDA-3 status was observed in 40.1% of CIS and 20.4% of RRMS patients after 1 year. After 4 years, 10.1% of CIS patients had NEDA-3 status. After 10 years, none of the RRMS patients had NEDA-3 status. Only 4.6% of CIS and 1.0% of RRMS patients maintained NEDA-4 status after 4 years. Loss of NEDA-3 status after the first year was associated with a higher risk of disability progression (hazard ratio (HR) = 2.3–4.0; p = 0.005–0.03) over 6 years. Conclusions: Despite intramuscular interferon beta-1a treatment, loss of NEDA status occurred in the vast majority of individuals. Loss of NEDA status during the first year was associated with disability progression over long-term follow-up; however, specificity for individual patient was low.