Change In Expanded Disability Status Scale Score Research Articles

Comparison of 2-year Teriflunomide Outcomes between DMT-naive and switch patients with Relapsing MS: subanalysis of the Real-World TERICARE study (P6-3.003)

<h3>Objective:</h3> To evaluate the effect of teriflunomide on clinical and patient-reported outcomes (PROs) in disease-modifying therapy (DMT)-naive and previously treated (switch) patients with relapsing-remitting multiple sclerosis (RRMS). <h3>Background:</h3> Clinical trials and real-world evidence have shown that patients with RRMS benefit from teriflunomide regardless of prior exposure to DMT. <h3>Design/Methods:</h3> TERICARE was a multicentre, observational and prospective study in Spain. RRMS patients with no relapses within the last 30 days before the inclusion received teriflunomide for 2-years. This analysis compared the annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS), disability worsening, quality of life (Multiple Sclerosis Impact Scale, MSIS-29), fatigue (Modified Fatigue Impact Scale-5), and depression (Beck Depression Inventory-II) between DMT-naive and switch patients. <h3>Results:</h3> Of 325 patients included, 117 were DMT-naive and 208 switch patients. At baseline, DMT-naive was younger than switch patients (40.9 <i>vs</i> 44.4 years; p=0.003), had shorter disease duration (3.1 <i>vs</i> 9.5 years; p&lt;0.001), lower EDSS score (1.3 <i>vs</i> 2.0; p&lt;0.001), higher number of relapses in the last 2 years (1.3 <i>vs</i> 0.6; p&lt;0.001) and ARR (95% CI) (0.63 [0.53–0.74] <i>vs</i> 0.31 [0.26–0.37]; p&lt;0.001). The ARR was significantly reduced in both groups after 12 months (DMT-naive=0.24; p&lt;0.001; switch=0.21; p=0.032) and 24 months (DMT-naive=0.19; switch=0.16; p&lt;0.001, both groups). A greater reduction of ARR was observed in DMT-naive both at 12 (63% <i>vs</i> 33%) and 24 months (70% <i>vs</i> 49%). Mean change in EDSS score did not vary between groups, nor the percentage of patients with disability worsening at 12 (20% <i>vs</i> 13.2%; p=0.167) and 24 months (24.2% <i>vs</i> 17.6%; p=0.246). DMT-naive experienced a greater and significant reduction (improvement) in psychological MSIS-29 score at month 24 compared to switch group (−7.11 <i>vs</i> −1.48; p=0.019). <h3>Conclusions:</h3> Teriflunomide shows effectiveness in both DMT-naive and switch RRMS patients with a trend towards better relapse and quality of life outcomes in DMT-naive. <b>Disclosure:</b> Dr. Meca Lallana has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Meca Lallana has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Meca Lallana has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Meca Lallana has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sandoz. Dr. Meca Lallana has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Meca Lallana has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristol Myers Squibb. Dr. Meca Lallana has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Meca Lallana has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Meca Lallana has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol-Myers-Squibb. Dr. Meca Lallana has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Meca Lallana has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Meca Lallana has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Dr. Meca Lallana has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. The institution of Dr. Meca Lallana has received research support from Merck. The institution of Dr. Meca Lallana has received research support from Novartis. The institution of Dr. Meca Lallana has received research support from Roche. The institution of Dr. Meca Lallana has received research support from Sanofi. The institution of Dr. Meca Lallana has received research support from Biogen. Dr. Prieto has nothing to disclose. Dr. Caminero Rodriguez has nothing to disclose. Javier Olaskoaga has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Sanofi-Genzyme. Rosa Casademont Portell has received personal compensation for serving as an employee of Sanofi. Mrs. Forner has received personal compensation for serving as an employee of Sanofi.

Low Disease Activity Over 4 Years of Ocrelizumab Therapy in Treatment-Naive Patients With Early-Stage Relapsing-Remitting Multiple Sclerosis; the Phase IIIb ENSEMBLE Study (S46.004)

Low Disease Activity Over 4 Years of Ocrelizumab Therapy in Treatment-Naive Patients With Early-Stage Relapsing-Remitting Multiple Sclerosis; the Phase IIIb ENSEMBLE Study (S46.004)

Progressive patterns of neurological disability in multiple sclerosis and neuromyelitis optica spectrum disorders

The progressive patterns of neurological disability in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) and the significance of clinical relapses to the progressions of neurological disability in these diseases have not been fully elucidated. In this study, to elucidate the impact of relapses to the progression of accumulated neurological disability and to identify the factors to affect the progression of neurological disability in MS and NMOSD, we followed 62 consecutive MS patients and 33 consecutive NMOSD patients for more than 5 years with the clinical symptoms, relapse occurrence, and Expanded Disability Status Scale (EDSS) in the chronic phase. All enrolled MS patients were confirmed to be negative for serum anti-myelin oligodendrocyte glycoprotein antibody. As a result, patients with NMOSD showed significantly severer neurological disability at 5 years from onset than MS patients. Progression in EDSS score was almost exclusively seen after clinical attacks in NMOSD, whereas progression could be observed apart from relapses in MS. Neurological disability did not change without attacks in NMOSD, whereas it sometimes spontaneously improved or deteriorated apart from relapses in MS (p < 0.001). In patients with MS, those with responsible lesions primarily in spinal cord were more likely to show such spontaneous improvement. In conclusion, clinical deterioration in NMOSD patients is irreversible and almost exclusively takes place at the timing of clinical attacks with stepwise accumulation of neurological disability. Meanwhile, changes in EDSS score can be seen apart from relapses in MS patients. Neurological disability in MS patients is partly reversible, and the patients with disease modifying drugs sometimes present spontaneous improvement of the neurological disability.

Efficacy and safety of alemtuzumab treatment in a real-world cohort of patients with multiple sclerosis.

Alemtuzumab is a monoclonal anti-CD52 antibody prescribed to treat relapsing-remitting multiple sclerosis (RRMS). Alemtuzumab affects the balance of the immune system by depleting circulating lymphocytes, leading to the formation of a new immune repertoire less likely to induce autoimmune attack against CNS myelin. We collected real-world data of RRMS patients treated with alemtuzumab. We assessed relapse rate, disability progression, and MRI-related disease activity over a 24month period. Our study included 35 RRMS patients (19 female and 16 male) with a mean age of 37.3years (SD = 10.5). The patient cohort had a mean disease duration of 10.4years, median previous disease modifying treatments (DMTs) of 3.0, and a median expanded disability status scale (EDSS) score of 4.0 (IQR 2.5-6.0). Neurological disability remained stable during treatment and there was no statistically significant change in EDSS score. Prior to treatment, the median relapse rate was 2.0 (IQR 1.0-3.0); after treatment the median relapse rate was 0.0. This 2.0 decrease in relapse rate is statistically significant (p < 0.0001). Moreover, the treated patients exhibited a statistically significant decrease in gadolinium (GD) enhancing lesions on MRI [both in number (p < 0.005) and volume (p < 0.005)]. Thirty-three percent of patients reached NEDA-3 (no evidence of disease activity) status by the end of treatment. In a real-world setting, alemtuzumab treatment significantly decreased relapse rate and GD-enhancing lesions while preventing disability progression. Tolerability of treatment was high, with patients experiencing only minor adverse events.

Brain Function Assessment of Patients with Multiple Sclerosis in the Expanded Disability Status Scale: A Proposal for Modification.

There is no consensus regarding assessment of the brain function functional system (FS) of the Expanded Disability Status Scale (EDSS) in patients with multiple sclerosis (MS). We sought to describe brain function FS assessment criteria used by Argentinian neurologists and, based on the results, propose redefined brain function FS criteria. A structured survey was conducted of 113 Argentinian neurologists. Considering the survey results, we decided to redefine the brain function FS scoring using the Brief International Cognitive Assessment for MS (BICAMS) battery. For 120 adult patients with MS we calculated the EDSS score without brain function FS (basal EDSS) and compared it with the EDSS score after adding the modified brain function FS (modified EDSS). Of the 93 neurologists analyzed, 14% reported that they did not assess brain function FS, 35% reported that they assessed it through a nonstructured interview, and the remainder used other tools. Significant differences were found in EDSS scores before and after the inclusion of BICAMS (P < .001). Redefining the brain function FS, 15% of patients modified their basal EDSS score, as did 20% of those with a score of 4.0 or less. The survey results show the importance of unifying the brain function FS scoring criteria in calculating the EDSS score. While allowing more consistent brain function FS scoring, including the modified brain function FS led to a change in EDSS score in many patients, particularly in the lower range of EDSS scores. Considering the relevance of the EDSS for monitoring patients with MS and for decision making, it is imperative to further validate the modified brain function FS scoring.

Autologous stem cell transplant in adult multiple sclerosis patients: A study from North India.

Autologous Stem Cell Transplant (ASCT) provides long periods of progression-free-survival in multiple sclerosis (MS). This is an observational study to demonstrate the safety of ASCT in MS patients at a transplant center in North India using a lymphoablative regimen. MS patients > 18 years referred by a neurologist or who came of their own volition were evaluated. Kurtzke Expanded Disability Status Scale (EDSS) score was calculated and those with a score of >7 were excluded. Informed written consent was taken. Mobilization was done with G-CSF with prednisolone to prevent disease flare-up. A minimum of 2 × 106 CD34 cells/kg was collected. Conditioning regimen consisted of rabbit ATG and cyclophosphamide. Rituximab 375 mg/m2 was given to prevent EBV reactivation and disease relapse. Antibiotic prophylaxis was given with levofloxacin, fluconazole, and valacyclovir. Any persistent change in EDSS scores ≥0.5 was considered significant. Twenty patients were included. Seven patients had positive urine cultures prior to transplant and were treated before starting any chemotherapy. Majority patients were women (13/20). All patients developed febrile neutropenia, which was managed as per department policy. There was no mortality. Subjective symptoms improved in all patients. EDSS score improved in 6/19 patients (5/6 with RRMS) with no disease progression in any patient at a median follow-up duration of 242 days. ASCT can be done safely for patients with relatively high EDSS scores with additional precautions for screening for infections. RRMS patients with the active disease show most improvement. SPMS patients may not show significant improvement in the short term.

Efficacy and safety of mesenchymal stem cell therapies for patients with multiple sclerosis: a systematic review and single arm meta-analysis

Background & Aim Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, characterized by an aberrant activation of the immune system and combining demyelination with neurodegeneration. Studies on experimental models of MS revealed immunomodulatory and immunosuppressive properties of mesenchymal stem cells (MSC). However, the efficacy and safety of these treatments are not yet fully understood. Therefore, we performed a meta-analysis of available single-arm studies using clinical trials using MSC in MS patients. Methods, Results & Conclusion Methods We searched MEDLINE, EMBASE, and the Cochrane database for studies of stem cell therapy in patients with MS from its inception through November, 2018. The articles included in the search were restricted to the English language, studies using MSC therapies for treating MS. Results Fourteen studies included in the meta-analysis. The pooled mean difference in Expanded Disability Status Scale (EDSS) scores from baseline to follow-up points was -0.31 points (95%CI: −0.58 to −0.03, I2=53.7%) decreased and the pooled mean difference in size of gadolinium-enhancing lesions on an MRI was decreased by -0.24 (95%CI: -0.56 to 0.08, I2=0%) at 12-month follow-up. The pooled incidence rate of infection was 35.4% (95%CI, 32.9-37.8%) during 12-month follow-up. Conclusions Disease stability was determined by less than a 1.0 point change in EDSS in the 12 months preceding entry into the treatment phase of the study, and lack of gadolinium-enhancing lesions on an MRI and by a stable MRI disease burden over the same period. The EDSS score changes was relatively low even it was statistically significant. The published data suggest that MSC therapy for patients with MS might not be judged as effective based on the current evidence. Transient risks remain associated with the MSC injection was relatively high. Clinical benefits of MSC for MS patients need further investigation and reevaluation to test the well-designed large clinical trials. This research was supported by a grant (18172MFDS182) from the Ministry of Food & Drug Safety in 2018.

Predicting clinical progression in multiple sclerosis after 6 and 12 years

Background and purposeTo predict disability and cognition in multiple sclerosis (MS) after 6 and 12 years, using early clinical and imaging measures.MethodsA total of 115 patients with MS were selected and followed up after 2 and 6 years, with 79 patients also being followed up after 12 years. Disability was measured using the Expanded Disability Status Scale (EDSS); cognition was measured only at follow‐up using neuropsychological testing. Predictors of interest included EDSS score, baseline brain and lesion volumes and their changes over 2 years, baseline age, clinical phenotype, sex and educational level.ResultsHigher 6‐year EDSS score was predicted by early EDSS score and whole‐brain volume changes and baseline diagnosis of primary progressive MS (adjusted R 2 = 0.56). Predictors for 12‐year EDSS score included larger EDSS score changes and higher T1‐hypointense lesion volumes (adjusted R 2 = 0.38). Year 6 cognition was predicted by primary progressive MS phenotype, lower educational level, male sex and early whole‐brain atrophy (adjusted R 2 = 0.26); year 12 predictors included male sex, lower educational level and higher baseline T1‐hypointense lesion volumes (adjusted R 2 = 0.14).ConclusionsPatients with early signs of neurodegeneration and a progressive disease onset were more prone to develop both disability progression and cognitive dysfunction. Male sex and lower educational level only affected cognitive dysfunction, which remains difficult to predict and probably needs more advanced imaging measures.

Neutralizing antibody production against Rebif® and ReciGen® in Relapsing-Remitting Multiple Sclerosis (RRMS) patients and its association with patient's disability

IntroductionHuman recombinant interferon beta (IFN-β) is one of the first line treatments for Relapsing-Remitting Multiple Sclerosis (RRMS). However, the production of neutralizing antibodies (NAb) can impair its function. The aim of this study was to investigate the production of neutralizing antibodies against Rebif® and ReciGen® (two brands of IFN-β-1a) and to evaluate its correlation with Expanded Disability Status Scale (EDSS). Materials and methodsSerum samples of 71 RRMS patients (34 in ReciGen®, 37 in Rebif® group) were collected. Neutralizing antibody was measured by Myxo-virus resistance protein A (MxA) assay using A549 cell line. The MxA concentration was measured by enzyme-linked immunosorbent assay (ELISA) kit. ResultsThe median period of treatment with IFN-β-1a was 18 months in ReciGen® and 24 months in Rebif® arms. The percentage of patients with positive titer of neutralizing antibody (NAb+) had no statistically significant difference between groups (P = 0.6). In both ReciGen® and Rebif® groups, the increase in EDSS score was significantly higher in NAb+ patients compared to NAb− patients (p ≤ 0.05). The duration of using ReciGen® or Rebif® for >24 months was influential in the NAb positivity (OR = 3.78). ConclusionReceiving interferon beta-1a for >24 months is correlated with higher possibility of NAb production. The type of IFN-β used in the study had no significant impact on NAb positivity. In addition, both groups had comparable EDSS score changes, and NAb status of patients was correlated with their EDSS score.

Safety and Efficacy of Natalizumab in Japanese Patients with Relapsing-Remitting Multiple Sclerosis: Open-Label Extension Study of a Phase 2 Trial.

IntroductionThe efficacy of natalizumab was evaluated in Japanese patients with relapsing-remitting multiple sclerosis (RRMS) in a 24-week, phase 2 bridging study. An open-label, 2-year extension study from this trial was conducted to assess the safety and efficacy of natalizumab treatment in Japanese patients.MethodsA total of 97 patients (43 previously on placebo; 54 previously on natalizumab) who had completed the bridging study were treated with 300 mg natalizumab every 4 weeks. Multiple sclerosis relapses, changes in Expanded Disability Status Scale (EDSS) scores, and adverse events were assessed at regular intervals. Anti-natalizumab and anti-JC virus (JCV) antibodies were measured.ResultsAfter 2 years of natalizumab treatment, the mean adjusted annualized relapse rate was 0.30 (95% confidence interval [CI]: 0.18–0.52) among previously-on-placebo patients and 0.13 (95% CI: 0.05–0.29) among previously-on-natalizumab patients. The mean change in EDSS score from baseline to week 120 was −0.03 among previously-on-placebo patients and −0.18 among previously-on-natalizumab patients. In both groups, >90% of patients experienced ≥1 adverse event. Two previously-on-placebo patients developed persistently positive anti-natalizumab antibodies. Approximately 65% of all patients tested positive for anti-JCV antibodies at open-label treatment initiation. No deaths or progressive multifocal leukoencephalopathy cases were reported.ConclusionsThe efficacy and safety findings from this 2-year open-label extension study are comparable to and confirm the results of other clinical trials of natalizumab conducted in non-Asian patient populations, and provide longer-term evidence of efficacy and safety in Japanese patients.Trial registrationClinicalTrials.gov identifier NCT01416155.FundingBiogen.

Health-related quality of life in patients with relapsing-remitting multiple sclerosis treated with subcutaneous interferon β-1a in Iran

Purpose: Multiple sclerosis (MS) requires long-term therapy and can affect many aspects of a patient's life, including quality of life. MS patients score lower on health-related quality of life (HRQoL) measures. The efficacy of subcutaneous interferon (IFN) β-1a has been extensively evaluated by using objective measures but its impact on HRQoL is currently unclear. In this observational study, we evaluated HRQoL of Iranian patients with relapsing-remitting MS (RRMS) treated with IFN β-1a by using short-form 36 (SF-36) and multiple sclerosis international quality of life (MusiQoL) questionnaires. Methods: Four hundred recruited RRMS patients were treated with human serum album free IFN β-1a for 1 year. Patients were required to fill in SF-36 and MusiQoL questionnaires at the first visit and at each follow-up visit. Expanded disability status scale (EDSS) evaluation was performed at baseline and at each visit. Comparisons in HRQoL between visits were calculated using Cohen's d effect size. The relationship between change in EDSS score and the score of each questionnaire was calculated using Pearson correlation coefficients. Results: Three-hundred and eighty three completed the study. Two-hundred and thirty nine were female. Mean (SD) age was 28.75 (±5.49). After 1 year, overall MusiQoL Index score effect size was −0.16 and SF-36 physical component and mental component showed overall effect sizes of −0.28 and −0.53, respectively. Mean (range) EDSS change was 1 (1–4). Three-hundred and seventy four were clinically stable with mean (range) EDSS change of 0.1 (−2–0.5). Increase in EDSS was linked to a decrease in both MusiQoL and SF-36. Conclusion: We found that, HRQoL did not change significantly over the first year of therapy. Furthermore, decreases in HRQoL were inversely correlated with increases in EDSS score.

Predictors of long‐term disability accrual in relapse‐onset multiple sclerosis

To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis. Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed. We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0-2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10(-22) ). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = -0.86, p = 1.3 × 10(-9) ). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = -0.36, p = 0.009). We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89-100.

Brain reserve against physical disability progression over 5 years in multiple sclerosis.

The brain reserve hypothesis links larger maximal lifetime brain growth (MLBG, estimated with intracranial volume [ICV]) with lower risk for cognitive decline/dementia. We examined whether larger MLBG is also linked to less physical disability progression over 5 years in a prospective sample of treatment-naive patients with multiple sclerosis (MS). Physical disability was measured with the Expanded Disability Status Scale (EDSS) at baseline and 5-year follow-up in 52 treatment-naive Serbian patients with MS. MRI measured disease burden (cerebral atrophy, T2 lesion volume) and MLBG: a genetically determined, premorbid (established during adolescence, stable thereafter) patient characteristic estimated with ICV (adjusted for sex). Logistic regression tested whether MLBG (smaller vs larger) predicts disability progression (stable vs worsened) independently of disease burden. Disability progression was observed in 29 (55.8%) patients. Larger MLBG predicted lower risk for progression (odds ratio 0.13, 95% confidence interval 0.02-0.78), independently of disease burden. We also calculated absolute change in EDSS scores, and observed that patients with smaller MLBG showed worse EDSS change (0.91 ± 0.71) than patients with larger MLBG (0.42 ± 0.87). Larger MLBG was linked to lower risk for disability progression in patients with MS over 5 years, which is the first extension of the brain reserve hypothesis to physical disability. MLBG (ICV) represents a clinically available metric that may help gauge risk for future disability in patients with MS, which may advance the science and practice of early intervention. Potential avenues for future research are discussed.

Factors influencing long-term outcomes in relapsing–remitting multiple sclerosis: PRISMS-15

AimAn exploratory study of the relationship between cumulative exposure to subcutaneous (sc) interferon (IFN) β-1a treatment and other possible prognostic factors with long-term clinical outcomes in relapsing–remitting multiple sclerosis (RRMS).MethodsPatients...

EDSS Change Relates to Physical HRQoL While Relapse Occurrence Relates to Overall HRQoL in Patients with Multiple Sclerosis Receiving Subcutaneous Interferon β -1a.

Objective. To compare patterns of associations of changes in mental and physical health dimensions of health-related quality of life (HRQoL) over time with relapse occurrence and changes in Expanded Disability Status Scale (EDSS) scores in patients with relapsing multiple sclerosis (RMS). Methods. This 24-month, phase IV, observational study enrolled 334 patients with RMS who received interferon β-1a 44 μg or 22 μg subcutaneously three times weekly. At each 6-month visit, patients completed the Multiple Sclerosis Quality of Life-54 (MSQOL-54) and site investigators assessed EDSS and recorded relapse occurrence. A generalized linear model procedure was used for multivariable analyses (per protocol) that explored unique associations of EDSS score change and relapse occurrence with MSQOL-54 physical health composite score (PCS) and mental health composite score (MCS). Results. HRQoL improved over 2 years among those who completed the study. Occurrence of ≥1 relapse was significantly associated with lower MSQOL-54 PCS and MCS. Changes in EDSS score were significantly associated with MSQOL-54 PCS, but not MCS. Conclusions. HRQoL assessments, particularly those that examine mental health, may provide information on the general health status of patients with RMS that would not be recognized using traditional clinician-assessed measures of disease severity and activity. This trial is registered with ClinicalTrials.gov; identifier: NCT01141751.

Quantitative texture analysis of brain white matter lesions derived from T2-weighted MR images in MS patients with clinically isolated syndrome

This study investigates the application of texture analysis methods on brain T2-white matter lesions detected with magnetic resonance imaging (MRI) for the prognosis of future disability in subjects diagnosed with clinical isolated syndrome (CIS) of multiple sclerosis (MS). Brain lesions and normal appearing white matter (NAWM) from 38 symptomatic untreated subjects diagnosed with CIS as well as normal white matter (NWM) from 20 healthy volunteers, were manually segmented, by an experienced MS neurologist, on transverse T2-weighted images obtained from serial brain MR imaging scans (0 and 6-12 months). Additional clinical information in the form of the Expanded Disability Status Scale (EDSS), a scale from 0 to 10, which provides a way of quantifying disability in MS and monitoring the changes over time in the level of disability, were also provided. Shape and most importantly different texture features including GLCM and laws were then extracted for all above regions, after image intensity normalization. The findings showed that: (i) there were significant differences for the texture futures extracted between the NAWM and lesions at 0 month and between NAWM and lesions at 6-12 months. However, no significant differences were found for all texture features extracted when comparing lesions temporally at 0 and 6-12 months with the exception of contrast (gray level difference statistics-GLDS) and difference entropy (spatial gray level dependence matrix-SGLDM); (ii) significant differences were found between NWM and NAWM for most of the texture features investigated in this study; (iii) there were significant differences found for the lesion texture features at 0 month for those with EDSS≤2 versus those with EDSS>2 (mean, median, inverse difference moment and sum average) and for the lesion texture features at 6-12 months with EDSS>2 and EDSS≤2 for the texture features (mean, median, entropy and sum average). It should be noted that whilst there were no differences in entropy at time 0 between the two groups, significant change was observed at 6-12 months, relating the corresponding features to the follow-up and disability (EDSS) progression. For the NAWM, significant differences were found between 0 month and 6-12 months with EDSS≤2 (contrast, inverse difference moment), for 6-12 months for EDSS>2 and 0 month with EDSS>2 (difference entropy) and for 6-12 months for EDSS>2 and EDSS≤2 (sum average); (iv) there was no significant difference for NAWM and the lesion texture features (for both 0 and 6-12 months) for subjects with no change in EDSS score versus subjects with increased EDSS score from 2 to 5 years. The findings of this study provide evidence that texture features of T2 MRI brain white matter lesions may have an additional potential role in the clinical evaluation of MRI images in MS and perhaps may provide some prognostic evidence in relation to future disability of patients. However, a larger scale study is needed to establish the application in clinical practice and for computing shape and texture features that may provide information for better and earlier differentiation between normal brain tissue and MS lesions.

Relating health-related Quality of Life to disability progression in multiple sclerosis, using the 5-level EQ-5D

Background: Increasing use of the Quality-Adjusted Life-Year to inform resource allocation decision-making has highlighted the importance of relating clinical and health-related quality of life (HRQoL) outcomes in multiple sclerosis (MS) patients. Objective and Methods: To investigate the relationship between the Expanded Disability Status Scale (EDSS) and HRQoL utility, using the 5-level EQ-5D (EQ-5D-5L). The discriminatory power of the EQ-5D-5L was assessed using Shannon’s indices. Results: A linear decline in utility was observed with changes in EDSS score from 0 to 6, after which point the relationship exhibited greater variability. Mean utility values ranged from −0.22 at EDSS 9 to 0.88 at EDSS 0. We found that the discriminative capacity of the EQ-5D-5L was considerably lower for the domains self-care and anxiety/depression, compared with other health-related domains. Conclusion: In its first reported use in an MS population, the EQ-5D-5L displayed good discriminatory capacity, although performance differed between the various domains of health, with evidence of a ceiling effect present in the domains of self-care and anxiety/depression. The EQ-5D-5L demonstrated a high correlation with EDSS in our MS cohort up to EDSS 6, after which point the utility valuation of severe health states exhibited much greater variability. Utility estimates from this study may be used in economic evaluations of disease-modifying therapies in MS, to inform resource-allocation decisions.

Treatment de-escalation after mitoxantrone therapy: results of a phase IV, multicentre, open-label, randomized study of subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis

The objective of this study was to assess the effect of treatment with interferon (IFN) β-1a, 44 µg subcutaneously (sc) three times weekly (tiw), on clinical and magnetic resonance imaging (MRI) outcomes in patients with relapsing multiple sclerosis (MS) following mitoxantrone therapy. This was an open-label, randomized, multicentre, rater-blinded, 96-week observational study conducted in Germany. Clinically stable patients with relapsing forms of MS, who had discontinued mitoxantrone treatment 1-6 months before study entry, were randomized to IFN β-1a sc 44 µg tiw, or no treatment. The primary endpoint was time to first relapse. Secondary endpoints included the number of relapse-free patients, disease activity assessed by MRI and time to 3-month confirmed Expanded Disability Status Scale (EDSS) progression, all at week 96. A total of 30 patients were randomized (intent-to-treat population: 14 IFN β-1a, 15 untreated; one patient from the safety population discontinued the study after 25 days owing to an adverse event and without providing any postbaseline efficacy data, and was thus excluded from the intent-to-treat population). Overall, 71.4% (10/14) of patients in the IFN β-1a group remained relapse free over 96 weeks, versus 46.7% (7/15) in the untreated group (p = 0.26). IFN β-1a delayed the time to first relapse versus no treatment (p = 0.14); time to first relapse (25th percentile) was 95.4 (IFN β-1a) versus 46.0 weeks (no treatment). Confirmed EDSS progression was observed in five patients in each treatment group. Mean change in EDSS score was 0.3 in both groups (p = 0.79). Changes in the number or volume of T1 and T2 lesions at week 96 were not significantly different between treatment groups (p > 0.05). There were no new or unexpected adverse events related to IFN β-1a treatment. Several endpoints appeared to show a benefit of IFN β-1a treatment, but no significant differences could be detected owing to the small sample. Therefore, these data only permit, at best, tentative conclusions about the disease course in patients with MS after de-escalation from mitoxantrone and continuation with or without IFN β-1a. Larger confirmatory studies are required.

Additional efficacy endpoints from pivotal natalizumab trials in relapsing-remitting MS

Standard clinical endpoints in multiple sclerosis (MS) studies, such as disability progression defined by the expanded disability status scale (EDSS) and annualized relapse rate, may not fully reflect all aspects of therapeutic benefit experienced by patients. Pivotal studies showed that natalizumab is effective both as monotherapy (AFFIRM study) and in combination with interferon beta-1a (IFNβ-1a) (SENTINEL study) in patients with relapsing MS. We present AFFIRM and SENTINEL data demonstrating the efficacy of natalizumab on prespecified tertiary endpoints, including extent of confirmed change in EDSS score from baseline, time to sustained progression to EDSS milestone scores, hospitalizations, corticosteroid use, and time to confirmed progression of cognitive deficits. Natalizumab significantly reduced changes in EDSS scores (P < 0.001) and proportion of patients progressing to an EDSS score ≥4.0 (P < 0.001) and ≥6.0 (P = 0.002) compared with placebo. Natalizumab + IFNβ-1a significantly reduced changes in EDSS scores compared with placebo + IFNβ-1a (P = 0.011). Based on 0.5 standard deviation change in paced auditory serial addition test-3 score, natalizumab treatment reduced the risk of confirmed progression of cognitive deficits by 43% compared with placebo (HR 0.57 [95% CI 0.37, 0.89], P = 0.013); however, no significant difference between groups was seen in SENTINEL. Natalizumab, both as monotherapy and in combination with IFNβ-1a, significantly reduced the annualized rate of MS-related hospitalizations (by 64 and 61%, respectively) and the annualized rate of relapses severe enough to require steroid treatment (by 69 and 61%, respectively) compared with placebo and placebo + IFNβ-1a (P < 0.001). These analyses underline beneficial effects of natalizumab therapy in relapsing MS patients.

Functional system scores provide a window into disease activity occurring during a multiple sclerosis treatment trial

<title/>Background: Average expanded disability status scale (EDSS) score on entry into pivotal trials of multiple sclerosis (MS) therapies lies between 2 and 3. These lower EDSS levels are determined by functional system score (FSS).Objective: We examined contributions of each FSS to characterization of MS patients at entry to and exit from the pivotal trial of intramuscular interferon beta-1a (IM IFN-beta-1a), as well as contribution of changes in FSS to changes in EDSS.Methods: We reviewed FSS and EDSS data collected at 6-month examinations during the IM IFN-beta-1a pivotal trial (n = 286). To describe which functional systems were most affected by disease, we used an FSS cutoff of 2 (mild to moderate impairment) and defined sustained progression as a 1 point change in EDSS score or FSS being maintained for 6 months.Results: The most frequently involved functional systems at baseline (FSS level of 2) were cerebellar (38%), pyramidal (37%), and sensory (34%). While all functional systems were affected to some extent by progressing MS, these FSSs were also most often affected at study end, with pyramidal and cerebellar FSSs being the greatest contributors to sustained EDSS progression. Treatment effect with IM IFN-beta-1a was most strongly seen in the pyramidal system.Conclusion: In this trial, some FSSs contributed more to detection of progression than others. While changes in lower EDSS were heavily weighted by the pyramidal FSS, all of the FSSs appeared to be important in understanding the overall impact of MS progression, demonstrating the responsive nature of the widely utilized EDSS.