A single-arm, open-label study of alemtuzumab in treatment-refractory patients with multiple sclerosis

Background: Alemtuzumab (CD52‐specific humanized monoclonal antibody) was found to be an effective therapy for treatment‐naive patients with relapsing‐remitting multiple sclerosis. Objective: Evaluate alemtuzumab’s effects in patients with treatment‐refractory relapsing‐remitting multiple sclerosis. Methods: Forty‐five relapsing‐remitting multiple sclerosis patients who experienced ≥2 relapses during 2 years prior to the study entry whilst receiving interferon therapy were administered 24 mg IV alemtuzumab/day for 5 days at baseline and 3 days 12 months later. Patients received premedication with 1 g IV methylprednisolone on days 1–3 at both times. Results: After 2‐year follow‐up, the annualized relapse rate was reduced by 94% compared to pre‐treatment levels, from 1.6 (2 years prior to treatment) to 0.17 for the 2 years following (P < 0.0001). Moreover, 86% of patients showed stable or improved scores on the Expanded Disability Status Scale, and only 1 experienced an increase in disability lasting ≥6 months. The majority (70–88%) showed stable or improved leg, arm and cognitive function as measured by the Multiple Sclerosis Functional Composite. Serious adverse events observed in single patients were transient neutropenia and pneumonia, pulmonary emboli and deep vein thrombosis. Five patients developed clinical thyroid disorders but no opportunistic infections or cases of immune thrombocytopenic purpura were observed. Conclusions: Alemtuzumab effectively reduced relapse rates and improved clinical scores in patients with active relapsing‐remitting multiple sclerosis not controlled by interferon therapy.     

Natalizumab vs interferon beta 1a in relapsing-remitting multiple sclerosis: a head-to-head retrospective study

Background – No head‐to‐head study has been performed yet to assess whether natalizumab is more effective than classical immunomodulators in multiple sclerosis (MS). Aim – To retrospectively compare the efficacy of natalizumab vs IFN beta 1a SC (44 μg; Rebif^®) on clinical and radiological findings in two matched cohorts of patients with MS. Patients and methods – We retrospectively enrolled two cohorts of 42 patients (F/M: 35/7) with relapsing‐remitting multiple sclerosis treated with natalizumab or IFN beta 1a for at least 12 consecutive months. Outcome measures were annualized relapse rate (ARR), changes in expanded disability status scale (EDSS) score, and number of contrast‐enhancing lesions (CELs) at magnetic resonance imaging (MRI). Results – In both groups, the ARR in the 12 months of treatment was lower than in the 12 months before therapy (0.24 vs 1.50 in natalizumab‐treated group, P < 0.0000; 0.55 vs 1.10 in IFN beta 1a‐treated group, P = 0.0006), being the effect of natalizumab significantly stronger (P = 0.0125). EDSS reduction was significantly different between the two groups in favor of natalizumab (P = 0.0018). The frequency and number of CELs per patient were decreased in both groups. In the second year, the treatment affected ARR and EDSS progression in the two groups of patients similarly to the first year, whereas number of CELs decreased more significantly in natalizumab group (P = 0.008). Conclusions – After 12 and 24 months of therapy, natalizumab was more effective than IFN beta 1a SC on both disease activity and disability progression. Prospective head‐to‐head studies would be helpful to further evaluate the differences observed in the MRI outcomes.     

Multiple sclerosis relapses: a multivariable analysis of residual disability determinants

Background – Recovery from multiple sclerosis (MS) relapses is variable. The factors influencing persistence of residual disability (RD) after a relapse are still to be thoroughly elucidated. Aims of study – To assess RD after MS relapses and to define the factors associated with persistence of RD. Methods – Data were retrospectively collected for all relapses in a population of relapsing–remitting MS patients during 3 years. Relapse severity and RD after 1 year were calculated on Expanded Disability Status Scale basis. A multivariable analysis for factors influencing RD and relapse severity was performed (variables: age, gender, disease duration, oligoclonal bands, relapse severity, monosymptomatic/polysymptomatic relapse, immunomodulating treatment, incomplete recovery at 1 month). Results – A total of 174 relapses were assessed. RD after 1 year was observed in 54.5% of the relapses. Higher risk of RD was associated with occurrence of a severe relapse (P = 0.024). Incomplete recovery at 1 month was highly predictive of RD at 1 year (P < 0.0001). Risk of a severe relapse was associated with age ≤ 30 years (P = 0.025) and inversely associated with the use of immunomodulating treatment (P = 0.006). Conclusions – Incomplete recovery at 1 month is a predictor of long‐term persistence of RD. Higher relapse severity is associated with higher risk of RD. Risk of severe relapses is lower in patients treated with immunomodulating drugs.     

Anti‐EBNA‐1 IgG is not a reliable marker of multiple sclerosis clinical disease activity

Background: Sero‐epidemiological studies have demonstrated the association between multiple sclerosis (MS) and prior Epstein–Barr virus (EBV) infection. It has been hypothesized that intermittent peripheral EBV reactivation may drive continuing central inflammation. Recent investigation has shown significant differences in median serum levels of anti‐EBV nuclear antigen‐1 (EBNA‐1) IgG between disease subgroups and positive correlation with disease activity reflected by number of Gd‐enhancing lesions and T2 lesion volume. These important data have led to hopes that anti‐EBNA‐1 IgG may be useful as an easily accessible and effective biomarker of disease activity. Methods: We examined the applicability of these findings in routine clinical practice, assessing a well‐characterized cohort of 100 subjects (25 primary progressive, 25 stable relapsing remitting, 25 active relapsing remitting seen in acute relapse and 25 controls) for serum anti‐EBNA‐1 IgG using both the Liaison quantitative chemiluminescent assay and Biotest ELISA. Results: We were unable to show a difference in quantitative analysis of serum anti‐EBNA‐1 IgG levels between disease subgroups and no correlation with phenotypic characteristics including age at onset (r = ?0.17, P = 0.16), disease duration (r = 0.03, P = 0.78), EDSS (r = 0.03, P = 0.78) or MSSS (r = 0.02, P = 0.9). In addition, there was only moderate correlation between the two test methods used (intraclass correlation coefficient 0.67; 0.56–0.78) suggesting potential problems with test interpretation. Conclusions: We have been unable to determine a clinical value for serum anti‐EBNA‐1 IgG levels in MS or to confirm reported association with disease course and clinical disease activity.     

Glatiramer acetate in treatment-naïve and prior interferon-beta-1b-treated multiple sclerosis patients

Objective – This prospective, open‐label study evaluated the efficacy, safety, and tolerability of glatiramer acetate (GA) in treatment‐naïve relapsing–remitting multiple sclerosis (RRMS) patients and in patients who had previously received interferon‐β (IFN‐β)‐1b therapy. Methods – Two treatment cohorts were defined based on prestudy IFN‐β‐1b use. At entry, prior IFN‐β‐1b patients (n = 247) were older, had longer disease duration, and had higher mean Expanded Disability Status Scale (EDSS) scores, relapse rates, and ambulation indexes than treatment‐naïve patients (n = 558). Safety was assessed every 3 months and EDSS every 6 months for up to 3.5 years. Results – Overall, 247 treatment‐naïve and 107 prior IFN‐β‐1b patients discontinued before study end. Median GA treatment durations were 36 and 24 months in treatment‐naïve and prior IFN‐β‐1b patients, respectively. At last observation, annual relapse rates had declined by 75% in both cohorts (0.42 ± 0.84 and 0.34 ± 0.71 in treatment‐naïve and prior IFN‐β‐1b groups, respectively, P = 0.1482). Mean changes in EDSS were less than 0.5 in both cohorts, regardless of entry EDSS, at 12 and 18 months and at last observation. Conclusions – Prior IFN‐β‐1b treatment does not negatively influence the efficacy, safety, or tolerability of subsequent GA therapy. Switching to GA can benefit patients who discontinue IFN‐β therapy.     

Natalizumab induces a rapid improvement of disability status and ambulation after failure of previous therapy in relapsing‐remitting multiple sclerosis

Background: Natalizumab (Tysabri) is a monoclonal antibody that was recently approved for the treatment of relapsing‐remitting multiple sclerosis (RRMS). Our primary objective was to analyse the efficacy of natalizumab on disability status and ambulation after switching patients with RRMS from other disease‐modifying treatments (DMTs). Methods: A retrospective, observational study was carried out. All patients (n = 45) initiated natalizumab after experiencing at least 1 relapse in the previous year under interferon‐beta (IFNB) or glatiramer acetate (GA) treatments. The patients also had at least 1 gadolinium‐enhancing (Gd+) lesion on their baseline brain MRI. Expanded Disability Status Scale (EDSS) scores, and performance on the Timed 25‐Foot Walk Test and on the Timed 100‐Metre Walk Test were prospectively collected every 4 weeks during 44 weeks of natalizumab treatment. Brain MRI scans were performed after 20 and 44 weeks of treatment. Results: Sixty‐two per cent of patients showed no clinical and no radiological signs of disease activity, and 29% showed a rapid and confirmed EDSS improvement over 44 weeks of natalizumab therapy. Patients with improvement on the EDSS showed similar levels of baseline EDSS and active T1 lesions, but had a significantly higher number of relapses, and 92% of them had experienced relapse‐mediated sustained EDSS worsening in the previous year. A clinically meaningful improvement in ambulation speed was observed in approximately 30% of patients. Conclusions: These results indicate that natalizumab silences disease activity and rapidly improves disability status and walking performance, possibly through delayed relapse recovery in patients with RRMS who had shown a high level of disease activity under other DMTs.     

Variation of serum uric acid levels in multiple sclerosis during relapses and immunomodulatory treatment

Uric acid (UA), a product of purine metabolism, may be an antioxidant, perhaps acting as a scavenger of peroxynitrite. Patients with gout have a reduced incidence of multiple sclerosis (MS). A number of studies found that patients with MS have low serum levels of UA, although it has not been established whether this represents a primary deficit or a secondary effect. UA has also been proposed as a marker of disease activity and response to immunosuppressive or immunomodulatory treatment. We retrospectively reviewed 83 relapsing–remitting or secondary progressive MS patients (64 females and 19 males) followed in our Neurology Unit. We collected data concerning demographic variables as age and sex, and clinical variables as age of onset, clinical type, disease duration, EDSS score and total number of relapses. We considered UA levels in three different situations: during a relapse, during remission period and during remission period under immunomodulatory treatment [Interferon Beta 1a im (Avonex; Biogen Idec Inc., Cambridge, MA, USA), Interferon Beta 1a sc (Rebif; Serono Europe Limited, London, UK), Interferon Beta 1b (Betaferon; Bayer Schering Pharma AG, Berlin, Germany) or Glatiramer Acetate (Copaxone; TEVA Neuroscience LLC, Kansas City, MO, USA)]. A Wilcoxon matched pairs test was carried out to determine differences between groups. A P‐value less than 0.05 was considered statistically significant. In 33 patients, we were able to compare at least one UA value obtained during a relapse with at least one when remission without treatment. Mean serum UA levels were significantly lower when measured during a relapse (r: 0.39, P: 0.024). In 27 cases, we compared at least one remission value without treatment with at least one obtained during remission and immunomodulatory treatment. Mean serum UA levels significantly increased when determined during Interferon Beta or Glatiramer Acetate therapy (r: 0.84, P < 0.001). Although we do not know exactly whether and how UA is involved in MS pathogenesis, our data suggest that UA might reflect disease activity or treatment response in MS.     

Headache and Chiari malformation in young age: clinical aspects and differential diagnosis

To evaluate the efficacy and safety of natalizumab in patients with active relapsing–remitting multiple sclerosis (MS). We included 285 MS patients receiving natalizumab. Clinical, neuroradiological and safety data were registered every 6 months. Neutralizing antibodies (NABs) were tested after 6 months of treatment. After 1 year, the annualized relapse rate decreased to 0.26, with a significant reduction compared to the previous year (2.13). At 24 months the proportion of “relapse free” patients was 78% while that of “MRI free” patients was 69%. Considering clinical and MRI cumulative activity, “disease free” patients were 63% at 24 months. A total of 18 patients showed NABs positivity. We reported 34 cases of treatment interruptions. In conclusion, our data confirm the remarkable efficacy of natalizumab in a group of patients with higher disease activity than that of pivotal studies.     

Impact of cladribine on soluble adhesion molecules in multiple sclerosis

Mitosek‐Szewczyk K, Stelmasiak Z, Bartosik‐Psujek H, Belniak E. Impact of cladribine on soluble adhesion molecules in multiple sclerosis.
Acta Neurol Scand: 2010: 122: 409–413.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Background – Soluble forms of vascular cell adhesion molecule‐1 (VCAM‐1), intracellular adhesion molecule‐1 (ICAM‐1) and E‐Selectin play a role in the regulation of blood–brain barrier damage and represent markers of the clinical course of multiple sclerosis (MS) and magnetic resonance imaging activity. We determined sICAM, sVCAM and sE‐Selectin concentrations in the cerebrospinal fluid (CSF) and serum of patients with remitting–relapsing multiple sclerosis before and after cladribine treatment as well as in a control group. Methods – We examined 17 patients diagnosed according to McDonald’s criteria. Thirteen healthy age‐matched subjects served as controls. The ELISA method was used to measure sICAM‐1, sVCAM‐1 and sE‐Selectin. Results – The concentration of sICAM and sE‐Selectin decreased in sera (difference between patients and controls was statistically significant, in the former P < 0.04, in the latter P < 0.0003) but not in the CSF of MS patients after cladribine treatment. Conclusions – The reduction in sICAM and sE‐Selectin concentrations after cladribine treatment indicates an immuno‐suppressive effect of the drug. The changes in levels of sICAM and sE‐Selectin after cladribine treatment reflect disease activity and indicate a reduction in the inflammatory reaction.     

Evaluation of health‐related quality of life,fatigue and depression in neuromyelitis optica

Background: The burden of multiple sclerosis (MS) includes fatigue, depression and worsening of health‐related quality of life (HRQOL). These changes have not been yet measured in neuromyelitis optica (NMO). Our aim was to assess the HRQOL, fatigue and depression in NMO. Methods: We administered French validated self‐questionnaires on HRQOL (SEP‐59), fatigue (EMIF‐SEP) and depression (EHD) to 40 patients followed up in two centres. We assessed the relationship of these parameters with gender, age, disability, disease duration, visual acuity and NMO‐antibody status and also compared our results with equivalent data in MS and normal subjects derived from previous studies. Results: Health‐related quality of life scores were lower (P < 0.01) in patients with NMO when compared to normal subjects. No significant difference was noted between patients with NMO and MS for most scores, the exceptions being HRQOL related to cognitive function (better in NMO than in MS), HRQOL related to sphincter dysfunction (worse in NMO than in MS) and the psychological dimension of fatigue (milder in NMO than in MS). Disability was the main predictive factor of an unfavourable evolution. Discussion: This study reveals the strong impact of NMO on HRQOL, fatigue and depression and the importance of screening patients, especially the more disabled, so as to initiate suitable treatment.     

Insulin‐like growth factor (IGF)‐I and IGF‐binding protein‐3 serum levels in relapsing–remitting and secondary progressive multiple sclerosis patients

Background: Insulin‐like growth factor (IGF)‐I has a role in remyelination, and insulin‐like growth factor‐binding protein‐3 (IGFBP‐3) might reduce its bioavailability. A role of IGFBP‐3 in multiple sclerosis (MS) progression was hypothesized in patients with primary progressive (PP) MS. Objective: To evaluate serum levels of IGF‐I and IGFBP‐3 in patients with relapsing–remitting (RR) and secondary progressive (SP) MS and their correlations with disease activity and progression. Methods: Sixty‐three (41 RR and 22 SP) ‘naive’ MS patients and 60 age‐matched healthy controls were enrolled. Patients were assessed through clinical [Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), number of relapses] and laboratory investigations. IGF‐I and IGFBP‐3 were measured by ELISA. Results: Levels of IGF‐I and IGFBP‐3 were similar in the two MS groups. IGFBP‐3 levels were higher in patients with MS than in controls (P < 0.001), with a reduction in IGF‐I/BP3 ratio (P < 0.001). Patients showing IGFBP‐3 levels higher than 2SD of the normal population had a higher EDSS (mean EDSS 3.7 vs. 2.8, P = 0.021). MSSS was not related to IGF‐I or IGFBP‐3 serum levels. Conclusions: Our patients showed high IGFBP‐3 serum levels respect to controls and higher serum levels were associated with a higher EDSS, despite of comparable disease duration. Therefore, MS and higher disability seem to be associated with a reduction in bioavailability of IGF‐I. MSSS score was not related to IGFBP‐3 levels, suggesting that IGFBP‐3 might not have the pathogenetic role previously suggested for PP MS, in the mechanism of progression in the SP form of disease.     

Serum and CSF PDGF‐AA and FGF‐2 in relapsing‐remitting multiple sclerosis: a case–control study

Background and purpose: Fibroblast growth factor‐2 (FGF‐2) and platelet‐derived growth factor‐A (PDGF‐AA) are potent modulators of oligodendrocytes, the main responsible cells for myelin regeneration. We measured FGF‐2 and PDGF‐AA in the sera and cerebrospinal fluid (CSF) of patients with relapsing‐remitting multiple sclerosis (RR‐MS) and compared these values with control subjects. Methods: Twenty‐three patients with RR‐MS and 23 subjects without inflammatory and demyelinating diseases were included. Serum samples of the patients were collected in both relapse and remission phases and were analyzed with ELISA method. CSF was drawn during the relapse period. Blood and CSF were drawn from control subjects for comparison. Wilcoxon and Mann–Whitney U‐test and Spearman’s rank correlation were used for analysis. P values of <0.05 were considered significant. Results: Age and sex distribution were similar in both groups. Serum values of FGF‐2 were higher in relapse phase compared with remission phase, with a trend toward significance (P = 0.052). CSF PDGF‐AA showed significant negative correlation with disease duration (correlation coefficient = ?0.58, P = 0.004). Serum levels of PDGF did not differ between two phases significantly. There was no difference in serum and CSF values of these factors between patients and controls. When we compared patients with prolonged disease with controls, a significant difference between the CSF levels of PDGF‐AA was observed (mean ± SEM 2.78 ± 0.8 in controls vs. 0.55 ± 0.29 in patients with MS ≥ 2 years, P < 0.05). Conclusion: Our study was the first to show that CSF PDGF‐AA is related to disease duration. Supporting previous findings we showed that serum and CSF levels of these factors are weak indicators of disease severity.     

A prospective, open-label treatment trial to compare the effect of IFN β-1a (Avonex), IFNβ-1b (Betaseron), and glatiramer acetate (Copaxone) on the relapse rate in relapsing-remitting multiple sclerosis

A prospective, non‐randomized, open‐label treatment trial was performed in patients with relapsing‐remitting multiple sclerosis (RRMS), with follow up for 12 months. Our primary objective was to prospectively compare the effect of IFNβ‐1a (Avonex), IFNβ‐1b (Betaseron), and glatiramer acetate (GA, Copaxone) on the relapse rate in patients with RRMS. Between August 1996 and September 1999, 156 consecutive patients with clinically definite RRMS with a Kurtzke scale (EDSS) score of 4 or less were followed for 12 months, from the time of initiating therapy or electing to remain untreated. Prior 2‐year relapse history and available chart information was carefully reviewed at the time of enrolment. Thirty‐three of 156 elected no treatment (mean age 32.5 years; mean EDSS 2.64) at enrolment; 40 elected IFNβ‐1a (mean age 32.4 years; mean EDSS 2.69), 41 IFNβ‐1b (mean age 32.1 years; mean EDSS 2.56), and 42 chose GA (mean age 31.5 years; mean EDSS 2.57). Annual relapse rate based upon the 2 years prior to enrolment was 1.08 in the untreated group, 1.20 in the AV group, 1.21 in the BE group, and 1.10 in the GA group. There were no statistically significant differences among the four groups at enrolment. After 12 months of treatment, patients in the untreated groups had a relapse rate of 0.97, whereas patients in the IFNβ‐1a, IFNβ‐1b, and GA groups had relapse rate of 0.85, 0.61, and 0.62, respectively. Compared to the untreated group, reduction in the relapse rate was statistically significant only in the GA (P=0.003) and IFNβ‐1b (P=0.002) groups, in contrast to the IFNβ‐1a treated patients, who did not show a significant reduction (P=0.309). Compared to the untreated patients, mean EDSS was significantly reduced only in the GA (P=0.001) and IFNβ‐1b (P=0.01), in contrast to IFNβ‐1a treated patients (P=0.51). In this prospective, controlled, open‐label, non‐randomized 12‐month study, treatment with only GA and IFNβ‐1b significantly reduced the relapse rate compared to untreated patients, supporting early treatment in RRMS. Our results are similar to the observations made after 12 months of therapy in phase III studies of IFNβ‐1a, IFNβ‐1b, and GA. Despite some limitations of the study design, the results provide helpful clinical information regarding the relative efficacy of each therapy in mildly affected treatment‐naïve RRMS patients.     

Elevated HSP27 levels during attacks in patients with multiple sclerosis

Ce P, Erkizan O, Gedizlioglu M. Elevated HSP27 levels during attacks in patients with multiple sclerosis.
Acta Neurol Scand: 2011: 124: 317–320.
© 2011 John Wiley & Sons A/S. Objectives – The small heat shock protein, HSP27, has been shown to have a more potent protective effect in the nervous system. However, there is limited information about the behavior of HSP27 in the course of multiple sclerosis (MS). Thus, we investigated the HSP27 levels during relapse and remission phases of MS. Materials and Methods – A total of 50 relapsing–remitting or secondary progressive MS patients and 45 age‐ and gender‐matched controls without any systemic diseases were enrolled. HSP27 levels were serologically detected in serum samples of both controls and MS patients during acute attacks and after a minimum of 2 months of each individual attack. Results – The mean HSP27 level was 12.41 ± 18.21 ng/ml in the attack phase, 4.58 ± 4.75 ng/ml during remission, and 2.58 ± 3.88 ng/ml in control patients. The heat shock proteins (HSP) levels of MS patients in the attack phase were significantly higher than those obtained in the remission phase (P = 0.005). Moreover, HSP levels in the attack and remission phases of MS patients were also significantly higher when compared to controls (P = 0.001 and P = 0.03, respectively). While there was no correlation between HSP27 levels in the attack phase and age, disease duration, or expanded disability status scale scores (P = 0.69, P = 0.32, and P = 0.91, respectively), a positive correlation was observed between the HSP27 levels and the total attack number (P = 0.001). Conclusions – Our findings revealed a marked elevation in HSP27 levels during the relapse phase. Therefore, it can be suggested that elevated HSP27 levels may guide in the accurate detection of an attack in patients with MS.     

Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing–remitting multiple sclerosis: subgroup analyses of the CONFIRM study

In the phase 3, randomized, placebo-controlled and active reference (glatiramer acetate) comparator CONFIRM study in patients with relapsing–remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) reduced the annualized relapse rate (ARR; primary endpoint), as well as the proportion of patients relapsed, magnetic resonance imaging lesion activity, and confirmed disability progression, compared with placebo. We investigated the clinical efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, Expanded Disability Status Scale score, T2 lesion volume, and gadolinium-enhancing lesions. BG-12 treatment demonstrated generally consistent benefits on relapse-related outcomes across patient subgroups, reflecting the positive findings in the overall CONFIRM study population. Treatment with BG-12 BID and TID reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in all subgroups analyzed. Reductions in ARR with BG-12 BID versus placebo ranged from 34 % [rate ratio 0.664 (95 % confidence interval 0.422–1.043)] to 53 % [0.466 (0.313–0.694)] and from 13 % [0.870 (0.551–1.373)] to 67 % [0.334 (0.226–0.493)] with BG-12 TID versus placebo. Treatment with glatiramer acetate reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in most patient subgroups. The results of these analyses indicate that treatment with BG-12 is effective on relapses across a broad range of patients with relapsing–remitting multiple sclerosis with varied demographic and disease characteristics.     

Autoantibody synthesis in primary progressive multiple sclerosis patients treated with interferon beta-1b

Abstract We conducted an open-labeled clinical trial of interferon beta-1b (IFNB) treatment in 20 patients with primary progressive multiple sclerosis (PPMS) and longitudinally monitored autoantibodies against double-stranded DNA (dsDNA), thyroid peroxidase (TPO),myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), synapsin and S-100B. Before treatment, one patient had elevated TPO antibodies, four patients had elevated antibodies against S-100B, two patients against MOG or synapsin and one patient against MBP. In two patients we observed a continuous increase of dsDNA or TPO antibodies above the normal range. This rise paralleled IFNB treatment. In addition, 11 of 20 patients developed neutralizing antibodies against IFNB. There was no increase of autoantibodies directed against central nervous system antigens. Like patients with relapsing remitting or secondary progressive multiple sclerosis, PPMS patients may be at risk of an autoimmune response during IFNB treatment.     

The macrophage activity marker sCD14 is increased in patients with multiple sclerosis and upregulated by interferon beta-1b

The soluble form of the CD14 molecule (sCD14), a macrophage activity marker, was measured in the plasma of 17 patients with primary progressive multiple sclerosis (PPMS) and 20 patients with relapsing remitting MS (RRMS). In patients with PPMS, sCD14 levels were determined before and after treatment with interferon beta (IFNB). In both PPMS and in RRMS, sCD14 levels were significantly elevated compared to healthy controls. In patients with PPMS, sCD14 levels increased significantly during the first 3 months of IFNB therapy, then slightly decreased, but still remained elevated compared with levels before therapy. Therefore, the elevated sCD14 levels may be a marker in evaluating biological response to IFNB therapy.     

Multiple sclerosis without treatment: characteristic features of 70 untreated patients in a cohort of 1187 patients

IntroductionFirst treatment protocols for multiple sclerosis (MS) have been established in France for over 15 years. Presently, a large majority of patients are treated, or has been treated in the past years, with one or more disease modifying drugs. However, despite a long-term follow-up, a certain patients remain untreated.ObjectiveThe aim of this study was to determine in a large cohort the proportion of patients who never received any medication for MS and to analyze their profiles and reasons for no treatment.Patients and methodsWe studied a cohort of 1187 MS patients followed in a French (Alsace) cohort, all included in the EDMUS (European database for Multiple Sclerosis). We then performed a retrospective study on patients followed from at least 5 years (724 patients) and retained those who had never received MS medication.ResultsSeventy patients (9.8% of the whole cohort) corresponded to the inclusion criteria. They were 57 women and 13 men, mean age 54.9 years (range 33–81). The mean duration of the disease was 20.6 years (range 5–56). MS was of relapsing remitting type in 46 patients (65.7%), primary progressive in 11 patients (15.7%) and secondary progressive in 13 patients (18.6%). In patients with relapsing remitting disease, the annualized relapse rate was 0.33 (range 0.08–1). Mean EDSS was 3.4 after a mean follow-up of 20.6 years. Progression index was 0.16 without any differences between progressive and relapsing remitting forms (0.15 and 0.16 respectively). Reasons for not treating were: lack of disease activity (65.8%), very slow disease progression (10%), patient's initial decision followed by very slow progression (14.2%), contraindication for treatment in patients with longstanding progressive disease (10%). There were also patients (4.3%) whose initially well-stabilized disease recently became active again, leading to reconsideration about starting treatment.ConclusionAfter a mean follow-up of 20 years, the proportion of treatment-free patients was around 10%. Most of these patients had a relapsing remitting form with a low rate of relapse or a progressive form with very slow progression.     

Coexistence of myasthenia gravis and serological markers of neurological autoimmunity in neuromyelitis optica

We systematically evaluated the frequency of neurological disorders and muscle and neural autoantibodies in 177 patients with neuromyelitis optica (NMO) and in 250 control subjects (173 healthy; 77 multiple sclerosis, MS, patients). An excess of myasthenia gravis (MG, 2%), and muscle‐type acetylcholine receptor antibody (11%) was detected among NMO patients. The presence of neural or muscle autoantibodies was more common in NMO patients (34%) than in MS patients or healthy controls (7%), P < 0.0001. The coexistence of NMO and MG should be considered in atypical or refractory presentations of either disorder. © 2008 Wiley Periodicals, Inc. Muscle Nerve 39: 87–90, 2009     

The Global Adherence Project (GAP): a multicenter observational study on adherence to disease‐modifying therapies in patients with relapsing‐remitting multiple sclerosis

Background: Most disease‐modifying therapies (DMTs) for multiple sclerosis (MS) are self‐injectable medications that must be taken on an ongoing basis to reduce disease activity. Thus, adherence to therapy becomes an important challenge that must be addressed to maximize benefits of therapy. This study evaluated rates of adherence to prescribed treatment and explored factors affecting adherence amongst patients with relapsing‐remitting MS. Methods: This was an observational, multicenter, multinational, phase 4 study. Patients and physicians received paper questionnaires regarding adherence to DMTs approved at the time of the study, including intramuscular interferon beta‐1a (IFNβ‐1a), subcutaneous IFNβ‐1a, IFNβ‐1b, and glatiramer acetate. Quality of life and cognition data also were collected. Multivariate analysis was conducted to identify factors associated with adherence to long‐term DMTs. Results: Two thousand six hundred and forty‐eight patients were studied, revealing an average treatment duration of 31 months. Seventy‐five percent of patients (n = 1923) were adherent to therapy. The most common reasons for non‐adherence were forgetting to administer the injection (50.2%) and other injection‐related reasons (32.0%). Adherent patients reported better quality of life (P < 0.05) and fewer neuropsychological issues (P < 0.001) than non‐adherent patients. Adherent patients had significantly shorter duration of disease (P < 0.001) and shorter duration of therapy (P = 0.005) than non‐adherent patients. Women were more likely than men to adhere to treatment. Conclusion: Identifying factors that affect adherence to prescribed treatments is the first step in improving adherence of patients with MS to therapy, thereby helping maximize the benefits of long‐term DMTs.