First-line therapy in relapsing remitting multiple sclerosis

Today, first-line treatments for multiple sclerosis include injectable immunomodulators – some of which have been on the market for nearly 25 years – as well as teriflunomide and dimethyl fumarate, which are more recent, but have opened the way for oral treatments. These drugs are considered similar in effectiveness, and their safety and side-effect profiles are generally reassuring. These treatments have been associated with a reduction in radiological and clinical disease activity, and a positive effect on patient quality of life, especially when introduced early in the disease process. This article will discuss data on first-line treatments currently available in France, their effectiveness and safety, and their place in pediatric patients and in woman who plan to become pregnant.     

Cyclophosphamide in relapsing remitting multiple sclerosis

7 patients with relapsing-remitting multiple sclerosis (MS) were subjected to an intensive course of intravenous (I.V.) cyclophosphamide (CY) therapy. All patients received induction therapy with 11 daily doses of 300 mg/m² and then a single dose every six months for three years. After one year of follow-up all patients showed a decrease in relapse rate (0.57.57); in the two subsequent years of follow-up 2 patients showed a mild worsening while the others were clinically stable. As suggested by others, our results indicate that I.V. CY therapy may influence the clinical course of relapsing-remitting MS.

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Sommario Sette pazienti affetti da Sclerosi Multipla di tipo remittente sono stati sottoposti a terapia immunosoppressiva con ciclofosfamide. Il trattamento consisteva di un ciclo di induzione con dosi di 300 mg/m2 di ciclofosfamide e.v. somminsstrate giornalmente per 11 giorni e di successive singole dosi di mantenimento di 300 mg/m² somministrate ogni 6 mesi per un periodo di 3 anni. Non sono stati osservati gravi effetti collaterali durante lo studio. Dopo il primo anno di trattamento tutti i pazienti hanno mostrato miglioramento nella frequenza di ricaduta; nei due anni successivi 4 pazienti sono rimasti stabili mentre gli altri hanno mostrato un nuovo peggioramento. Come indicato da altri Autori, i risultati dello studio indicano che la terapia immunosoppressiva con ciclofosfamide ad alte dosi non presenta gravi effetti collaterali e può modificare il decorso della Sclerosi Multipla di tipo remittente.

     

Cognitive disturbances in patients with relapsing remitting multiple sclerosis

The performance of 42 patients with relapsing remitting (RR) multiple sclerosis was compared with that of 24 age-, education-, and gender-matched control subjects on a battery of neuropsychological tests known from previous studies to be sensitive to the impairments of patients with chronic progressive (CP) multiple sclerosis. Like CP patients, RR patients exhibited deficits on tests of information-processing speed, verbal fluency, and problem solving, and on recall measures of anterograde and remote memory. Although a few patients were mildly dysnomic, the RR patients were not generally impaired on visual confrontation naming and they did not exhibit perseverative responding on verbal fluency measures. The pattern of neuropsychological deficits exhibited by RR patients closely approximates the profile observed in other subcortical dementias and does not contain the features of cortical dementia evident in some CP patients. The impairment of RR patients on cognitive tests were less severe than those observed in CP patients in our previous studies. Differences in the age of patients in the CP and RR groups did not account for group differences in the severity of cognitive impairments, but differences in disease duration or severity of disability, as well as disease course, could explain why CP patients exhibit more serious cognitive disturbances than RR patients.     

Efficacy of disease-modifying therapies in relapsing remitting multiple sclerosis: a systematic comparison

The treatment of relapsing-remitting multiple sclerosis (RRMS) has become more effective over the last decade with the advent of the currently available disease-modifying therapies (DMTs). Pivotal clinical studies differ in many characteristics, such that cross-comparisons of relative risk reductions are of limited value and can be misleading. Our objective was to compare the clinical efficacy of currently approved first-line DMTs in patients with RRMS, applying an evidence-based medicine approach. We reviewed all phase III pivotal trials of DMTs. Six clinical trials of Avonex, Betaseron, Copaxone, Rebif and Tysabri in patients with RRMS were identified for analysis. Only randomized, placebo-controlled, double-blind studies were included. The clinical efficacy endpoints compared were: proportion of relapse-free patients at 1 and 2 years; annualized relapse rate at 2 years; proportion of progression-free patients at 2 years, and proportion of patients free of gadolinium-enhancing lesions at 1 year or 9 months. Based on these analyses, Betaseron, Rebif, and Tysabri show comparable effects, whereas for several endpoints Avonex or Copaxone did not significantly differ from placebo. In the absence of head-to-head studies for all products used to treat RRMS, it still may be possible to compare treatment effects by applying evidence-based medicine principles.     

Mitoxantrone as induction therapy in aggressive relapsing remitting multiple sclerosis: a descriptive analysis of 100 consecutive patients

INTRODUCTION: On the basis of the French and British (FB) MS Trial, Mitoxantrone (MITOX) was approved by the AFSAPPS in October 2003 in patients with aggressive multiple sclerosis (MS), given as induction therapy monthly for 6 months (ELSEP). We report an observational study of 100 aggressive relapsing remitting (RR) MS patients treated by induction therapy with MITOX and followed up to 5 years. METHODS: One hundred patients with aggressive RR MS received an induction therapy with MITOX 20 mg monthly combined with methylprednisolone 1 g for 6 months. MRI data within 12 months before and 6 months after MITOX induction were collected (mean cumulative dose 65 mg/m2). Clinical evaluation was performed every 6 months and data (relapses and EDSS scores) were prospectively recorded in the EDMUS Database. After MITOX, a maintenance therapy was given to 57 patients (MITOX every 3 months: 21; Interferon beta: 13; Azathioprine: 14; Methotrexate: 7; Glatiramer acetate: 2). The mean follow-up period was of 3.8 years. RESULTS: Patients were treated at a mean age of 27 +/- 9 years after 5 +/- 3 years of MS duration. Within the 12 months preceding MITOX onset, the annual relapse rate (ARR) was 3.2, the mean EDSS increased by 2.2 +/- 1 points (to a score of 4 at M0), 87 patients worsened by 1 point EDSS or more and 85 percent of patients had Gd enhancing lesions on MRI. During the 12 months following MITOX onset, the inflammatory activity of the disease dropped dramatically with a reduction of the ARR by 91 percent whereas 76 percent of patients were free of new relapse and MRI activity was reduced by 89 percent. In addition, the mean EDSS decreased by 1.2 points (p<10-6) and 60 percent of patients improved by 1 point EDSS or more. At a longer term, the reduction of the ARR was confirmed (0.28-0.37 up to 5 years) and the median time to the first relapse was 2.8 years. A significant improvement of disability was maintained until 4 years and got back to the initial level at year 5. The ARR was significantly lower (0.09) for patients treated with MITOX every 3 months as maintenance therapy than for patients treated by other disease modifying therapies (0.33-0.39) or not (0.43) after the induction. Three patients presented an asymptomatic decrease of the left ventricular ejection fraction under 50 percent, reversible in one case. CONCLUSION: MITOX as induction therapy monthly for 6 months was safe and had a rapid and strong impact on the inflammatory process and on the evolution of disability. The drug might be a good candidate as induction therapy followed by a maintenance therapy in patients with aggressive MS.     

Immunological and gadolinium-DTPA MRI evaluation of relapsing remitting multiple sclerosis

The levels of lymphocytes, blood lymphocytes subsets (CD3+, CD4+, CD8+, DR+, CD25+, CD4+, CD45RA+, CD4+, CD29+ cells) and sIL-2r of 10 patients affected by relapsing-remitting multiple sclerosis were serially studied. The identification of the activity of the disease was made by gadolinium-DTPA (Gd-DTPA) MRI. The immunological determinations and the MRI of the brain and spinal cord were performed every 14th day for a period of three months. No significant difference of the immunological values were found between the presence and the absence of Gd-DTPA enhancing areas, except lymphocytes (p < 0.05). These immunological parameters, evaluated in the peripheral blood, are not a marker of disease activity in relapsing-remitting MS patients.     

Natalizumab is effective as second line therapy in the treatment of relapsing remitting multiple sclerosis

Background:  Natalizumab has been recommended for the treatment of patients with relapsing remitting multiple sclerosis with insufficient response to interferon-beta (IFN-beta) or glatiramer acetate (GA).
Method:  Prospective, observational study.
Results:  We found a reduction of the annualized relapse rate from 2.1 under IFN-beta or GA to 0.2 one year after switching to natalizumab. There were 94% fewer gadolinium enhancing lesions with natalizumab.
Conclusion:  Natalizumab reduced short term clinical and MRI activity in second line therapy and efficacy is comparable to first line therapy as demonstrated in the pivotal trials.     

Contrast-enhanced magnetic resonance activity in relapsing remitting multiple sclerosis patients: a short term natural history study

Magnetic resonance imaging (MRI) has been used to study the history of multiple sclerosis (MS). We analyze the relationship between MRI activity in the first scan compared to the subsequent five scans, and we evaluate whether a shorter observation period of 3 months may predict the subsequent 3 months. Monthly enhanced MRI was performed in 103 relapsing remitting (RR) MS patients for 6 months. Thirty-five per cent of patients had an inactive scan on the initial examination. More than 80% of them developed MRI activity during the following 5 months. Eighteen per cent of patients had three consecutive inactive scans; 65% of them had at least one active scan on the subsequent 3 monthly MRI's. The relationship between the first scan and all subsequent scans demonstrates a clear weakening over time. Eighty-two per cent of patients had at least one active scan during the initial 3 consecutive months, the chance of becoming inactive decreased from 23% to 0% over the subsequent 3 months, according with the mean number of enhancing lesions during the first 3 months. These results suggest that neither a single scan nor a short baseline of 3 months may adequately describe the natural history of disease in an individual RRMS patient.     

Clinical outcome of relapsing remitting multiple sclerosis among Hong Kong Chinese

Background

Clinical outcome of Chinese relapsing remitting multiple sclerosis (RRMS) patients is uncertain.

Aim

To study the long-term clinical outcome of Chinese RRMS patients.

Method

RRMS patients with duration of 10 years or longer followed up in our hospital is retrospectively studied.

Results

61 RRMS patients (75% female) were studied. Their mean symptom onset age was 25.9 years and mean duration was 20.6 years (range 10-33); 36% patients had received β-interferon and 30% azathioprine. Their mean EDSS scores were 3.3 (range 1-7) and 4.7 (range 1-8) at 10 years and latest follow-up (mean duration 20.6 years) respectively. At 10 years, 30% patients had EDSS score ≤2, 34% EDSS 2.5-3.5, 20% EDSS 4.0-5.5 and 16% ≥6; 18% developed SPMS. At latest follow-up, 15% patients had EDSS ≤2, 20% EDSS 2.5-3.5, 19% EDSS 4.0-5.5 and 46% ≥6.0; 53% developed SPMS. The median time from symptom onset to EDSS 6 was 22 years. No differences were detected in demographic characteristics, presenting neurological features, number of attacks in first 2 years, neuroradiological findings and disease modifying therapies between patients with EDSS <6 and ≥6 at ten years. EDSS scores at 10 years and latest follow-up were similar for patients who had received β-interferon and those who had not.

Conclusion

Hong Kong Chinese RRMS patients may have worse long-term clinical outcome than Caucasian patients.     

Clinical and electronystagmographical evaluation of vestibular symptoms in relapsing remitting multiple sclerosis

Abstract

Objective: Multiple sclerosis (MS) may give rise to a variety of clinical signs and symptoms including vertigo and/or other problems related with equilibrium. In this study, we aimed to evaluate clinical and electronystagmographical (ENG) characteristics of relapsing remitting MS (RRMS) patients.

Design: This is a prospective controlled study consisting of 30 patients who were diagnosed as definite RRMS according to McDonald's diagnostic criteria and 30 healthy individuals.

Setting: Entire population of patients were examined and followed up at the same tertiary centre during the period of September 2003 and March 2005. Clinical examination and detailed electronystagmographic investigations were performed in each group.

Methods: Vestibular laboratory testing was carried out by a computerized ENG system. All ENG subtests including tracking, saccade, optokinetic, gaze, positional and Dix-Hallpike tests were performed in each group but caloric, which is relatively an invasive test, was performed only in the patient group.

Main outcome measures: We aimed to find the ratio of abnormal tests indicating, central and/or peripheral pathology in ENG. We also analyzed the correlation of total number of abnormal tests in ENG with clinical parameters.

Results: Differences of ENG abnormality indicating central and/or peripheral pathology and ENG abnormality indicating only central pathology between the two groups were statistically significant. Correlation of total number of abnormal tests in ENG with EDSS score was statistically significant.

Conclusion: ENG is sensitive in detecting the vestibular system involvement in RRMS patients if all subtests are performed and evaluated in detail with clinical symptoms and signs.     

Cord atrophy separates early primary progressive and relapsing remitting multiple sclerosis

Background and objective

The onset of multiple sclerosis is relapsing remitting or primary progressive. An improved understanding of the causes of early progressive disability in primary progressive multiple sclerosis (PPMS) could provide mechanistic targets for therapeutic intervention.

Methods

Five magnetic resonance imaging (MRI) parameters that could potentially cause progressive disability were investigated in 43 patients with early PPMS and in 37 patients with early relapsing remitting multiple sclerosis (RRMS): atrophy in brain, both grey matter and white matter; intrinsic abnormality in brain, both grey matter and white matter (measured by the magnetisation transfer ratio (MTR)); and atrophy of the upper cervical spinal cord. Both groups were also compared with controls.

Results

Patients with PPMS were older and more likely to be men. Both patient groups had atrophy of brain grey matter and white matter, and intrinsic abnormality in MTR of normal‐appearing grey matter and white matter. Cord atrophy was present only in the PPMS (mean cord area: PPMS, 67.8 mm²; RRMS, 72.7 mm²; controls, 73.4 mm²; p = 0.007). This was confirmed by multivariate analysis of all five MRI parameters, age and sex.

Conclusion

Grey matter and white matter of the brain are abnormal in both early RRMS and PPMS, but cord atrophy is present only in PPMS. This is concordant with myelopathy being the usual clinical presentation of PPMS. Measurement of cord atrophy seems to be clinically relevant in PPMS treatment trials.About 15% of patients with multiple sclerosis present with a steadily accumulating neurological deficit—usually a spastic paraplegia that indicates spinal cord dysfunction—known as primary progressive multiple sclerosis (PPMS). These patients are older at onset (mean age 40 v 30 years) and the proportion of male patients is higher than in those with an onset of relapsing remitting multiple sclerosis (RRMS).¹ The mechanisms of disability in patients with PPMS are not well understood. Patients with PPMS become disabled at an earlier stage despite having no greater load of lesions visible on magnetic resonance imaging (MRI) of the brain,² nor have differences been noted between patients with RRMS and those with PPMS in terms of the number of focal spinal cord lesions that are visible on T2‐weighted MRI scans.^3,4 One study reported a higher frequency of diffuse hyperintensity on proton‐density‐weighted scans of the spinal cord in patients with PPMS.⁵In recent years, we have recruited two cohorts of patients in the early stages of RRMS and PPMS to investigate—using serial multimodal MRI and clinical follow‐up—potential prognostic markers and pathogenic mechanisms in the two types of multiple sclerosis. The present study directly compares quantitative MRI measures in these patients with early RRMS, those with early PPMS, and controls using identical analysis methods applied to anonymised scans by a blinded investigator (MB) to identify imaging features that might associate with the more disabling clinical course seen in PPMS. Five MRI parameters were pre‐selected for investigation because each could—if more severely abnormal—help explain disability in PPMS: (a) brain grey matter volume; (b) brain white matter volume; (c) normal‐appearing brain grey matter magnetisation transfer ratio (MTR); (d) normal‐appearing brain white matter MTR; and (e) upper cervical cord cross‐sectional area. We hypothesised that patients with early PPMS have a more disabling course of their multiple sclerosis, because one or more of the five MRI parameters is abnormal when compared with patients with early RRMS.     

Campath 1-H treatment in patients with aggressive relapsing remitting multiple sclerosis

Campath 1-H (Alemtuzumab) is a humanised monoclonal antibody which targets the CD52 antigen, a low molecular weight glycoprotein present on the surface of most lymphocyte lineages, causing complement mediated lysis and rapid and prolonged T lymphocyte depletion. Following encouraging initial data from other centres we report our open label experience of using Campath 1-H as a treatment in aggressive relapsing multiple sclerosis in a consecutive series of 39 highly selected patients treated across three regional centres and followed for a mean of 1.89 years. The mean annualised relapse rate fell from 2.48 pre treatment to 0.19 post treatment with 29% of documented relapses observed in the 12 weeks following initial infusion. Mean change in EDSS was –0.36 overall and –0.15 in those patients completing ≥1 year of follow- up. Eighty-three per cent of patients had stable or improved disability following treatment. Infusion related side effects were common including rash, headache and pyrexia but were usually mild and self limiting. Transient worsening of pre-existing neurological deficits during infusion was observed in 3 patients. 12 patients developed biochemical evidence of autoimmune dysfunction, 2 patients developed thyroid disease and 1 patient autoimmune skin disease. We conclude that relapse rates fall following Campath 1-H. Whilst side effects were common these were normally self limiting or easily managed, suggesting Campath 1-H may be of use in the treatment of very active relapsing remitting multiple sclerosis.     

Peripheral nerve conductions in relapsing remitting multiple sclerosis (RRMS) patients

PurposeThe purpose of this study was to investigate with Elektromioneurografija (EMNG) whether there is any affection on peripheral nerves in (RRMS) patients.Material and MethodMotor and sensory nerve conductions were studied in the control group including 33 RRMS patients and 25 healthy individuals. Expanded Disability Status Scale (EDSS) scores, mean annual attack frequency, duration of disease and treatments of RRMS patients were recorded.ResultsThere was a statistically significant (p < 0.05) elongation in motor distal latency of the right peroneal nerve, slowing in the left peroneal nerve conduction velocity, and an elongation in the F-wave response in the RRMS group compared to the control group. It was observed that motor nerve conduction velocities were slower, albeit not statistically significant, and F wave latencies were longer than control group.ConclusionThere are studies in the literature related to the association between MS and peripheral neuropathy. In this study, we found demyelinating type changes, differing significantly from the control group, in motor nerve conductions in RRMS patients. There may be demyelinating type affection in peripheral nervous system with common autoimmune mechanism in MS, a demyelinating disease of the central nervous system.     

Natalizumab prevents the accumulation of cortical lesions in relapsing remitting multiple sclerosis: a preliminary report

Natalizumab has been demonstrated to be highly effective in reducing measures of disease activity, such as clinical relapse rate, and gadolinium (Gd)-enhancing and new or enlarging T2 lesions appearance in patients with relapsing remitting multiple sclerosis (RRMS). Up to date, no data on the effect of natalizumab on cortical pathology have been published. We studied the efficacy of natalizumab in preventing the accumulation of new cortical lesions (CL) in 35 RRMS patients treated for 1 year. While confirming the high impact of natalizumab in reducing the relapse rate (>90%, 85% relapse-free patients) and white matter (WM) pathology (80% patients free from new T2 WM lesions, 97% patients free from new T1 Gd-enhancing lesions), we found that this monoclonal antibody was highly effective in reducing the appearance of new CL (86% patients free from new CL). Our findings indicate a relevant activity of natalizumab against cortical inflammation in RRMS.

     

Stability of intraindividual variability as a marker of neurologic dysfunction in relapsing remitting multiple sclerosis

Background: Impairments in information processing speed are common in multiple sclerosis (MS), with affected individuals demonstrating slower responses and more intraindividual variability (IIV) in their performance on timed tasks. Evidence suggesting that IIV provides novel information about cognitive deficits in MS is accumulating; however, little is known about the stability of IIV across multiple assessments. In this study, we investigated IIV in response speed in persons with MS across 6 monthly sessions using the Attention Network Test–Interaction (ANT-I). Method: Individuals with relatively mild relapsing remitting MS and healthy controls completed the ANT-I at 6 monthly intervals. Clinical assessments (Sessions 1 and 6) and conventional magnetic resonance imaging (MRI) studies (Sessions 1–6) were examined for individuals with MS. Results: The MS group’s clinical and neuroimaging measures were stable during the 6-month period. Individuals with MS were slower and more variable in reaction time performance on the ANT-I than were controls. Differences in IIV between groups were maintained across the 6 sessions, with IIV demonstrating less susceptibility to across-session practice effects than mean latency scores. Conclusions: IIV provides a stable measure of cognitive performance in mildly affected persons with MS who are clinically and radiologically stable. Further studies exploring its utility as a clinical outcome are warranted.     

Brain excitability changes in the relapsing and remitting phases of multiple sclerosis: a study with transcranial magnetic stimulation.

OBJECTIVE: Recent functional and imaging studies have substantially contributed to extend the concept of multiple sclerosis (MS), classically regarded as a disease limited to the myelin axonal sheath. Several findings, in fact, point to a parallel involvement of neuronal components of the central nervous system (CNS) in the course of MS. In the present study, therefore, we explored, in MS patients, some characteristics of central motor pathways related to changes of neuronal excitability as measured using transcranial magnetic stimulation (TMS). METHODS: Seventy-nine patients affected by relapsing-remitting (RR) MS were examined using single and paired TMS in order to assess excitability changes in the hand motor cortex occurring during relapse and/or remission of the disease. The analyzed parameters were: motor-evoked potential (MEP) threshold, silent period (SP), intracortical inhibition (ICI) with paired pulses from 1 to 6 ms interstimulus intervals (ISIs), and central motor conduction time (CMCT). RESULTS: The analysis of variance exhibited a strong correlation (P<0.001) between the clinical phase and the type of excitability changes: 'relapsing' patients showed increased threshold and reduced SP duration. 'Relapsing' patients also displayed a significant lack of normal intracortical inhibition (ICI). By contrast, 'remitting' patients showed a significant SP prolongation with normal motor thresholds. CONCLUSIONS: The present findings reveal changes in cortical excitability that might play a role in the pathophysiology of MS symptoms. In particular, the relapsing phase of MS has been found to be associated with cortical hyperexcitability irrespective of the site of clinical manifestation or new plaque formation. These results might help to explain the puzzling picture of neurological symptoms observed in MS patients during different phases of the disease. SIGNIFICANCE: Alterations of neuronal components of the CNS play a role in MS.     

A study of subtle blood brain barrier disruption in a placebo-controlled trial of natalizumab in relapsing remitting multiple sclerosis

Natalizumab, an anti-α4 integrin antibody, significantly reduces the number of visibly enhancing multiple sclerosis (MS) lesions. In this substudy of a 2-year trial of natalizumab monotherapy versus placebo, contrast-enhanced imaging investigated for subtle blood brain barrier (BBB) leakage in relapsing remitting (RRMS) patients, and whether such leakage is modified by natalizumab. After 24 weeks on treatment, 40 patients from 3 centres (27 on natalizumab and 13 on placebo) were studied. T₁ weighted images were obtained before and at set timepoints up to 46 minutes after gadolinium (Gd)-DTPA (0.3mmol/kg to 18 patients, 0.15mmol/kg to 22). Paired regions of interest were placed around non-enhancing lesions and contralateral normal appearing white matter (NAWM). BBB leakage was inferred through post-Gd T₁ weighted signal intensity (SI) change. SI change was greater in T₂ non-enhancing lesions than paired NAWM at all timepoints (P < 0.005), indicating BBB leakage in lesions. No significant difference in inferred BBB leakage was observed between treatment arms as measured by SI change of lesions (P > 0.05 for all timepoints, joint test P = 0.24), or in SI change of NAWM (joint test P = 0.37). T₁ hypointense and isointense lesions exhibited similar SI changes (joint test P = 0.12). There is evidence of a subtle BBB leakage within visibly non-enhancing lesions in RRMS that was not modified by α4 integrin blockade in this substudy cohort. Received in revised form: 18 June 2006     

Gadolinium-pentetic acid magnetic resonance imaging in patients with relapsing remitting multiple sclerosis.

Ten patients with relapsing-remitting multiple sclerosis have been studied by serial gadolinium-pentetic acid magnetic resonance imaging (MRI) every 14 days for 3 months. At the end of the follow-up, seven relapses occurred in six patients; no therapy was administered during the study. Ninety-three enhancing lesions were collected in eight patients. With regard to the duration of the enhancement, 32 lesions were detected in only one MRI scan and 32 were found in more MRI scans (most of the lesions occurring in two serial examinations). Four old lesions increased their size with delayed enhancement. Correlation was found between the relapses and the gadolinium-pentetic acid-enhancing areas only for one brain-stem and two cervical spinal cord lesions. Gadolinium-pentetic acid MRI provides useful information about activity of the disease that cannot be obtained clinically even if the dynamic of the lesions may be undervalued in old plaques.