Efficacy of natalizumab in second line therapy of relapsing–remitting multiple sclerosis: results from a multi-center study in German speaking countries

Background:  Natalizumab has been recommended for the treatment of relapsing–remitting multiple sclerosis (RRMS) in patients with insufficient response to interferon-beta/glatiramer acetate (DMT) or aggressive MS. The pivotal trials were not conducted to investigate natalizumab monotherapy in this patient population.
Method:  Retrospective, multicenter study in Germany and Switzerland. Five major MS centers reported all RRMS patients who initiated natalizumab ≥12 months prior to study conduction.
Results:  Ninety-seven RRMS patients were included [69% female, mean age 36.5 years, mean Expanded Disability Status Scale (EDSS) 3.4; 93.8% were pre-treated with DMT], mean treatment duration with natalizumab was 19.3 ± 6.1 months. We found a reduction of the annualized relapse rate from 2.3 to 0.2, 80.4% were relapse free with natalizumab. EDSS improved in 12.4% and 89.7% were progression free (change of >/= 1 EDSS point). Eighty-six per cent of patients with highly active disease (>/= 2 relapses in the year and >/= 1 Gadolinium (Gd)+ lesion at study entry, n  = 20) remained relapse free. The mean number of Gd enhancing lesions was reduced to 0.1 (0.8 at baseline). Discontinuation rate was 8.2% (4.1% for antibody-positivity).
Conclusion:  Natalizumab is effective after insufficient response to other DMT and also in patients with high disease activity.     

Evaluation of response of multiple sclerosis (MS) relapse to oral high-dose methylprednisolone: usefulness of MS functional composite and Expanded Disability Status Scale

To compare the usefulness of multiple sclerosis functional composite (MSFC) to the Expanded Disability Status Scale (EDSS) in assessing functional changes related to relapse. A prospective 12-week follow-up study after relapse was conducted among 14 multiple sclerosis (MS) patients treated with oral high-dose (1 g) methylprednisolone for 3 days. MSFC and the EDSS were assessed on day 0, before treatment and, 1, 4 and 12 weeks afterwards. In relapses, EDSS (2.5 ± 1.2 to 3.8 ± 1.0) and z-score of the MSFC (0.15 ± 0.58 to −0.59 ± 0.70) worsened. After 1 week of treatment, the EDSS improved (3.3 ± 1.2; P  =   0.002) while the MSFC did not change significantly. At week 4, EDSS improvement was maximal (2.8 ± 1.3; P  =   0.001). At week 12, EDSS remained stable whereas z-score continued improving (0.26 ± 0.74). z-9peg-hole-test was the most sensitive subtest. There was correlation between baseline values of both scales (−0.620, P  <   0.05) and between changes due to relapse (−0.535, P  <   0.05). 78.5% of patients had improved at week 4 (35.7% at week 1). There were no serious adverse effects. MSFC and the EDSS were sensitive to changes due to relapses, although the dynamics for restoring baseline function were different. Our data support the usefulness of both scales in clinical trials, providing complementary information about outcome of MS patients with relapses.     

A longitudinal observational study of a cohort of patients with relapsing–remitting multiple sclerosis treated with glatiramer acetate

Immunomodulatory treatments for relapsing–remitting multiple sclerosis (RRMS) are not efficacious or tolerated in all patients. It is important to evaluate alternative classes of treatment in patients failing first-line therapy. The objective of this prospective observational study was to evaluate the efficacy and safety of glatiramer acetate in patients, to whom β -interferons could not be administered. The study included patients with RRMS who were intolerant to or had contraindications to β -interferon. After initiation of glatiramer acetate treatment, follow-up visits were made every 3 months, when data on neurologist-ascertained relapses and disability [Expanded Disability Status Scale (EDSS) score] were collected. Tolerability was evaluated by spontaneous adverse event reporting. Overall, 205 patients were studied and 113 (55.1%) treated for at least 4 years. The proportion of patients presenting over three relapses per year decreased from 51.2% to 8.4% in the 2 years following treatment initiation. Over 5 years of treatment, mean annualized relapse rates and mean EDSS scores remained stable (0.4–0.6 relapses/year and 3.6 ± 1.8–3.3 ± 2.1 respectively). Adverse events were reported by 179 patients, leading to discontinuation of treatment in 10 patients. Patients with RRMS to whom β -interferons cannot be prescribed can benefit from treatment with glatiramer acetate.     

Pulsed steroids followed by glatiramer acetate to prevent inflammatory activity after cessation of natalizumab therapy: a prospective, 6-month observational study

In this study, the tolerability and safety of treatment with pulsed steroids and glatiramer acetate and the occurrence of clinical and radiological activity after natalizumab (NTZ) cessation in multiple sclerosis (MS) patients were assessed. MS patients with NTZ were discontinued after 2 years of treatment, or if adverse events or disease progressed during NTZ. They were offered as alternative treatment 1 g methylprednisolone per month during 3 months followed by daily 20 mcg glatiramer acetate and were prospectively studied. Adverse events, occurrence of immune reconstitution inflammatory syndrome, clinical exacerbations, and gadolinium-enhancing lesions in MRI performed at 3 and 6 months after NTZ cessation were recorded. EDSS change during follow-up was also recorded. A total of 18 MS patients entered the study and were followed up for a mean of 10 months (range 6–18 months). There were no significant adverse events. At month 3, no patient had clinical or radiological disease activity. At month 6, 16.6% of patients had had a relapse and 55.5% of patients showed gadolinium-enhancing lesions in the MRI. After 6 months, 33.3% of patients had a further relapse. There was no IRIS, severe relapses, or significant difference between EDSS at NTZ discontinuation and after follow-up. The alternative treatment with monthly prednisolone followed by GA prevents the development of IRIS, but not the return to previous inflammatory activity, which occurs between 5 and 6 months after NTZ withdrawal.     

Use of mitoxantrone in early multiple sclerosis with malignant disease course. Observational study in 30 patients with clinical and MRI outcomes after one year

IntroductionIn an observational multicenter study, we analyzed retrospectively 30 patients with malignant form of multiple sclerosis (MS) treated with mitoxantrone the year following the first neurological event.MethodsThe 30 patients were selected according to Weinshenker criteria of malignant MS (either a “catastrophic” relapse or a quickly aggressive form). We compared clinical and MRI findings the year before with the year following mitoxantrone onset treatment: annualized relapse rates (ARR), EDSS score and percentage of patients with gadolinium enhancing lesions on MRI.ResultsA total of 87 relapses were observed in the 5.7 months before and 10 during the year following onset of mitoxantrone treatment. The ARR decreased by 95% (6.0 ± 2 before and 0.3 ± 0.7 after). Twenty-four patients (80%) were relapse-free one year after onset of mitoxantrone treatment. The EDSS score improved in 87% of MS patients and the mean EDSS decreased by 1.9. Ninety-seven percent had at least gadolinium enhancing lesions before the start of mitoxantrone treatment as compared to 17% after.ConclusionIn our experience, mitoxantrone had a rapid and strong impact on the malignant forms of MS with a short disease duration. In this MS subgroup, mitoxantrone should be considered as an early treatment option.     

Mitoxantrone for the treatment of Japanese patients with multiple sclerosis]

We retrospectively evaluated the benefits of mitoxantrone (MITX) treatment in Japanese patients with multiple sclerosis (MS) with more than 3 relapses per year or a deterioration of more than one Expanded Disability Status Scale (EDSS) of Kurtzke score per year despite having IFN beta 1b therapy. Monthly intravenous injections of MITX, 10-12 mg/m2, for 3 months were followed by an additional treatment every 3 months. Nine patients (6 women, 3 men) with a mean age of 39 years, a mean disease duration of 3.9 years, and a mean EDSS score of 6.7 were studied. Seven patients had long spinal cord lesions (LCL-MS). Most patients tolerated the treatment, although 2 patients stopped MITX therapy after 3 injections because of severe appetite loss. The 7 patients who continued MITX therapy for more than 3 times significantly decreased their relapse rate and EDSS deterioration. The average relapse count in the year preceding initiation of MITX therapy was 4.3 (range: 3-6)/year, EDSS score increased by 2.7 (range: 1-7)/year. The average relapse count was 2.3 (range: 0-4)/year from 0 to 6 months after MITX therapy (p = 0.114), and 1.1 (range: 0-4)/year from 7 to 12 months (p = 0.285). The average EDSS deterioration was -0.4 (range -2-1) from 0 to 6 months after MITX therapy (p = 0.018), and there was no deterioration from 7 to 12 months. Most patients received granulocyte colony stimulating factor because of leukocytopenia caused by MITX. No patients showed any decrease in cardiac ejection fraction during this observation period. For Japanese MS patients, MITX therapy was very effective to suppress relapses without incurring severe adverse events.     

Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group

OBJECTIVE: To evaluate the safety and efficacy of two doses of cladribine in patients with progressive MS. BACKGROUND: Treatment of progressive MS patients with cladribine in a previous single-center, placebo-controlled clinical trial was associated with disease stabilization. METHODS: In the current study, 159 patients with a median baseline Kurtzke's Expanded Disability Status Scale (EDSS) score of 6.0 were randomly assigned to receive placebo or cladribine 0.07 mg/kg/day for 5 consecutive days every 4 weeks for either two or six cycles (total dose, 0.7 mg/kg or 2.1 mg/kg, respectively), followed by placebo, for a total of eight cycles. Thirty percent had primary progressive MS (PPMS) and 70% had secondary progressive MS (SPMS). EDSS and Scripps Neurologic Rating Scale (SNRS) scores were assessed bi-monthly and MRI was performed every 6 months. The primary outcome measure was disability (mean change in EDSS). RESULTS: Mean changes in disability did not differ among the groups at the end of the 12-month double-blind phase. Both cladribine treatments were superior to placebo for the proportion of patients having gadolinium-enhanced T1 lesions and for the mean volume and number of such lesions (p < or = 0.003). Differences were statistically significant at the 6-month evaluation time, with < or =90% reduction in volume and number of enhanced T1 lesions, which was maintained through final evaluation. This effect segregated largely with the SPMS group. The T2 burden of disease showed a modest improvement in cladribine-treated patients and worsened in placebo-treated patients. Most adverse events were mild or moderate in severity and not treatment limiting. CONCLUSION: No significant treatment effects were found for cladribine in terms of changes in EDSS or SNRS scores. Both doses of cladribine produced and sustained significant reductions in the presence, number, and volume of gadolinium-enhanced T1 brain lesions on MRI, and cladribine 2.1 mg/kg reduced the accumulation of T2 lesion load. Cladribine at doses up to 2.1 mg/kg was generally safe and well tolerated.     

Combination of IFNβ-1a (Avonex®) and mycophenolate mofetil (Cellcept®) in multiple sclerosis

To determine the safety of a combination of mycophenolate mofetil (Cellcept®, MMF) and IFN β -1a (Avonex®) in relapsing-remitting multiple sclerosis (RRMS) and to evaluate the effects of the combination on clinical and magnetic resonance imaging (MRI) measures of disease activity. Secondary objectives were clinical and MRI data. An open-label, single-centre study including 30 RRMS patients was performed. Inclusion criteria were patients expanded disability status scale (EDSS) score <6.0, treated by Avonex® for at least 6 months, with at least two relapses during the previous 2 years and at least one during the previous 6 months. MMF at a progressive dose of 2 g per day orally was added to Avonex® for a duration of 6 months. MRI data were obtained at baseline and at the end of the study. The pre-study annual relapse rate was 2.0 ± 0.7 and the EDSS score at baseline was 2.9 ± 1.3. Eleven patients had gadolinium (Gd)-enhanced lesions at baseline for a total number of 35 lesions. Two patients interrupted the combination, one after the first dose for personal reasons unrelated to the study and the other due to diarrhoea. A few of the patients also reported nausea and abdominal pains. Adverse events included benign infectious diseases, insomnia and dizziness. No significant biological abnormalities were noted. The annualized relapse rate was 0.57 ± 0.3 at the end of the study ( P  < 0.001). The mean EDSS score was 2.6 ± 1.5 and no Gd-enhanced lesions were detected on MRI at the end of the study. MMF and IFN β -1a (Avonex®) combined therapy is safe and very well-tolerated. Clinical and MRI data suggest that this combination may be beneficial.     

Oral prednisone taper following intravenous steroids fails to improve disability or recovery from relapses in multiple sclerosis

Background:  A short course of intravenous methylprednisolone (IVMP) followed by oral prednisone taper (OPT) is often used for the treatment of relapses in multiple sclerosis (MS). We examined the effect of IVMP plus OPT compared with IVMP only on neurologic disability 1 year after treatment of a relapse in patients with relapsing–remitting multiple sclerosis..
Methods:  Two hundred eighty-five consecutive relapses were analyzed in a retrospective fashion. One hundred fifty-two patients with a total of 171 relapses received IVMP plus an OPT at the time of relapse whilst 112 patients who experienced 114 relapses received IVMP without OPT.
Results:  There was no difference between the two groups in the baseline characteristics as well as the mean or categorical EDSS at baseline, at the time of relapse confirmation, and at months 3, 6 and 12 after relapse confirmation.
Conclusion:  Our observations suggest that OPT following treatment with IVMP for an MS relapse does not lead to improved neurologic outcome after 12 months compared with treatment with IVMP only. Moreover, our findings raise concerns regarding the common practice of using OPT following IVMP. Further studies are indicated to validate our findings and minimize exposure to systemic corticosteroids, well known for systemic toxicity.     

Long-term clinical experience with weekly interferon beta-1a in relapsing multiple sclerosis

Post-marketing surveillance studies are needed to assess the long-term safety, compliance and clinical efficacy of interferon beta-1a (IFN β -1a) therapy in multiple sclerosis (MS) patients. The goals of this study were to (i) assess the safety, compliance and clinical efficacy of long-term intramuscular (i.m.) IFN β -1a therapy in a large cohort of patients, and (ii) suggest possible predictors of therapeutic response. A total of 255 patients were included in the study. Mean time on therapy was 31.7 ± 19.3 months. Within 3 years, 31% of patients discontinued treatment, mainly for disease activity. No significant sustained blood analysis alteration was observed over time, apart from a decrease of cholesterol levels. After 3 years of treatment, mean Expanded Disability Status Scale (EDSS) scores increased by 0.4 points compared with baseline. The mean annual relapse rate was reduced compared with baseline. Patients with ≤2 relapses in the previous 2 years and with baseline EDSS scores of ≤2 had a longer estimated time to first relapse and to progression and first relapse, respectively. These results confirm the safety and suggest a sustained effectiveness of i.m. IFN β -1a, extending the reported follow-up period to 6.3 years, and hypothesize the presence of possible predictors of clinical outcome.     

Efficacy of natalizumab in multiple sclerosis patients with high disease activity: a Danish nationwide study

Introduction:  Previous studies of natalizumab (Tysabri®) in relapsing multiple sclerosis (MS) patients have included patients with moderate disease activity. We studied a patient population with high disease activity.
Patients and Methods:  We analyzed data from 234 consecutive, natalizumab-treated patients, followed for at least 3 months. Three groups of patients were eligible for natalizumab therapy: patients with two or more documented relapses or sustained increase of 2 EDSS points on disease modifying therapy (DMT) in the previous year; patients switching from mitoxantrone; and patients with very active MS as de novo therapy.
Results:  During a median observation time of 11.3 months (range 3.0–21.5) the annualized relapse rate decreased to 0.68 from a pre-treatment rate of 2.53 (73% reduction). We assessed the annualized relapse rate in three subgroups: (i) 0.83 in 14 (6.0%) de novo treated patients; (ii) 0.71 in 175 (74.8%) patients with ≥2 relapses or sustained increase in EDSS of ≥2 points on a first-line DMT; and (iii) 0.56 in 45 (19.2%) patients switching from mitoxantrone. Nine anaphylactoid reactions, two severe, were reported. Out of 215 patients 7 (3%) were persistently positive for antibodies to natalizumab.
Conclusions:  Tysabri appears to be effective in MS patients with high disease activity, but the relapse rate was higher than in the pivotal study after the first treatment year. This is likely to reflect differences in disease activity before the initiation of natalizumab treatment.     

Acute partial transverse myelitis: risk factors for conversion to multiple sclerosis

Acute partial transverse myelitis (APTM) may be the first clinical manifestation of multiple sclerosis (MS), of relapsing myelitis, or remain a monophasic event. Identification of risk factors associated with relapse or conversion to MS is important, as prognostic information might help to guide management. The objective of this study was to define clinical, laboratory and neuroimaging factors in patients with first-ever APTM that predict relapses or conversion to MS. We identified 73 patients with a first-ever APTM admitted to our institution from January 1999 to June 2005. The follow-up time ranged from 12 to 90 months (mean follow-up 46 months). Patient demographics, clinical impairment at onset and after 3 months, ancillary tests including cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), evoked potentials, recurrent and new symptoms and signs during follow-up were analysed. APTM remained a monophasic event in 35 patients (47.9%), conversion to MS occurred in 32 (43.8%) and recurred as relapsing myelitis in six patients (8.2%). According to univariate analysis, a family history of MS ( P  = 0.02), higher expanded disability status scale (EDSS) at onset ( P  = 0.03) and lesions on brain MRI ( P  = 0.03) were predictive factors for conversion to MS. CSF-specific oligoclonal bands ( P  = 0.04) or abnormal IgG-index ( P  = 0.04) were associated with increased risk for MS as well. In patients with a first-ever APTM, a family history of MS, high EDSS at presentation, lesions on brain MRI, CSF-specific oligoclonal bands or abnormal IgG-index may indicate an increased risk for conversion to MS.     

Predictive value of clinical characteristics for 'benign' multiple sclerosis

We studied a cohort of 496 patients who had multiple sclerosis (MS) for at least 10 years. Ten years after disease onset, 151 had benign MS defined as an Extended Disability Status Scale (EDSS) ≤3. Between benign and non-benign patients we compared gender, age at clinical onset, relapsing–remitting or primary progressive, symptoms at onset, recovery from first relapse, time between first and second relapse, number of relapses in the first 5 years, use of immunomodulatory drugs, and EDSS scores at 2, 5 and 10 years. A multivariate regression analysis showed that a relapsing–remitting course, a low EDSS score at 5 years, and a low number of relapses in the first 5 years were predictive for benign MS at 10 years. Other factors had no additional value. Thirty-five of the 51 patients (69%) with benign MS at 10 years were still benign at 20 years. A low 10-year EDSS score was the only clinical variable associated with a benign course at 20 years. Our results suggest that within the first 5 years from onset it is not possible to predict a benign course. Disease course, EDSS score and relapse rate at 5 years are predictors for benign MS at 10 years.     

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.     

The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study

Minocycline has immunomodulatory and neuroprotective activities in vitro and in an animal model of multiple sclerosis (MS). We have previously reported that minocycline decreased gadolinium-enhancing activity over six months in a small trial of patients with active relapsing-remitting MS (RRMS). Here we report the impact of oral minocycline on clinical and magnetic resonance imaging (MRI) outcomes and serum immune molecules in this cohort over 24 months of open-label minocycline treatment. Despite a moderately high pretreatment annualized relapse rate (1.3/year pre-enrolment; 1.2/year during a three-month baseline period) prior to treatment, no relapses occurred between months 6 and 24. Also, despite very active MRI activity pretreatment (19/40 scans had gadolinium-enhancing activity during a three-month run-in), the only patient with gadolinium-enhancing lesions on MRI at 12 and 24 months was on half-dose minocycline. Levels of the p40 subunit of interleukin (IL)-12, which at high levels might antagonize the proinflammatory IL-12 receptor, were elevated over 18 months of treatment, as were levels of soluble vascular cell adhesion molecule-1. The activity of matrix metalloproteinase-9 was decreased by treatment. Thus, clinical and MRI outcomes are supported by systemic immunological changes and call for further investigation of minocycline in MS.     

Glatiramer acetate (Copaxone): comparison of continuous versus delayed therapy in a six-year organized multiple sclerosis trial

The aim of this study was to assess the long-term safety and efficacy of glatiramer acetate (GA) for patients with multiple sclerosis (MS) who received active treatment versus those on placebo for approximately 30 months (24-35 months) before receiving GA during a six-year organized, prospective open label study. Entry required two relapses in the previous two years and an Expanded Disability Status Scale (EDSS) score of 0-5. Patients (251) were equally randomized to daily subcutaneous GA, 20 mg, or to placebo. After approximately 30 months, 208 patients continued in an open label study: 101 continued on GA and 107 switched from placebo to active drug. Groups were well matched at randomization and entry to the open label study. Patients always on GA showed a steady decline in relapses: a mean of 1.5 per year at entry, a mean of 0.42 over the entire six years (95% CI = 0.34-0.51), a 72% reduction (P = 0.0001). They averaged a relapse every four + years (yearly rate 0.23 in year six) and 26/101 remain relapse free. Patients did less well if on placebo for 30 months, but relapses then declined, and by year six the rates were similar. Of patients always on GA, 69% showed neurological improvement of > or = 1 EDSS steps or remained stable compared with 57% if GA treatment was delayed. Of relapse-free patients always on GA over six years, only three of 26 (11%) were worse by > or = 1 EDSS steps, whereas nine of 21 (43%) in the placebo/active group were worse (P < 0.03). Disability, measured every six months, showed that the group of patients always on GA was relatively stable over the six years, while the group who received placebo for the first two-and-a-half years did significantly less well. Daily injections of GA were well tolerated. This longest ever organized MS treatment trial shows that delaying therapy with GA increases the risk of neurologic disability, reinforcing the rationale for using GA as a first-line treatment early in the course of relapsing-remitting MS.     

Effect of relapses over early progression of disability in multiple sclerosis patients treated with beta-interferon

Observational study designed to explore the effect of demographical variables and number of relapses over the disability progression in the two first years of beta-interferon treatment for multiple sclerosis. One hundred and sixty two patients treated with beta-interferon for at least two years were included, 70.9% females, mean age 33.4 years, mean disease duration 75.1 months, mean EDSS 2.4, previous year relapse rate 1.3. Main end-point was defined as a sustained EDSS increase (1.5 if previous EDSS 0-2.0; 1.0 if previous EDSS 2.5-4.0; 0.5 if previous EDSS 4.5 or higher). 62.3% of patients presented one or more relapses and 32.7% patients reached sustained disability increase. The univariate and multivariate Cox regression analysis only showed statistical significance for the relapses in the two first years after the treatment (HR 1 relapse: 3.4, p = 0.05; HR > or = 2 relapses: 4.3, p < 0.001). The Kaplan-Meier survival analysis showed a higher probability of EDSS progression for patients with one relapse (log rank 10.9, p = 0.02) and with > or = 2 relapses (log rank 17.7, p < 0.001), with no differences between them (p = 0.38). In conclusion, patients with one or more relapses in the first two years of interferon treatment developed an earlier sustained progression of the disability.     

Influence of climatic factors in the incidence of multiple sclerosis relapses in a Portuguese population

Background and purpose:  Environmental factors are thought to be important in multiple sclerosis (MS) pathophysiology. We aimed to evaluate if there was an association between MS relapses and some climatic factors in a Portuguese population.
Methods:  Four year retrospective study analyzing 414 MS relapses in 249 consecutive relapsing–remitting patients. Non-parametric statistics were used to compare the distribution of relapses across months and seasons. Spearman's coefficient was determined to evaluate the correlation between relapses frequency and maximum and minimum atmospheric temperatures, humidity and atmospheric pressure.
Results:  The mean number of relapses was not significantly different between months or seasons. No correlation was found between relapse frequency and any climatic factor.
Conclusion:  Our series is one of the largest addressing the influence of specific climatic factors on MS relapses. The number of clinical MS relapses seems to be unrelated to climatic factors.     

The combination of cyclophosphamide plus interferon beta as rescue therapy could be used to treat relapsing–remitting multiple sclerosis patients

The aim of the present study was to evaluate the efficacy of the combination of cyclophosphamide (CTX) and interferon beta (IFN β) in a group of relapsing remitting (RR) multiple sclerosis (MS) patients who experienced treatment failure during IFN β therapy. It is the general experience that immunomodulatory agents (IMA) are only partially effective in RR patients. Recent data on the efficacy of immunosuppressive therapies for these patients are encouraging. The anti–inflammatory and immunosuppressive effects of CTX have been utilized to treat selected cases of multiple sclerosis with a progressive and worsening course as rescue therapy. Thirty RR MS patients with clinically defined MS who experienced treatment failure during IFN β therapy (2 or more relapses per year or 1.5 EDSS point worsening in one year) were enrolled in the study and treated with CTX iv pulse therapy added to IFN β and followed up for 24 months. As primary endpoints we evaluated the yearly relapse rate. We also evaluated the percentage of patients free of relapses and of EDSS variations. We analysed the results at one year before entry (T0: IFN β alone), 12 (T1) and 24 (T2) months after entry. Brain MRI was performed at T0, at T1 and T2. The 30 RR patients who had experienced a high number of relapses (r r =1.4) at T0 showed a significant improvement in yearly relapse rate (rr = 0.4) at T1 and a further improvement (rr = 0.17) at T2 (p < 0.001). The percentage of patients free of relapse was 70% at T2 (p < 0.0001). EDSS score changed from 2.6±1.23 at T0 to 2.2 ± 1.5 at T2, showing only a trend of improvement.No significant variation of MRI lesion load and no severe adverse events were recorded during the study. These data showed that the combination of CTX plus IFN β halted the progression of disease in active and deteriorating MS patients suggesting the necessity of RCTs to test the efficacy of this combination therapy in active RRMS patients or in patients who experienced treatment failure in response to disease modifying drugs (DMDs).     

Cladribine impedes in vitro migration of mononuclear cells: a possible implication for treating multiple sclerosis

Background:  Damage of the blood–brain barrier and the migration of immunocompetent cells into the CNS represent key events in the immunopathogenesis of multiple sclerosis (MS). Cladribine is an immunosuppressive drug currently investigated in a phase-III clinical trial for relapsing–remitting MS. However, its precise mode of action remains elusive so far.
Methods:  Peripheral blood mononuclear cells (PBMCs) were isolated from five patients with MS and five healthy donors. PBMCs were treated with cladribine in vitro . The migratory capacity was studied in an in vitro Boyden chamber assay; cells and their rate of migration were analyzed by light microscopy and flow cytometry.
Results:  Cladribine decreased the migratory capacity of CD14⁺ monocytes, as well as of CD4⁺ and CD8⁺ T lymphocytes. T lymphocytes were affected more than monocytes. There was no difference in this effect when comparing mononuclear cells from MS patients with cells from healthy controls.
Conclusions:  Cladribine might achieve, at least in part, its clinical and paraclinical efficacy by inhibiting the migration of inflammatory cells into and within the CNS.