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PubMed2003

Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial.

BACKGROUND: Patients with primary progressive MS have atypical clinical and MRI characteristics and have been excluded from most therapeutic trials. The authors report a randomized, controlled trial restricted to primary progressive MS. METHODS: Fifty subjects were randomized to weekly IM interferon beta-1a 30 microg, 60 microg, or placebo for 2 years. The primary endpoint was time to sustained progression in disability. Secondary outcomes included the timed 10-meter walk, nine-hole peg test, and on MRI, T2 and T1 brain lesion loads and brain and spinal cord atrophy. RESULTS: The 30- microg dose of interferon beta-1a was well tolerated, but the 60- microg dose caused severe flulike reactions and raised liver enzymes. No treatment effect was seen on the primary endpoint. Subjects on interferon beta-1a 30 microg had a lower rate of accumulation of T2 lesion load than controls (p = 0.025); subjects on 60 microg had a greater rate of ventricular enlargement than controls (p = 0.025). CONCLUSIONS: This study has demonstrated that interferon beta-1a 30 microg was well tolerated, identified useful outcome measures, but showed no efficacy on the primary outcome measure or on most of the secondary outcome measures.

Adult↗
PubMed1999

Clinical and laboratory features of primary progressive and secondary progressive MS.

OBJECTIVE: To compare the clinical and laboratory features of primary progressive (PP) and secondary progressive (SP) MS, to evaluate the role of CSF and urine myelin basic protein-like material (MBPLM) in differentiating PP from SP MS, and to assess the utility of urine MBPLM as a surrogate marker of disease activity in progressive MS. BACKGROUND: The current categorization of subtypes of MS is based solely on clinical and temporal characteristics of the disease. Laboratory markers are needed that can differentiate reliably the subtypes of MS and serve as surrogate markers of disease progression. METHODS: Clinical and paraclinical data of 51 PPMS and 140 SPMS patients were reviewed retrospectively. CSF and urine MBPLM were measured using a double-antibody radioimmunoassay. RESULTS: PPMS was more likely to present with progressive myelopathy (p < or = 0.001) after the age of 40 years (p = < or = 0.001), and it affected men relatively more often than SPMS (male-to-female ratio, 1:1.7 versus 1:3.2 respectively). Ambulatory assistance was required by PP patients more often and earlier than in those with SPMS. The incidence of abnormal CSF, evoked potential, and cranial MRI studies was similar in the two groups. Spinal cord MRI abnormalities were noted significantly more often in SP disease. There was an insignificant trend of higher CSF MBPLM in SPMS compared with PPMS. Urine MBPLM and MBPLM/creatinine were significantly higher in SPMS than in PPMS. However, the values of urine MBPLM and MBPLM/creatinine at the initial visits of patients with PPMS and SPMS were not significantly different. Urine MBPLM/creatinine was significantly higher in both PPMS and SPMS compared with normal control subjects. No correlation was found between urine MBPLM and disease duration or between urine MBPLM and clinical disability. There was no correlation between urine MBPLM/creatinine and either disease duration or clinical disability. CONCLUSIONS: These findings provide additional evidence of the differences in PPMS and SPMS, notably in the associated changes in MBPLM in urine, and also suggest a possible role for urine MBPLM in identifying patient cohorts. The high urine MBPLM levels in progressive MS patients indicate a potential role of this marker for assessing responsiveness to therapeutic interventions.

Adult↗
PubMed2000

The effect of cladribine on T(1) 'black hole' changes in progressive MS.

We compared the changes of the volumes of T(1)-hypointense lesions seen on the magnetic resonance imaging scans of the brain from 159 progressive multiple sclerosis (MS) patients who were enrolled in a double-blind, placebo-controlled trial assessing the efficacy of two doses of cladribine. Although in patients treated with cladribine there was a tendency to have a lower increase of T(1)-hypointense lesion volumes than those treated with placebo, no statistically significant effect of cladribine on T(1)-hypointense lesion accumulation was found over the one-year double-blind phase. Furthermore, no significant treatment effect was also detected in a subset of 22 patients who received placebo during the double-blind phase of the study and cladribine during the subsequent one-year open-label phase. We conclude that cladribine does not have a major impact on the mechanisms leading to severe tissue destruction in progressive MS.

Analysis of Variance↗
PubMed2003

Interferon beta-1a in primary progressive multiple sclerosis.

There is currently no disease-modifying treatment proven to be of efficacy in primary progressive multiple sclerosis (PPMS). However, a number of therapeutic trials have recently been specifically designed for this group. These include a randomised controlled trial of interferon beta-1a which is discussed here. It is hoped that therapeutics in primary progressive multiple sclerosis will continue to expand and effective therapeutic agents will be developed.

Adjuvants, Immunologic↗
PubMed2004

Treatment of progressive forms of multiple sclerosis by cyclophosphamide: a cohort study of 490 patients.

There are no generally effective disease-modifying drugs for progressive forms of multiple sclerosis (MS). Some MS centres use cyclophosphamide (CYC) in secondary progressive (SP) forms of MS, especially after interferon beta-1b (INFbeta-1b) treatment failure. Moreover, there are currently no approved drugs for primary progressive (PP) MS. Using the collected data of patients with progressive MS, we studied clinical patterns that predicted a good response to CYC treatment. Secondly, we compared the therapeutic response of SPMS and PPMS patients to the treatment. Data from 490 MS patients were collected. All patients presented an SP (n = 362) or PP (n = 128) form of the disease and 476 had been treated for at least one year with a monthly pulse of CYC associated with methylprednisolone (MP). CYC treatment was justified because of at least a 1-point worsening on the Expanded Disability Status Scale (EDSS) during the previous year. The EDSS score was assessed at baseline and after 6 months (M6) and 12 months (M12) of treatment. After 12 months of CYC treatment, 78.6% of SPMS and 73.5% of PPMS patients had stabilised or had an improved EDSS score. Response to CYC was not significantly different in the two progressive forms of MS. Twenty-two patients presented noticeable drug side effects, one of whom withdrew from the treatment due to intolerance. Patients with an improved EDSS at M12 had a shorter mean progressive time course (5.1 years) than patients who stabilised or worsened (7.1 years) (p = 0.02). We also observed that poor responders at M6 were also poor responders at M12 (p < 0.001). This large cohort study showed that CYC treatment was well tolerated and suggested that a better response occurred in cases with a short progressive time course. We did not find any difference in treatment response between the two progressive forms of MS. To date, no treatment is approved for PPMS and we therefore propose a trial to test the use of CYC treatment early in the course of the disease in PPMS patients with disability progression.

Adult↗
PubMed2001

Final analysis of the European multicenter trial on IFNbeta-1b in secondary-progressive MS.

BACKGROUND: Based on a prospectively planned interim analysis, the European study of interferon beta-1b (IFNbeta-1b) provided evidence that the treatment delays neurologic deterioration in patients with secondary progressive MS (SPMS). The authors analyzed all data collected until closure of the double-blind study to further scrutinize the consistency of the findings. METHODS: The multicenter, double-blind, randomized, placebo-controlled trial treated patients for up to 36 months. The primary and all secondary endpoints of this study were evaluated using the data set at study termination, with a mean follow-up under double-blind conditions of 1054 +/- 199 and 1068 +/- 176 days for the placebo and IFNbeta-1b group. Alternative and more demanding definitions of disease progression were explored. Confirmed progression was analyzed in subgroups according to baseline demographics and baseline indicators of disease activity. RESULTS: Forty-eight of 358 placebo and 40 of 360 IFNbeta-1b-allocated patients were lost to follow-up. Time to confirmed 1.0-point Expanded Disability Status Scale (EDSS) progression for patients receiving IFNbeta-1b was delayed (p = 0.007). The proportion of patients with a confirmed 2.0-point EDSS progression was approximately 27% lower for the group treated with IFNbeta-1b, both including and excluding EDSS data collected during relapses. The proportion of patients with either progression or relapses decreased by nearly 30% in patients treated with IFNbeta-1b compared with placebo. Analysis of subgroups suggests that patients with higher prestudy disease activity (more than two relapses or EDSS progression by more than 1.0 point or both) seem to have a more pronounced treatment effect. CONCLUSION: Analysis of the data set at study termination including additional post hoc outcome measures is consistent with the original findings, thus supporting the conclusion that treatment with IFNbeta-1b is effective in patients with SPMS fulfilling the inclusion criteria of this study.

Adjuvants, Immunologic↗
PubMed2003

IFNbeta lowers MMP-9/TIMP-1 ratio, which predicts new enhancing lesions in patients with SPMS.

OBJECTIVE: To 1)determine serum levels of matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 in patients with secondary progressive (SP) MS; 2)determine the relationship between these serum levels and MRI activity; and 3) evaluate the effect of interferon (IFN) therapy on these measures. BACKGROUND: High serum levels of MMP-9 and low levels of TIMP-1 predict the appearance of new gadolinium-enhancing (Gd+) lesions in relapsing-remitting (RR) MS. METHODS: Monthly Gd+ brain MRI and measures of serum MMP-2, MMP-9, TIMP-1, and TIMP-2 at 3-month intervals were performed for up to 3 years in 33 patients with SPMS participating in a phase III study of IFNbeta-1b. RESULTS: Patients who developed new Gd+ lesions had higher levels of MMP-9 than patients who did not develop Gd+ lesions (median 351 vs 226 ng/mL, p = 0.049). The ratio of MMP-9/TIMP-1 predicted new Gd+ lesion on the concurrent scan (OR = 2.23, 95% CI 0.99 to 4.99, p = 0.052) and on the following scan (OR = 2.16, 95% CI 1.01 to 4.63, p = 0.048), whereas levels of MMP-2/TIMP-2 did not. Median levels of TIMP-1 were higher and MMP-9 trended lower for IFNbeta compared to placebo recipients (TIMP-1: 1,450 vs 1,185 ng/mL, p = 0.024; MMP-9: 225 vs 339 ng/mL, p = 0.081). IFNbeta did not influence levels of MMP-2 and TIMP-2. CONCLUSION: The ratio of MMP-9/TIMP-1 may predict MRI activity in SPMS. The effect of IFNbeta-1b in MS, as measured by reduction in new Gd+ lesions, may be partly explained by altering MMP-9/TIMP-1 ratio.

Disease Progression↗
PubMed2000

T1 hypointensities and axonal loss.

T1 hypointensities are lesions that are hypointense on moderately T1-weighted conventional spin-echo sequences and serve as markers of matrix destruction and axonal loss. They correlate better with clinical disability than T2-weighted images, are found in patients with progressive multiple sclerosis, and can be used as surrogate outcome measures in treatment trials.

Axons↗
PubMed2003

Neutralizing antibodies during treatment of secondary progressive MS with interferon beta-1b.

OBJECTIVE: To investigate the relationship between neutralizing antibodies (NAB) and disease progression, relapses, and MR measures of MS. METHODS: Sequential serum samples from all 718 patients of the European Study Group in Interferon beta-1b in Secondary Progressive MS were analyzed to investigate relations between NAB and disease progression, relapses, and MR measures. RESULTS: This study showed no attenuating effect of NAB development on progression in disability. The effects of NAB on relapse rate showed substantial variation, depending on the statistical approach and definition of positivity, though analyses comparing low- and high-NAB+ periods with NAB- periods suggested a titer-related effect. MR T2 lesion volume changes from baseline were significantly higher for NAB+ patients but remained lower than for placebo patients. A substantial proportion of NAB+ patients became NAB-. No untoward effect of NAB development on safety was observed. CONCLUSION: These results support the conclusion that even though high NAB titers appear to have impact on treatment efficacy with respect to relapses, treatment decisions should be based primarily on clinical grounds.

Adult↗
PubMed2002

The pathology of primary progressive multiple sclerosis.

The present review will focus on the current knowledge of the pathology of primary progressive multiple sclerosis lesions. Multiple sclerosis (MS) is an inflammatory demyelinating disease with a broad clinical variability. The main disease courses are relapsing-remitting, secondary progressive and primary progressive MS. Pathological studies examining the specific underlying pathology of a defined clinical subtype are rare. Here, we focus on the pathological characteristics of the MS lesions and summarize the current findings of the pathology of primary progressive MS with respect to inflammation, oligodendrocyte myelin pathology, axon destruction and immunopathology of the lesions.

Alleles↗
PubMed1999

Bradykinin B1 receptor expression and function on T lymphocytes in active multiple sclerosis.

BACKGROUND: Lesion development in MS is initiated by migration of inflammatory cells into the central nervous system, a process dependent on endothelial cell-lymphocyte interaction. Bradykinin B1 receptor is a membrane-bound G protein-coupled receptor shown to be upregulated on the surface of various cells types during inflammation. OBJECTIVE: To assess the expression and function of the bradykinin B1 receptor on T lymphocytes from MS patients. METHODS: The authors used multiplex polymerase chain reaction amplification and Western blot techniques to demonstrate B1 receptor expression by T cells. A modified Boyden chamber assay also was used to assess the effect of B1 agonist and antagonist on T cell migration. RESULTS: The authors demonstrated that the expression of B1 receptor was upregulated on T cells derived from peripheral blood of MS patients. Expression of this receptor was upregulated on T cells from patients with secondary progressive MS and relapsing-remitting patients in active relapse. Expression was lower in relapsing remitting patients in remission and least in control subjects, including patients with epilepsy, chronic inflammatory demyelinating polyneuritis, and systemic lupus erythematosus. In vitro treatment of cells from healthy control subjects with tumor necrosis factor-alpha and interferon-gamma also induced the expression of B1 receptors. The authors also found that the significantly higher rate of migration of MS T lymphocytes, compared with control subjects in the Boyden chamber assay, could be prevented by the addition of the selective and stable B1 agonist Sar (D-Phe8) desArg9-BK. CONCLUSION: The authors demonstrate that B1 receptors are upregulated by T lymphocytes during the course of MS and that signaling through this receptor with a B1 agonist can negatively regulate T-cell migration in vitro.

Adult↗
PubMed2000

Heterogeneity of T-lymphocyte function in primary progressive multiple sclerosis: relation to magnetic resonance imaging lesion volume.

We found that in vitro migration and interferon-gamma production by lymphocytes derived from primary progressive multiple sclerosis patients preselected on the basis of a high T2-weighted lesion volume (>10 cm3) on magnetic resonance imaging, were increased compared with that in primary progressive multiple sclerosis patients with a low T2-weighted lesion volume (<3 cm3) and controls. Whether the heterogeneity of immune function within the primary progressive population will correlate with response to therapy remains to be established.

Adult↗
PubMed2001

Interferon-beta1b in the treatment of secondary progressive MS: impact on quality of life.

BACKGROUND: The recent randomized, controlled trial of interferon-beta1b (IFN-beta1b) in 718 patients with secondary progressive MS (SP-MS) demonstrated a significant effect on the development of disability as evaluated by the physician. Its effect on patient-reported health-related quality of life (HrQoL) is reported herein. METHODS: In this multicenter, double-blind, randomized, placebo-controlled trial, outpatients with SP-MS scoring between 3.0 and 6.5 on the Expanded Disability Status Scale received either 8 x 10(6) IU of IFN-beta1b or placebo for up to 3 years. A range of outcomes was measured, including HrQoL, which was assessed using the Sickness Impact Profile (SIP), a self-report questionnaire validated for use in MS. Measurements were undertaken at baseline and at 6-monthly intervals thereafter for 36 months. RESULTS: A slight positive effect on the HrQoL of the IFN group in comparison with the placebo group was found, which reached significance in the physical scale of the SIP at 6 and 12 months and at last visit. There was moderate correlation between physician-assessed evaluation of change and patient-reported change. CONCLUSIONS: IFN-beta1b may delay sustained deterioration in patient-reported HrQoL in SP-MS. Methods of interpreting change in HrQoL are currently insufficiently developed to determine how clinically important these changes are for this population.

Activities of Daily Living↗
PubMed2002

Evidence for widespread movement-associated functional MRI changes in patients with PPMS.

BACKGROUND: Previous work has suggested that functional reorganization of cortical motor areas might have a role in limiting the motor deficits in patients with MS. OBJECTIVE: To test whether movement-associated cortical changes in MS might extend beyond the "classic" motor areas and involve sites for multimodal integration. METHODS: fMRI was used to assess patterns of brain activations associated with 3 different motor tasks in 30 right-handed patients with primary progressive MS (PPMS) and variable degrees of motor impairment, which were compared with those from 15 right-handed, sex- and age-matched control subjects. RESULTS: Compared with control subjects, patients with MS showed increased activation of brain regions within both traditional motor planning and execution regions (including the supplementary motor area and the cingulate motor area), the insula (a region implicated in sensory processing), and several multimodal cortical regions in the temporal, parietal, and occipital lobes. In patients, the extent of the fMRI activations was strongly correlated with MR lesion burden (r ranging from 0.70 to 0.86, p < 0.001). CONCLUSIONS: This study shows that movement-associated cortical activation in patients with PPMS is widely distributed and also involves multimodal "nonmotor" cortical networks. It also suggests that adaptive cortical reorganization might be one of the mechanisms limiting the clinical impact of MS in the progressive phases of the disease.

Adult↗
PubMed2004

[Treatment of progressive multiple sclerosis with monthly pulsed cyclophosphamide-methylprednisolone: predictive factors of treatment response].

INTRODUCTION: Cyclophospamide is used in the treatment of progressive multiple sclerosis. We were looking for predictive indicators of treatment response. MATERIAL AND METHODS: Forty-seven patients with secondary progressive multiple sclerosis and seven others with primary progressive received monthly infusions of cyclophosphamide (750mg/m2) and methylprednisolone (500mg). During the year before cyclophosphamide the EDSS had worsened one point in all patients with or without surimposed relapses. Evaluation was based on EDSS change at 6, 12, 24 months and 5 years. RESULTS: Among secondary progressive patients, 91 per 100 (43/47) were stable or improved at 12 months, 65 per 100 (26/40) at 24 months and 22 per 100 (5/23) at 5 years. Annual relapse rate decreased from 0.81 before treatment to 0.48 during treatment and 0.12 after treatment (p<0.001). At 24 months, efficacy was correlated to a progressive phase lasting less than 5 years (p<0.01) and to a rapid increase of EDSS of at least 2 points the year before treatment (p<0.05). There were no influences of age, EDSS and surimposed relapses at the beginning of treatment, and other immunoactive drugs administrated before cyclophosphamide. There was no significant difference in quality of response to treatment between patients with primary progressive and secondary progressive multiple sclerosis. CONCLUSION: Cyclophosphamide appears to be more efficient in early stage of progressive multiple sclerosis independently of age, relapses or neurological disability scale.

Adjuvants, Immunologic↗
PubMed1999

1H magnetic resonance spectroscopy of normal appearing white matter in primary progressive multiple sclerosis.

Recent magnetic resonance imaging (MRI) and pathological studies have indicated that axonal loss is a major contributor to disease progression in multiple sclerosis. 1H magnetic resonance spectroscopy (MRS), through measurement of N-acetyl aspartate (NAA), a neuronal marker, provides a unique tool to investigate this. Patients with primary progressive multiple sclerosis have few lesions on conventional MRI, suggesting that changes in normal appearing white matter (NAWM), such as axonal loss, may be particularly relevant to disease progression in this group. To test this hypothesis NAWM was studied with MRS, measuring the concentration of N-acetyl derived groups (NA, the sum of NAA and N-acetyl aspartyl glutamate). Single-voxel MRS using a water-suppressed PRESS sequence was carried out in 24 patients with primary progressive multiple sclerosis and in 16 age-matched controls. Ratios of metabolite to creatine concentration (Cr) were calculated in all subjects, and absolute concentrations were measured in 18 patients and all controls. NA/Cr (median 1.40, range 0.86-1.91) was significantly lower in NAWM in patients than in controls (median 1.70, range 1.27-2.14; P = 0.006), as was the absolute concentration of NA (patients, median 6.90 mM, range 4.62-10.38 mM; controls, median 7.77 mM, range 6.60-9.71 mM; P = 0.032). There was no significant difference in the absolute concentration of creatine between the groups. This study supports the hypothesis that axonal loss occurs in NAWM in primary progressive multiple sclerosis and may well be a mechanism for disease progression in this group.

Adult↗
PubMed2002

[Quality of life in multiple sclerosis and pharmaco-economic studies].

Early disability and its rapid progression emphasize the medico-social importance of MS. The widely used disease-modifying treatments allowed to delay the time of severe disability, but this way of treatment is very expensive. The cost of MS is discussed based on literature data. The level of the cost of MS greatly depends on the disease severity and activity. Thus the studies of quality of life (QL) and pharmacoeconomical analysis, besides neurological scales, can give important additional information for clinical trials. First such studies in Europe in patients with secondary progressive MS showed a delay in progression of QL indexes in patients under Betaferon treatment in comparison to placebo. We studied changes in MOS SF-36 and WHO QL scales in groups of 60 MS patients, receiving Rebif or Copaxone. After 3 months of Rebif significant positive changes in scales, reflecting physical and social activity of MS patients, were found. At the same time negative changes in the "Pain" scale might reflect the presence of local side effects of beta-interferons treatment. No statistically significant changes in QL indexes under treatment with Copaxone were seen. The results of QL testing were associated with data of neuropsychological tests, characterizing chronic fatigue and depression. Thus the measurement of QL indexes may be a source of significant additional information, estimating the effecis of treatment and is the basic for pharmacoeconomical analysis.

Adjuvants, Immunologic↗