MRI and assessment of treatment in multiple sclerosis.
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Atrophy↗
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Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores.
There were 21 patients with rapidly progressive multiple sclerosis (MS) treated on a phase 1/2 study of intense immune suppressive therapy and autologous hematopoietic stem cell (HSC) support with no 1-year mortality. Following transplantation, one patient had a confirmed acute attack of MS. Neurologic progression defined by the expanded disability status scale (EDSS) did not increase in disability by 1.0 or more steps in any of 9 patients with a pretransplantation EDSS of 6.0 or less. In 8 of 12 patients with high pretransplantation disability scores (EDSS > 6.0), progressive neurologic disability as defined by at least a 1-point increase in the EDSS has occurred and was manifested as gradual neurologic deterioration. There were 2 patients with a pretransplantation EDSS of 7.0 and 8.0 who died from complications of progressive disease at 13 and 18 months following treatment. Our experience suggests that intense immune suppression using a total body irradiation (TBI)-based regimen and hematopoietic stem cell transplantation (HSCT) are not effective for patients with progressive disease and high pretransplantation disability scores. Further studies are necessary to determine the role of intense immune suppressive therapy and HSC support in ambulatory patients with less accumulated disability and more inflammatory disease activity. Specifically, more patients and longer follow-up would be required in patients with an EDSS of 6.0 or less before drawing conclusions on this subgroup.
Adult↗
Neutralizing antibodies during treatment of secondary progressive MS with interferon beta-1b.
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Antibodies↗
A phase I trial of solubilized DR2:MBP84-102 (AG284) in multiple sclerosis.
OBJECTIVE: To assess the safety, tolerability, and biologic and clinical activity of a solubilized complex comprised of human leukocyte antigen-DR2 with myelin basic protein84-102 (AG284)in patients with secondary progressive MS. BACKGROUND: Soluble species-specific major histocompatibility complex myelin basic protein91-103 complexes ameliorate disease in a dose-dependent manner when administered to SJL/J mice with chronic relapsing experimental allergic encephalomyelitis. Preincubation with AG284 reduces the proliferative response of a DR2-restricted, myelin basic protein84-102-reactive T cell clone, derived from a MS patient, to myelin basic protein84-102 in the presence of autologous antigen-presenting cells. METHODS: Thirty-three patients with secondary progressive MS were randomly assigned to receive three alternate day IV doses of AG284 or placebo in a double-masked dose escalation study. The primary outcome was safety and tolerability. Secondary outcomes included a comparison of pre- and post-treatment gadolinium-enhanced brain MRI activity, Kurtzke Expanded Disability Status Scale, and Nine Hole Peg Test scores. RESULTS: The frequency of adverse events was similar in the AG284 and placebo recipients. No significant treatment effect was detected by Expanded Disability Status Scale, Nine Hole Peg Test, or number of new gadolinium-enhancing MRI lesions. CONCLUSIONS: AG284 as administered during this study was safe and well tolerated. Further studies are warranted to determine the biologic activity and clinical efficacy of this potential treatment for MS.
Adult↗
Erythrocyte membrane fatty acids in benign and progressive forms of multiple sclerosis.
BACKGROUND: There is no good explanation why a proportion of patients with multiple sclerosis (MS) have a relatively benign form of the disease. An imbalance between saturated and unsaturated fatty acids (FA) might influence the disease course of MS. AIM: To assess whether the erythrocyte membrane fatty acid composition, which is a biological marker of long term dietary FA consumption, is different between patients with benign and progressive MS. METHODS: The erythrocyte membrane FA composition was measured by gas chromatography in 23 healthy controls, 27 patients with benign MS, 32 patients with secondary progressive MS and 23 patients with primary progressive MS. None of the patients was following a special diet. RESULTS: No significant differences in levels of saturated and unsaturated FA or in omega-3- and omega-6-polyunsaturated FA were found between controls and patients with the different subtypes of MS. CONCLUSION: Our data suggest that factors other than dietary fatty acid consumption are responsible for the different disease courses of MS.
Adult↗
Low interleukin-10 production is associated with higher disability and MRI lesion load in secondary progressive multiple sclerosis.
Abnormalities in T-cell-derived cytokine production are a well-known phenomenon in multiple sclerosis (MS). An association between disability and the production of interferon gamma has been demonstrated recently. The present study investigated associations between disability, cytokine production in stimulated blood lymphocytes and magnetic resonance imaging data in 37 patients with the secondary progressive course in the stable phase of the disease. Patients with high interleukin-10 (IL-10) production had significantly lower disability scores (p=0.009) and lower T2 lesion load (p=0.03). Interleukin-10 might not only play a role in the pathological process of multiple sclerosis but has an impact on disease outcome as well.
Adult↗
Grey and white matter volume changes in early primary progressive multiple sclerosis: a longitudinal study.
We have recently reported brain atrophy in the early stages of primary progressive multiple sclerosis (PPMS), affecting both grey and white matter (GM and WM). However, to date no clinical or radiological predictors of GM and WM atrophy have been identified. The aim was to investigate short-term changes in GM and WM volumes and to assess the predictive value of demographic, clinical and radiological variables in order to gain a better understanding of the pathological substrate underlying these changes. Thirty-one subjects with PPMS within 5 years of symptom onset were studied at baseline and after 1 year. At baseline, patients underwent neurological examination and were scored on the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite. They had 3D inversion-prepared fast spoiled gradient recalled (FSPGR), dual-echo and triple-dose post-contrast T1-weighted spin echo MRI scans. Proton density and enhancing lesion loads were determined. The 3DFSPGR sequence was repeated after 1 year and brain volume changes were calculated using two techniques, SPM99 (statistical parametric mapping) and SIENA (structural image evaluation, using normalization, of atrophy). Stepwise linear regression models were applied to baseline variables to identify independent predictors of atrophy development. Using SPM99, a decrease in brain parenchymal fraction (-1.03%; P < 0.001) and GM fraction (-1.49%; P < 0.001) was observed. The number of enhancing lesions independently predicted decrease in brain parenchymal fraction (P = 0.019) and decrease in WM fraction (P = 0.002). No independent predictors of GM fraction decrease were found. A mean brain volume change of -0.63% (range -4.27% to +1.18%; P = 0.002) was observed using SIENA, which was independently predicted by EDSS (P = 0.004). Global and GM atrophy can be detected over a 1-year period in early PPMS. The former may be predicted by the degree of inflammation, while the latter seems to be independent of it. SIENA and SPM-based methods appear to provide complementary information.
Adult↗
Two-year follow-up study of primary and transitional progressive multiple sclerosis.
This study documents changes in clinical and magnetic resonance imaging (MRI) characteristics in a large cohort of patients with primary and transitional progressive multiple sclerosis (PP and TPMS) over 2 years. Patients with PPMS and TPMS were recruited from six European centres and underwent clinical and MRI examination at three time points: baseline, year one and year two. Of the 190 patients recruited clinical data were available on 125 patients (66%, five centres) and MRI data were available on 113 patients (59%, four centres) at 2 years. Significant increases were seen in T2 load and T1 hypointensity, while brain and cord volume decreased. In PPMS significantly higher lesion loads were found in those who presented with non-cord syndromes when compared to cord presentation and there was a trend to greater brain atrophy in those who deteriorated clinically over the course of the study compared to those who remained stable. Significant cord atrophy was only seen in those with a cord presentation. Measurable changes in MRI parameters can be detected in PPMS patients over a relatively short period of time. MRI quantification is likely to be useful in elucidating disease mechanisms in PPMS and in the execution of clinical trials.
Adult↗
[Fas receptor expression on peripheral blood T lymphocytes in patients with secondary progressive multiple sclerosis].
The percentages of CD4, CD8 subsets and Fas co-expression on them were assessed in secondary progressive multiple sclerosis (MS) patients and in control group. The MS patients were subdivided into two groups. The first group--active, consisted of patients who progressed by one or more degrees on EDSS scale in the preceding year, while the second group--stable, consisted of patients who showed no progression of the disease in the same period of time. Quantitative assessment of the individual subsets and Fas co-expression was carried out with the use of monoclonal anti-CD4, anti-CD8, as well as anti-CD95 antibodies, and Pas/Dako, Galaxy flow cytometer. There were no significant differences in CD4, CD8 subsets among the active, stable MS patients, and the control group. In the active MS group Fas co-expression on both subsets was significantly higher, as compared to controls. In the stable MS group, as compared to controls, a significantly higher Fas co-expression on CD8 subsets was observed. The investigation of Fas receptor expression on T lymphocytes in peripheral blood may be useful in order to monitor the progression of clinical activity in secondary progressive MS.
Antibodies, Monoclonal↗
Randomized controlled trial of interferon- beta-1a in secondary progressive MS: Clinical results.
BACKGROUND: The beneficial effect of interferon beta on exacerbations in relapsing-remitting MS has been demonstrated repeatedly, but results concerning disability vary. OBJECTIVE: This multicenter, randomized, parallel-group, placebo-controlled study tested two doses of interferon beta-1a in patients with secondary progressive MS, which may include relapses but is dominated by accumulating disability. METHODS: A total of 618 patients received subcutaneous placebo or interferon beta-1a, 22 or 44 microg three times weekly for 3 years. Patients were assessed every 3 months. RESULTS: The primary outcome, time to confirmed progression in disability, was not significantly affected by treatment (hazard ratio, 0.83; 95% CI, 0.65 to 1.07; p = 0.146 for 44 microg versus placebo). Relapse rate was reduced from 0.71 per year with placebo to 0.50 per year with treatment (p < 0.001 for both doses). Significant treatment effects were seen on other exacerbation-related outcomes and on a composite measure incorporating five separate clinical and MRI outcomes. The hazard ratio for time to progression for the combined interferon beta-1a groups compared with placebo was 0.74 among patients reporting relapses in the 2 years before study (p = 0.055), and 1.01 for those without prestudy relapses (p = 0.934). An unexpected treatment-by-sex interaction favored women. The drug was well tolerated. CONCLUSIONS: Treatment with interferon beta-1a did not significantly affect disability progression in this cohort, although significant treatment benefit was observed on exacerbation-related outcomes. Exploratory post hoc analyses suggested greater benefit in women and in patients who had reported at least one relapse in the 2 years before the study.
Adjuvants, Immunologic↗
Clinical-MRI correlations in a European trial of interferon beta-1b in secondary progressive MS.
BACKGROUND: The recently completed placebo-controlled multicenter randomized trial of interferon beta-1b (Betaferon) in 718 patients with secondary progressive MS shows significant delay of disease progression and reduction of relapse rate. This study provides an opportunity to assess the level of relationship between clinical and MRI outcomes in this cohort of patients with secondary progressive MS. METHODS: Brain T2-weighted lesion volume was measured annually in all available patients, with visual analysis to identify any new or enlarging (active) T2 lesions at each annual time point. A subgroup of 125 patients had monthly gadolinium-enhanced, T1-weighted imaging at months 0 to 6 and 18 to 24. Relapses were documented and expanded disability status scale (EDSS) was measured every 3 months. RESULTS: For the annual MRI outcomes, a significant but modest correlation was identified between the change in T2 lesion volume from baseline to the final scan and the corresponding change from baseline in EDSS (r = 0.17, p < 0.0001). There were significant correlations between the cumulative number of active T2 lesions and 1) change in EDSS (r = 0.18, p < 0.0001) and 2) relapse rate (r = 0.24, p < 0.0001). In the subgroup of 125 patients undergoing monthly imaging, MRI lesion activity was correlated with relapse rate over months 0 to 24 (r = 0.24, p = 0.006) but not with change in EDSS. CONCLUSIONS: These results confirm that the clinical-MRI relationships previously identified in relapsing-remitting MS still are apparent in the secondary progressive phase of the disease and support the use of MRI as a relevant outcome measure. In view of the relatively modest nature of the correlations, it seems unwise to rely on such MRI measures alone as primary efficacy variables in secondary progressive MS trials.
Brain↗
No association between the APOE epsilon4 allele and outcome and susceptibility in primary progressive multiple sclerosis.
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Alleles↗
Lesion pathology predicts response to plasma exchange in secondary progressive MS.
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Adult↗
Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study.
RATIONALE: Phase I/II studies of autologous hematopoietic stem cell transplantation (HSCT) for multiple sclerosis ( MS) were initiated, based on results of experimental transplantation in animal models of multiple sclerosis and clinical observations in patients treated concomitantly for malignant disease. PATIENTS: Eighty-five patients with progressive MS were treated with autologous HSCT in 20 centers and reported to the autoimmune disease working party of the European Group for Blood and Marrow Transplantation (EBMT). 52 (61 %) were female, median age was 39 [20-58] years. The median interval from diagnosis to transplant was 7 [1-26] years. Patients suffered from severe disease with a median EDSS score of 6.5 [4.5-8.5]. Active disease prior to transplant was documented in 79 of 82 evaluable cases. RESULTS: The stem cell source was bone marrow in 6 and peripheral blood in 79, and stem cells were mobilized into peripheral blood using either cyclophosphamide combined with growth factors or growth factors alone. Three patients experienced transient neurological complications during the mobilization phase. The high dose regimen included combination chemotherapy, with or without anti-lymphocyte antibodies or, with or without, total body irradiation. The stem cell transplants were purged of lymphocytes in 52 patients. Median follow-up was 16 [3-59] months. There were 7 deaths, 5 due to toxicity and infectious complications, 2 with neurological deterioration. The risk of death of any cause at 3 years was 10 (+/-7)% (95 % confidence interval). Neurological deterioration during transplant was observed in 22 patients; this was transient in most but was associated with MS progression in 6 patients. Neurological improvement by > or = 1 point in the EDSS score was seen in 18 (21 %) patients. Confirmed progression-free survival was 74 (+/-12)% at 3 years being 66 (+/-23)% in patients with primary progressive MS but higher in patients with secondary progressive or relapsing-remitting MS, 78 (+/-13)%; p = 0.59. The probability of confirmed disease progression was 20 (+/-11)%. MRI data were available in 78 patients before transplant showing disease activity (gadolinium enhancing, new or enlarging lesions) in 33 %. Posttransplant MRI showed activity at any time in 5/61 (8 %) evaluable cases. CONCLUSION: Autologous HSCT suggest positive early results in the management of progressive MS and is feasible. These multicentre data suggest an association with significant mortality risks especially in some patient groups and are being utilised in the planning of future trials to reduce transplant related mortality.
Adult↗
Immunological patterns identifying disease course and evolution in multiple sclerosis patients.
Reliable, and easy to measure, immunological markers able to denote disease characteristics in multiple sclerosis (MS) patients are still lacking. We applied a multivariate statistical analysis on results obtained by measuring-by real-time RT-PCR-mRNA levels of 25 immunological relevant molecules in PBMCs from 198 MS patients. The combined measurement of mRNA levels of IL-1beta, TNF-alpha, TGF-beta, CCL20 and CCR3 was able to distinguish MS patients from healthy individuals. CXCR5, CCL5, and CCR3 combined mRNA levels identify primary progressive MS patients while TNF-alpha, IL-10, CXCL10 and CCR3 differentiate relapsing MS patients. Our results indicate that multi-parametric analysis of mRNA levels of immunological relevant molecules in PBMCs may represent a successful strategy for the identification of putative peripheral markers of disease state and disease activity in MS patients.
Adult↗
Resistance to glucocorticoid-induced apoptosis in PLP peptide-specific T cell clones from patients with progressive MS.
Glucocorticoids (GC) are commonly used to treat inflammatory disorders such as multiple sclerosis (MS) and may exert their immunosuppressive activity by inducing apoptosis in activated lymphocytes. However, unlike relapsing-remitting MS patients, those with progressive disease respond poorly to GC treatment. The data in this communication indicate that PLP peptide-specific T cell clones from progressive, but not relapsing-remitting MS patients are resistant to GC-induced apoptosis in vitro, in a fashion associated with expression of B-7 co-stimulatory molecules. Thus, failure to respond to GC treatment may reflect defect in apoptosis that develop during the progressive stages of chronic inflammatory disease.
Adult↗
T(1) hypointense lesions in secondary progressive multiple sclerosis: effect of interferon beta-1b treatment.
Recently, the clinical efficacy of interferon beta-1b (IFNbeta-1b) was demonstrated for secondary progressive (SP) multiple sclerosis in a European multicentre study. We evaluated the effect of IFNbeta-1b treatment on the rate of development of hypointense T(1) MRI lesions, a putative marker of axonal damage. Unenhanced T(1)-weighted images were obtained in a subgroup of 95 multiple sclerosis patients from five centres at 6-month intervals; this subgroup was similar to the total study population for all demographic, clinical and MRI parameters. An experienced observer blinded to the clinical data and treatment allocation measured volumes. The median baseline lesion load for hypointense T(1) lesions was 5.1 cm(3) for placebo-treated and 4.9 cm(3) for IFNbeta-1b-treated patients (P = 0.56). Placebo-treated patients showed an increase in T(1) lesion load by a median of 14% per year (P = 0.0002 compared with baseline); this was reduced to 7.7% per year in the IFNbeta-1b-treated patients (P = 0.003 versus placebo). In the IFNbeta-1b arm there was a statistically significant correlation between absolute change in Expanded Disability Status Scale scores and T(1) lesion load by month 36 (r = 0.38, P = 0.0015). In patients with SP multiple sclerosis, IFNbeta-1b treatment reduces the development of hypointense T(1) lesions, suggesting that reduced axonal damage in lesions may play a part in the beneficial effect that is observed clinically.
Adult↗
The effect of interferon beta-1b on quantities derived from MT MRI in secondary progressive MS.
BACKGROUND: Magnetization transfer (MT) MRI can provide in vivo markers reflecting the severity of irreversible, MS-related brain damage occurring within and outside T2-visible lesions. OBJECTIVE: To assess the effect of interferon (IFN) beta-1b treatment on the accumulation of brain damage in patients with secondary progressive (SP) MS, measured using MT MRI. METHODS: Eighty-two patients with SPMS from five centers participating in a European, multicenter, double-blind, placebo-controlled trial of IFNbeta-1b in SPMS underwent brain T2-weighted and MT MRI at baseline. Evaluable follow-up data were available for 75 patients at 12 months, 54 at 24 months, and 47 at 36 months. MT MRI scans were postprocessed and analyzed to obtain histograms of MT ratio (MTR) values from the whole brain. A region of interest-based analysis of MTR values from the normal-appearing white matter (NAWM) was also performed. RESULTS: In both the treatment arms, there was a decrease of average brain MTR values from baseline to month 24 (mean change -4.9%) and month 36 (mean change -4.3%). These changes were significant for the placebo group at both timepoints and for the IFNbeta-1b group at month 24 only, with no significant treatment effect. A decrease of NAWM MTR was also observed, with no significant difference between the two treatment arms. CONCLUSION: In this cohort of patients with secondary progressive MS, interferon beta-1b did not show an overall effect on the worsening of magnetization transfer MRI measures, when compared with placebo. The data show that change in magnetization transfer ratio is a promising tool for monitoring disease evolution in secondary progressive MS and that the information obtained from magnetization transfer MRI complements that obtained from MRI measures of lesion load and inflammation.
Adult↗