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L Kappos

Publications and source records attributed to L Kappos.

At least 19 recordsLinked to original sources
PubMed2003

MRI metrics as surrogate endpoints for EDSS progression in SPMS patients treated with IFN beta-1b.

BACKGROUND: Although metrics derived from conventional MRI (cMRI) are widely used as outcome measures in clinical trials of MS, no formal study has been performed to validate cMRI metrics as surrogate endpoints for disability progression in MS. METHODS: A validation procedure was applied to the clinical and MRI data collected in the context of the European randomized, double-blind, placebo-controlled trial of interferon beta-1b (IFNbeta-1b) in patients with secondary progressive MS. The Prentice operational criteria were used to assess surrogacy for the number of active lesions seen on the first year T2-weighted MRI scans and the percentage T2 lesion volume change between the baseline and the first year MRI scans. The primary clinical outcome was disability at study exit (3 years), adjusted for the baseline disability. RESULTS: The number of active T2 lesions and the T2 lesion volume percentage change over the first year of the study accounted for 57% of the treatment effect on disability progression over the entire study duration. On the contrary, the same cMRI metrics accounted for 79% of the treatment effect on the relapse rate. CONCLUSIONS: This study shows that the beneficial effect of IFNbeta-1b on disability accumulation in patients with secondary progressive MS is, to a large extent, independent of the changes detected using cMRI. As a consequence, cMRI metrics should not be used as a stand-alone measure of outcome in phase III trials of IFNbeta in secondary progressive MS.

Biomarkers↗
PubMed2003

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↗
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↗
PubMed2003

Can the Expanded Disability Status Scale be assessed by telephone?

Information from patients who are unable to continue their visits to a study centre may be of major importance for the interpretation of results in multiple sclerosis (MS) clinical trials. To validate a questionnaire based on the Expanded Disability Status Scale (EDSS), patients in five different European centres were assessed independently by pairs of trained EDSS raters, first by telephone interview and a few days later by standardized neurological examination. Seventy women and 40 men with an average age of 43.7 years (range 19-74 years) were included in the study. Mean EDSS score at the last visit was 4.5 (0-9). EDSS assessment by telephone was highly correlated with the EDSS determined by physical examination (Pearson's correlation coefficient = 0.95). An intraclass correlation coefficient (ICC) of 94.8% was found for the total sample; 77.6% and 86%, respectively, for patients with EDSS < 4.5 (n = 46) and > 4.5 (n = 64). Kappa values for full agreement were 0.48; for variation by +0.5 steps and +1.0 steps, 0.79 and 0.90, respectively. Best agreement could be found in higher EDSS scores, where assessment by telephone interview might be needed most. The telephone questionnaire is a valid tool to assess EDSS score in cases where the patient is unable to continue visiting a study centre or in long-term follow-up of trial participants.

Adult↗
PubMed2003

Oral interferon beta-1a in relapsing-remitting multiple sclerosis: a double-blind randomized study.

BACKGROUND: Interferon beta (IFNB) is available in parenteral formulations for treatment of multiple sclerosis (MS). The purpose of this study was to evaluate safety, tolerability and effects on MRI lesions of three different doses of oral IFNB-1a compared with placebo over six months in relapsing-remitting (RR) MS patients. METHODS: In this multicenter; double-blind randomized trial, RR-MS patients received 0.06, 0.6 or 6 million international units (MIU) IFNB-1a or placebo every other day for up to six months. Gadolinium DTPA-enhanced brain MRI scans were performed at screening and monthly during treatment. The primary variable was the cumulative number of newly active lesions. Secondary variables included volume of enhancing lesions on T1-weighted images each month and lesion volume on T2-weighted images at months three and six. Safety measures included adverse events, laboratory variables, vital signs, ECG, physical examination, EDSS and number of relapses. Neopterin was measured in 21 patients and neutralizing antibodies in 24 patients. RESULTS: Of 194 screened patients, 173 were randomized (42-44 patients per group) in 15 centers. Median cumulative numbers of newly active lesions over six months were 4.0 in the placebo and 0.6 MIU groups, compared with 7.5 and 9.0 in the 0.06 and 6 MIU groups (no significant differences). Secondary efficacy endpoints showed small and inconsistent differences between groups. Adverse events showed no notable group differences. Approximately two-thirds of patients in each group remained relapse free. No patients showed neutralizing antibodies. Neopterin levels were comparable between groups. CONCLUSION: Oral IFNB-1a showed neither beneficial effects in RRMS nor any systemic biological effects. Treatment was safe and well tolerated.

Adjuvants, Immunologic↗
PubMed2002

A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS.

BACKGROUND: Interferon beta-1a (IFNbeta-1a; Avonex) is effective for the treatment of relapsing MS; however, the optimal dose of IFNbeta-1a is not known. OBJECTIVE: To determine whether IFNbeta-1a 60 micro g IM once weekly is more effective than IFNbeta-1a 30 micro g IM once weekly in reducing disability progression in relapsing MS. METHODS: In a double-blind, parallel-group, dose-comparison study, 802 patients with relapsing MS from 38 centers in Europe were randomized to IFNbeta-1a 30 micro g (n = 402) or 60 micro g (n = 400) IM once weekly for >/=36 months. The primary endpoint was disability progression, defined as time to a sustained increase of >/=1.0 point on the Expanded Disability Status Scale (EDSS) persisting for 6 months. Additional endpoints included relapses, MRI, safety, immunogenicity, and subgroup analyses of disability progression. RESULTS: Both groups showed equal rates of disability progression (hazard ratio, 0.96; 95% CI, 0.77 to 1.20; p = 0.73). In both groups the proportion of subjects with progression of disability by 36 months estimated from Kaplan-Meier curves was 37%. No dose effects were observed on any of the secondary clinical endpoints. Only one MRI measure at one time point, number of new or enlarging T2 lesions at month 36 compared with month 24, showed a difference favoring the 60- micro g dose. Both doses were well tolerated; however, slightly higher incidences of flulike symptoms and muscle weakness were observed in the 60- micro g group. The incidences of neutralizing antibodies (titers >/= 20) were 2.3% in the 30- micro g group and 5.8% in the 60- micro g group. CONCLUSION: There was no difference between IFNbeta-1a 30 micro g and 60 micro g IM in clinical or MRI measures.

Adolescent↗
PubMed2002

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↗
PubMed2001

The effect of IFNbeta-1b on the evolution of enhancing lesions in secondary progressive MS.

BACKGROUND: After the resolution of contrast enhancement, the majority of new MS lesions become isointense with surrounding white matter on T1-weighted MRI. Less commonly, a hypointense T1 lesion develops, representing the development of more severe focal tissue damage. Interferon beta (IFNbeta) reduces both the number of new enhancing lesions and the duration of contrast enhancement. OBJECTIVE: To determine if IFNbeta affects the degree of tissue damage within new lesions and if its effects are related to lesion size. METHODS: One hundred twenty-five patients with secondary progressive MS from seven European sites were randomized to receive either IFNbeta-1b or placebo. Monthly, contrast-enhanced T1-weighted MR images were acquired at baseline, at months 1 to 6, and at months 19 to 24. The size of all new enhancing lesions developing between months 1 and 6 was recorded and their appearance at follow-up documented. RESULTS: In the first 6 months, fewer new enhancing lesions occurred in the IFNbeta-1b arm. This difference was greater for small (70% decrease) than for large (46% decrease) lesions. Hypointense T1 lesions were more likely to form from large (25%) than from small (9%) enhancing lesions in both treatment arms. Patients taking IFNbeta-1b developed fewer hypointense T1 lesions; however, the proportion of enhancing lesions developing into hypointense T1 lesions was similar in both arms. CONCLUSION: IFNbeta-1b reduced the number of new enhancing lesions, with a greater effect on small lesions. However, when a new enhancing lesion did become established, treatment with IFNbeta-1b did not alter its subsequent course.

Adult↗
PubMed2001

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↗
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↗
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↗
PubMed2001

Swallowing abnormalities in multiple sclerosis: correlation between videofluoroscopy and subjective symptoms.

The purpose of this study was to evaluate if subjective symptoms indicating an impaired deglutition correlate with videofluoroscopic findings in patients with multiple sclerosis (MS). Videofluoroscopic examinations of 18 MS patients were analyzed by a radiologist and a logopedist and compared with the symptoms of these patients. Four patients complained about permanent dysphagia. Six patients reported mild and intermittent difficulties in swallowing, but were asymptomatic at the time of videofluoroscopy. Eight patients had no symptoms regarding their deglutition. All patients ( n=4) who complained of permanent dysphagia showed aspiration. All patients ( n=6) with mild and intermittent difficulties in swallowing showed undercoating of the epiglottis and/or laryngeal penetration. Of those 8 patients without any swallowing symptoms, only 2 had a normal videofluoroscopy. Swallowing abnormalities seem to be much more frequent in patients with MS than generally believed and they may easily be missed clinically as long as the patients do not aspirate.

Adult↗
PubMed2001

Interleukin 15 stimulates production of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by human peripheral blood mononuclear cells.

In peripheral blood mononuclear cells (PBMC), matrix metalloproteinase (MMP)-9 mediates the extravasation of immune cells and may be involved in tissue destruction during inflammation. We investigated the effect of the pro-inflammatory cytokines interleukin (IL-)12 and 15 on the secretion of MMP-9 in PBMC. IL-15, but not IL-12, induces MMP-9 in PBMC and in T cells. Moreover, the combination of IL-15 and IL-2 had an additive effect. In contrast, both IL-12 and IL-15 induced the release of tissue inhibitor of metalloproteinases (TIMP)-1. IL-15 led to a dose-dependent increase of the MMP-9/TIMP-1 ratio as a measure for increased proteolytic capacity. We conclude that IL-15 mediates its effects in inflammation in part through MMP-9.

Cells, Cultured↗
PubMed2001

Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis.

Matrix metalloproteinases (MMPs) are a family of Zn2+-dependent endopeptidases targeting extracellular matrix (ECM) compounds as well as a number of other proteins. Their proteolytic activity acts as an effector mechanism of tissue remodeling in physiologic and pathologic conditions, and as modulator of inflammation. In the context of neuro-inflammatory diseases, MMPs have been implicated in processes such as (a) blood-brain barrier (BBB) and blood-nerve barrier opening, (b) invasion of neural tissue by blood-derived immune cells, (c) shedding of cytokines and cytokine receptors, and (d) direct cellular damage in diseases of the peripheral and central nervous system. This review focuses on the role of MMPs in multiple sclerosis (MS) and bacterial meningitis (BM), two neuro-inflammatory diseases where current therapeutic approaches are insufficient to prevent severe disability in the majority of patients. Inhibition of enzymatic activity may prevent MMP-mediated neuronal damage due to an overactive or deviated immune response in both diseases. Downregulation of MMP release may be the molecular basis for the beneficial effect of IFN-beta and steroids in MS. Instead, synthetic MMP inhibitors offer the possibility to shut off enzymatic activity of already activated MMPs. In animal models of MS and BM, they efficiently attenuated clinical disease symptoms and prevented brain damage due to excessive metalloproteinase activity. However, the required target profile for the therapeutic use of this novel group of compounds in human disease is not yet sufficiently defined and may be different depending on the type and stage of disease. Currently available MMP inhibitors show little target-specificity within the MMP family and may lead to side-effects due to interference with physiological functions of MMPs. Results from human MS and BM indicate that only a restricted number of MMPs specific for each disease is up-regulated. MMP inhibitors with selective target profiles offer the possibility of a more efficient therapy of MS and BM and may enter clinical trials in the near future.

Animals↗
PubMed2001

Evoked potentials for evaluation of multiple sclerosis.

The role of evoked potentials (EP) in the assessment of multiple sclerosis (MS) has changed over the last decade. This is largely due to progress in imaging techniques. But while MRI has a greater diagnostic sensitivity, EP remain a useful diagnostic tool in many clinical situations. Moreover, recent studies demonstrate the utility of EP for monitoring and predicting the course of the disease in patient groups, although not yet in individuals. For these purposes, EP show better results than conventional MRI. In the near future, new developments in electrophysiology, immunology and imaging may allow to differentiate between different subtypes of MS early in the course, and consequently to tailor therapeutic measures more precisely to the individual patients.

Evoked Potentials↗