Scoring treatment response in patients with relapsing multiple sclerosis.

BACKGROUND: We employed clinical and magnetic resonance imaging (MRI) measures in combination, to assess patient responses to interferon in multiple sclerosis. OBJECTIVE: To optimize and validate a scoring system able to discriminate responses to interferon treatment in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Our analysis included two large, independent datasets of RRMS patients who were treated with interferons that included 4-year follow-up data. The first dataset ("training set") comprised of 373 RRMS patients from a randomized clinical trial of subcutaneous interferon beta-1a. The second ("validation set") included an observational cohort of 222 RRMS patients treated with different interferons. The new scoring system, a modified version of that previously proposed by Rio et al., was first tested on the training set, then validated using the validation set. The association between disability progression and risk group, as defined by the score, was evaluated by Kaplan Meier survival curves and Cox regression, and quantified by hazard ratios (HRs). RESULTS: The score (0-3) was based on the number of new T2 lesions (>5) and clinical relapses (0,1 or 2) during the first year of therapy. The risk of disability progression increased with higher scores. In the validation set, patients with score of 0 showed a 3-year progression probability of 24%, while those with a score of 1 increased to 33% (HR = 1.56; p = 0.13), and those with score greater than or equal to 2 increased to 65% (HR = 4.60; p < 0.001). CONCLUSIONS: We report development of a simple, quantitative and complementary tool for predicting responses in interferon-treated patients that could help clinicians make treatment decisions.

Comparison between visual scoring of cyclic alternating pattern (CAP) and computerized assessment of slow EEG oscillations in the transition from light to deep non-REM sleep.

Ten healthy volunteers (six men and four women) aged between 20 and 30 years underwent a nocturnal polygraphic recording on paper and on tape. Spectral analysis was accomplished and EEG sleep scored according to standard criteria and to the guidelines for the identification of cyclic alternating pattern (CAP). The initial 25 min of sleep, starting from the first clear-cut k-complex and ending within stage 4, was subdivided into five consecutive blocks of 5 min each. Using a zero-crossing technique, we evaluated the number of total power oscillations in each block and we tested the hypothesis of significant modifications of the number of total power oscillations and of their periodicity in the successive sessions. In addition, we measured the gap between the maximum and minimum values, respectively, of two successive half-waves making up each oscillation. The hypothesis of time-related trends of the values of the gaps was tested by means of linear regression techniques. Within the 25-min time span, the number of periodic oscillations and the number of CAP cycles showed significant increases. The amplitude gaps underwent a decreasing trend. The present data suggest that slow rhythmic oscillations expressed by CAP can be detected by means of spectral analysis. Their dynamics suggests a close relationship with the EEG synchronization processes.

Combined MRI lesions and relapses as a surrogate for disability in multiple sclerosis.

OBJECTIVE: In multiple sclerosis (MS), the aim of therapies is to prevent the accumulation of irreversible disability. This is difficult to assess given the short time course of clinical trials. MRI markers and relapses are often used as surrogate of disability in MS studies, but their validity remains controversial. We sought to validate, at the individual patient level, MRI lesions and relapses as surrogates for disability progression over the course of MS trials. METHODS: Individual patient data from a large, placebo-controlled trial of interferon ß-1a in relapsing-remitting MS (RRMS) were analyzed. The Prentice criteria were applied to evaluate surrogacy of 1-year MRI active lesions and relapses for disability worsening (Expanded Disability Status Scale [EDSS]) over the 2-year follow-up. RESULTS: All Prentice criteria were satisfied. Treatment reduced by 31% the odds of having EDSS worsening over 2 years, reducing the mean number of MRI lesions by 61% and the mean number of relapses by 36% over 1 year. Both 1-year MRI lesion activity and relapses, when considered independently, accounted for more than 60% of the treatment effect on 2-year EDSS worsening. A combination of 1-year MRI lesion activity and relapses explained 100% of the treatment effect on EDSS worsening over 2 years. CONCLUSIONS: A combined measure of 1-year changes in MRI lesions and relapses after interferon therapy fully estimated the corresponding effect on 2-year EDSS worsening. This short-term combined measure appears to be a surrogate for disability progression over a longer term when evaluating the effect of interferon in RRMS.

Safety and immunogenicity of a new formulation of interferon beta-1a (Rebif New Formulation) in a Phase IIIb study in patients with relapsing multiple sclerosis: 96-week results.

BACKGROUND: A new formulation of subcutaneous (s.c.) interferon-beta-1a has been developed (Rebif New Formulation, RNF), produced without fetal bovine serum and without human serum albumin as an excipient, with the aim of improving injection tolerability, and reducing immunogenicity. OBJECTIVES: This article reports 96-week analyses of a Phase IIIb, open-label study of the safety and immunogenicity of RNF compared with historical (EVIDENCE study) and recent (REGARD study) data on the original formulation. METHODS: Patients with relapsing multiple sclerosis (McDonald criteria) and an Expanded Disability Status Scale score < 6.0 received RNF, 44 microg s.c. three times weekly. RESULTS: The proportion of neutralizing antibody-positive (NAb+) patients (serum NAb status >or=20 neutralizing units/mL) at week 96 (last observation carried forward; primary endpoint) was 17.4% (exact 95% confidence interval [CI]: 13.0-22.5), compared with 21.4% (95% CI: 17.2-26.2) in the EVIDENCE study, and 27.3% (95% CI: 22.8-32.1) in the REGARD study. The proportion of patients NAb+ at any time during the 96 weeks was 18.9% (95% CI: 14.4-24.2), compared with 27.1% (95% CI: 22.4-32.2) and 33.7% (95% CI: 28.9-38.7), respectively. Most pre-specified categories of adverse events were reported by patients in the RNF study at a similar or lower proportion than in the EVIDENCE and REGARD studies. Injection-site reactions were experienced by fewer patients than in the EVIDENCE and REGARD studies. CONCLUSIONS: RNF has improved overall immunogenicity and safety profiles compared with the original formulation.

Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS.

OBJECTIVE: To conduct systematic long-term follow-up (LTFU) of patients in the Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study to provide up to 8 years of safety, clinical and MRI outcomes on subcutaneous (s.c.) interferon (IFN) beta-1a in relapsing-remitting multiple sclerosis (RRMS). METHODS: The original cohort of 560 patients was randomized to IFNbeta-1a, 44 or 22 microg three times weekly (TIW) or to placebo; after 2 years, patients on placebo were rerandomized to active treatment and the blinded study continued for a further 4 years. The LTFU visit was scheduled 7 to 8 years after baseline. RESULTS: LTFU was attended by 68.2% of the original PRISMS study cohort (382/560 patients). 72.0% (275/382) were still receiving IFNbeta-1a s.c. TIW. Patients originally randomized to IFNbeta-1a 44 microg s.c. TIW showed lower Expanded Disability Status Scale progression, relapse rate and T2 burden of disease up to 8 years compared with those in the late treatment group. Brain parenchymal volume did not show differences by treatment group. Overall, 19.7% of patients progressed to secondary progressive MS between baseline and LTFU (75/381). No new safety concerns were identified and treatment was generally well tolerated. CONCLUSIONS: Despite the limitations inherent in any long-term study (for example, potential differences between returning and nonreturning patients), these results indicate that patients with relapsing-remitting multiple sclerosis can experience sustained benefit over many years from early interferon beta-1a subcutaneous therapy three times weekly compared with patients whose treatment is delayed. This effect was more apparent in the patients receiving the higher dose.

Accuracy of 133-xenon regional cerebral blood flow and quantitative electroencephalography in systemic lupus erythematosus.

OBJECTIVE: Comparative assessment of sensitivity and specificity of regional Cerebral Blood Flow (rCBF) by 133-Xenon inhalation and quantitative Electroencephalography (qEEG) in patients with Neuropsychiatric Systemic Lupus Erythematosus (NP-SLE). METHODS: Sixty-two combined rCBF and qEEG examinations were performed in fifty-two SLE patients. Group A: 27 SLE patients without NP-SLE; group B: 17 patients with florid (within 1 month) NP-SLE; group C: 12 patients previous NP-SLE examined in the remission phase (four patients of which already considered in group B). The study also included data deriving from two sets of examinations in ten patients who were observed twice, in different phases of the clinical course of NP-SLE. RESULTS: In comparison to healthy controls, rCBF lower (p < .001) in group B only, whereas qEEG showed similar increases of both delta and theta relative powers together with a reduction of alpha relative power in groups A-C. As compared to group A, sensitivity and specificity in detecting cerebral abnormalities in group B were 76% and 78% for rCBF, and 59% and 44% for qEEG, respectively. In the ten patients examined twice, rCBF was consistent with clinical course in 90% of cases and qEEG in 60%. CONCLUSION: Total accuracy in detecting cerebral functional abnormalities during florid NP-SLE is better by rCBF than by qEEG. rCBF and, in selected cases, qEEG examinations are reliable markers of NP-SLE.