Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

MRI correlates of disability progression in patients with CIS over 48 months

Background: Gray matter (GM) and white matter (WM) pathology has an important role in disease progression of multiple sclerosis (MS). Objectives: To investigate the association between the development of GM and WM pathology and clinical disease progression in patients with clinically isolated syndrome (CIS). Methods: This prospective, observational, 48-month follow-up study examined 210 CIS patients treated with 30 µg of intramuscular interferon beta-1a once a week. MRI and clinical assessments were performed at baseline, 6, 12, 24, 36 and 48 months. Associations between clinical worsening [24-weeks sustained disability progression (SDP) and occurrence of a second clinical attack] and longitudinal changes in lesion accumulation and brain atrophy progression were investigated by a mixed-effect model analysis after correction for multiple comparisons. Results: SDP was observed in 32 (15.2%) CIS patients, while 146 (69.5%) were stable and 32 (15.2%) showed sustained disability improvement. 112 CIS patients (53.3%) developed clinically definite MS (CDMS). CIS patients who developed SDP showed increased lateral ventricle volume (p < .001), and decreased GM (p = .011) and cortical (p = .001) volumes compared to patients who remained stable or improved in disability. Converters to CDMS showed an increased rate of accumulation of number of new/enlarging T2 lesions (p < .001), decreased whole brain (p = .007) and increased lateral ventricle (p = .025) volumes. Conclusions: Development of GM pathology and LVV enlargement are associated with SDP. Conversion to CDMS in patients with CIS over 48 months is dependent on the accumulation of new lesions, LVV enlargement and whole brain atrophy progression

An example of automated volumetric assessment.

<p>A, FLAIR image from a patient with the usual extent of T2 hyperintense lesions seen in patients with clinically isolated syndrome. B, T1-weighted image with hypointense T1 lesions (arrows, lesion volume = 0.3 cm³). It is apparent that the T1 lesions were included in calculation of the overall brain volume (red area). C, T1-seighted image segmented by SIENAX. The T1 hypointense lesions (arrows) were misclassified into grey matter.</p

Volumetric MRI Markers and Predictors of Disease Activity in Early Multiple Sclerosis: A Longitudinal Cohort Study

<div><h3>Objectives</h3><p>To compare clinical and MRI parameters between patients with clinically isolated syndrome and those converting to clinically definite multiple sclerosis within 2 years, to identify volumetric MRI predictors of this conversion and to assess effect of early relapses.</p> <h3>Methods</h3><p>The SET study comprised 220 patients with clinically isolated syndrome treated with interferon beta (mean age, 29 years; Expanded Disability Status Scale, 1.5). Three patients with missing data were excluded from the analysis. Physical disability, time to clinically definite multiple sclerosis and volumetric MRI data were recorded for 2 years.</p> <h3>Results</h3><p>Patients reaching clinically definite multiple sclerosis showed impaired recovery of neurological function, faster decrease in corpus callosum cross-sectional area, higher T2 lesion volume and more contrast-enhancing lesions. Six-month decrease in corpus callosum cross-sectional area (≥1%) and baseline T2 lesion volume (≥5 cm³) predicted clinically definite multiple sclerosis within 2 years (hazard ratios 2.5 and 1.8, respectively). Of 22 patients fulfilling both predictive criteria, 83% reached clinically definite multiple sclerosis (hazard ratio 6.5). More relapses were associated with poorer recovery of neurological function and accelerated brain atrophy.</p> <h3>Conclusions</h3><p>Neurological impairment is more permanent, brain atrophy is accelerated and focal inflammatory activity is greater in patients converting to clinically definite multiple sclerosis. Six-month corpus callosum atrophy and baseline T2 lesion volume jointly help predict individual risk of clinically definite multiple sclerosis. Early relapses contribute to permanent damage of the central nervous system.</p> </div

Gray matter atrophy patterns in multiple sclerosis: A 10-year source-based morphometry study

Objectives: To investigate spatial patterns of gray matter (GM) atrophy and their association with disability progression in patients with early relapsing-remitting multiple sclerosis (MS) in a longitudinal setting. Methods: Brain MRI and clinical neurological assessments were obtained in 152 MS patients at baseline and after 10years of follow-up. Patients were classified into those with confirmed disability progression (CDP) (n=85) and those without CDP (n=67) at the end of the study. An optimized, longitudinal source-based morphometry (SBM) pipeline, which utilizes independent component analysis, was used to identify eight spatial patterns of common GM volume co-variation in a data-driven manner. GM volume at baseline and rates of change were compared between patients with CDP and those without CDP. Results: The identified patterns generally included structurally or functionally related GM regions. No significant differences were detected at baseline GM volume between the sub-groups. Over the follow-up, patients with CDP experienced a significantly greater rate of GM atrophy within two of the eight patterns, after correction for multiple comparisons (corrected p-values of 0.001 and 0.007). The patterns of GM atrophy associated with the development of CDP included areas involved in motor functioning and cognitive domains such as learning and memory. Conclusion: SBM analysis offers a novel way to study the temporal evolution of regional GM atrophy. Over 10years of follow-up, disability progression in MS is related to GM atrophy in areas associated with motor and cognitive functioning. Keywords: Multiple sclerosis, Disability, MRI, Atrophy, Gray matte

Disability and volumetric MRI parameters in patients with CIS and in those converting to CDMS.

<p>Dashed lines delineate 95% confidence intervals. Statistically significant p-values are shown. CIS, clinically isolated syndrome; CDMS, clinically definite multiple sclerosis; EDSS, Expanded Disability Status Scale; Gd+, gadolinium positive; MSFC, Multiple Sclerosis Functional Composite.</p

Cumulative risk of CDMS by number of volumetric MRI predictors.

<p>The MRI predictors found to be statistically significant by the logistic model were tested. These comprised decrease in corpus callosum area at 6 months ≥1%, and baseline T2 lesion volume ≥5 cm³. Hazard ratios with 95% confidence intervals are shown. CDMS, clinically definite multiple sclerosis, HR, hazard ratio.</p

Demographic, clinical and MRI characteristics of the sample.

*<p>t-test, Mann-Whitney U or χ2 tests; T2 lesion volumes and cumulative number of Gd+lesions were compared after logarithmic transformation.</p><p>CDMS, clinically definite multiple sclerosis; CIS, clinically isolated syndrome; EDSS, Expanded Disability Status Scale; Gd+, gadolinium positive; GM, grey matter; MSFC, Multiple Sclerosis Functional Composite; NS, not significant; SD, standard deviation; WM, white matter.</p

Effect of relapses on disability change and volumetric MRI parameters at 2 years of CIS.

<p>Patients were categorised by the number of relapses during the 2-year follow-up period (0: n = 125, 1: n = 30, 2: n = 35, 3: n = 16, 4+: n = 11). Least-squares regression lines (dashed) and statistically significant p-values are shown. EDSS, Expanded Disability Status Scale; Gd+, gadolinium positive; MSFC, Multiple Sclerosis Functional Composite; T2LV, T2 lesion volume.</p