Author Of 2 Presentations
P0382 - Reduction in CUA MRI lesions in the first 6 months of cladribine tablets treatment for highly active relapsing multiple sclerosis: MAGNIFY-MS study (ID 982)
The MAGNIFY-MS study (NCT03364036) aims to determine the onset of action of cladribine tablets 3.5 mg/kg over 2 years (CT3.5) in patients with relapsing multiple sclerosis (RMS). Efficacy data from the pivotal trial CLARITY showed that outcomes in CT3.5-treated patients were superior to placebo with regard to number and relative reduction of standardized combined unique active (CUA) lesions over the 96-week trial. Carrying out early and frequent magnetic resonance imaging (MRI) will provide valuable insights into the onset of action of CT3.5.
To report on the onset of action of CT3.5 by observing changes in counts of CUA MRI lesions during the first 6 months of the MAGNIFY-MS study.
MRI scans were performed at screening, baseline, and at months 1, 2, 3 and 6 following CT3.5 treatment on patients with highly active RMS. Differences in CUA lesions between post-baseline periods (period 1, months 1–6, period 2, months 2–6, and period 3, months 3–6) were compared to the baseline period. CUA lesion count was standardized to period length and number of MRIs in a period. A mixed effects linear model was used to account for within pooled centre correlation and adjusted for CUA lesion count during the baseline period, age, and baseline expanded disability status scale (EDSS; >3, ≤3). Type-I-error inflation due to multiple testing was controlled by a gatekeeping procedure.
The full analysis set considered for primary analysis included 270 patients. Reductions in mean CUA count were observed from month 1 onwards compared to baseline; by -1.193 in period 1, -1.500 in period 2 and -1.692 in period 3 (all p<0.0001). In particular, the mean T1 Gd+ lesion counts were decreased from month 2 onwards compared to baseline; by -0.857 at month 2, -1.355 at month 3 and -1.449 at month 6 (all p<0.0001). Sensitivity analysis using negative binomial distribution showed that the treatment effect increased with time measured as lack of CUA in subsequent periods; by 61% in period 1, 77% in period 2, and 87% in period 3 (all p<0.0001). The proportion of patients without any CUA lesions increased in the first 6 months; by 52% in period 1 (p=0.0241), 66% in period 2 (p<0.001), and 81% in period 3 (p<0.001).
MRI was used to assess disease activity in a group of highly active RMS on CT3.5 treatment from one month onwards. Data show an early onset of action on CUA lesions that was significant from month 1 versus baseline, with a treatment effect that increased over the first 6 months.
P0955 - Diffuse inflammation relates to demyelination and clinical parameters in primary (PP) and secondary progressive multiple sclerosis (SP). (ID 1181)
In primary progressive MS (PP), brain plaques are smaller and remyelinate better than in secondary progressive MS (SP) yet prognosis and response to systemic immunotherapy in PP is poor.
To investigate relations between inflammation and myelin injury in PP vs SP and find correlates of clinical progression.
Large brain sections from clinically well-described post-mortem cohorts (12 PP, 14 SP and 11 controls) were stained with HE and Luxol-fast blue (myelin). Patients were additionally stained for proteolipid protein and CD68. We measured area loads of total plaque, microglia-rimmed slowly expanding plaque and macrophage-filled filled active plaque (% of WM area). Myelin density in the white matter overall, the normally appearing (NAWM), and the diffusely injured white matter (DIWM) was assessed by densitometry in ImageJ. In white matter compartments, we measured the density and mean size of perivascular mononuclear infiltrates (PMI; #/Cm2). The minimal PMI (grade one) had 3-4 perivascular cell rows and 20-50 cells whereas max. grade six had >19 rows and >500 cells. T- and B-cells in PMI’s were confirmed by CD3 and CD20. EDSS was estimated by chart review in a blinded fashion among 20 patients (10 PP and 12SP) from whom charts were available from two time points including one within three yrs. before death. Among these, we calculated Δ EDSS/yr before death.
In parallel, in-vivo cohorts (26 PP, 26 SP and 24 controls) were analyzed for MRI lesions with/without Gadolinium-enhancement and cerebrospinal fluid (CSF)-biomarkers of demyelination (MBP), axonal damage (NFL) and inflammation.
Densities and sizes of PMI’s in NAWM as well as CSF-markers of inflammation (e.g. IgG-indices, CXCL13, MMP9) were equally increased in PP and SP and equally large PMI’s located to periventricular zones (median gr 1,8 IQR 1,5-2,1). Active and total lesion formation were higher in SP than in PP in both post-mortem and in-vivo cohorts and (post-mortem) juxtacortical and meningeal PMI’s were larger in SP than PP. By contrast, more DIWM-pathology was found in PPMS than in SPMS. The overall myelin density (post-mortem) and NAWM magnetic-transfer-ratio (in-vivo) were equally reduced while MBP and NFL levels in the CSF (in-vivo) were equally increased in both groups.
Plaque-distant (NAWM/DIWM) PMI-density (post-mortem cohort) and CSF-inflammation (in-vivo cohort) correlated with active lesion formation in SP, but not in PP. PMI-density and size in NAWM and in the white matter overall correlated with shorter survival. PMI-density in the white matter overall also correlated with slowly exp. plaque load, which in turn, correlated with Δ EDSS/yr before death in PP and in SP.
Perivascular inflammation is pathogenic and may contribute to white matter demyelination in PP and SP. Inflammatory demyelination in the white matter may not differ greatly but may be more diffuse and less focal in PP compared to SP.