Neuromyelitis optica (NMO) is a life-threatening disease without any validated treatment strategy. Recent retrospective studies suggested the efficacy of B cell depletion without any distinction ...between first-line or rescue therapy. To assess whether rituximab as first-line therapy in NMO could efficiently control the occurrence of relapses. A retrospective analysis of NMO patients from NOMADMUS network found 32 patients receiving rituximab as first-line therapy. Main measures were number of relapse-free patients, changes in the annualized relapse rate (ARR), and changes in the EDSS. Tolerance was reported. At baseline, NMO patients were 45 ± 12.1 years old, with a sex ratio of 5.4, and 87.5 % of them had AQP4 antibodies. The median disease duration was 6.5 months (1–410), the mean EDSS was 5.8 ± 2.4 and the mean ARR was 3.8 ± 4.3. After rituximab with a mean follow-up of 28.7 ± 21 months, twenty-seven patients (84.3 %) were relapse free. Patients presented a 97 % decrease of ARR (
p
= 0.00001). EDSS decreased significantly to 3.9 ± 2.6 (
p
= 0.01). No relevant side effect was noted. New retrospective data are presented on RTX use in NMOSD. When used as first-line therapy RTX is highly effective and well tolerated.
OBJECTIVETo evaluate the frequency of asymptomatic optic nerve lesions and their role in the asymptomatic retinal neuroaxonal loss observed in multiple sclerosis (MS).
METHODSWe included patients ...with remitting-relapsing MS in the VWIMS study (Analysis of Neurodegenerative Process Within Visual Ways In Multiple Sclerosis) (ClinicalTrials.gov Identifier03656055). Included patients underwent optical coherence tomography (OCT), optic nerve and brain MRI, and low-contrast visual acuity measurement. In eyes of patients with MS without optic neuritis (MS-NON), an optic nerve lesion on MRI (3D double inversion recovery DIR sequence) was considered as an asymptomatic lesion. We considered the following OCT/MRI measuresperipapillary retinal nerve fiber layer thickness, macular ganglion cell + inner plexiform layer (mGCIPL) volumes, optic nerve lesion length, T2 lesion burden, and fractional anisotropy within optic radiations.
RESULTSAn optic nerve lesion was detected in half of MS-NON eyes. Compared to optic nerves without any lesion and independently of the optic radiation lesions, the asymptomatic lesions were associated with thinner inner retinal layers (p < 0.0001) and a lower contrast visual acuity (p ≤ 0.003). Within eyes with asymptomatic optic nerve lesions, optic nerve lesion length was the only MRI measure significantly associated with retinal neuroaxonal loss (p < 0.03). Intereye mGCIPL thickness difference (IETD) was lower in patients with bilateral optic nerve DIR hypersignal compared to patients with unilateral hypersignal (p = 0.0317). For the diagnosis of history of optic neuritis, sensitivity of 3D DIR and of mGCIPL IETD were 84.9% and 63.5%, respectively.
CONCLUSIONSAsymptomatic optic nerve lesions are an underestimated and preponderant cause of retinal neuroaxonal loss in MS. 3D DIR sequence may be more sensitive than IETD measured by OCT for the detection of optic nerve lesions.
Eculizumab, a humanized monoclonal antibody targeting the C5 complement protein, has been approved for the treatment of neuromyelitis optica spectrum disorders (NMOSD) in adult patients who are ...anti-aquaporin-4 (AQP4) antibody positive (Ab+). The aim of this study is to evaluate the long-term effectiveness and safety of eculizumab in French adults with NMOSD and to describe patients' characteristics, disability, and quality of life using data collected in a real-world setting.
This is the protocol for ECUP4, an ongoing prospective, observational, non-comparative, multicenter study conducted in 32 reference centers in France. Eligible patients must also be enrolled in NOMADMUS, a nested cohort of the French national multiple sclerosis registry (OFSEP). The primary endpoint is the annualized relapse rate. Secondary endpoints include the long-term safety of eculizumab, as well as patients' characteristics, treatment outcomes, disability, pain, visual acuity, and quality of life. Visits and treatments follow routine clinical practice. The case report forms (CRF) comprise data recorded in the context of the NOMADMUS cohort, collected during routine visits. The inclusion period is planned for 3 years, with no limitation on the number of patients enrolled. The maximum follow-up duration will be 5.5 years.
The efficacy and safety of eculizumab in patients with AQP4+ NMOSD have been demonstrated in randomized clinical trials that showed a significant reduction in the risk of relapse, with a safety profile consistent with other indications. This study will provide clinical and patient-reported evidence of the benefits of eculizumab, using data from a real-world setting in France.
This study is registered at the French public repertory Health data Hub, N° F20211228123801. All information can be accessed at: https://www.health-data-hub.fr/.
Treatment options for patients suffering from progressive forms of multiple sclerosis (MS) remain inadequate. Mast cells actively participate in the pathogenesis of MS, in part because they release ...large amounts of various mediators that sustain the inflammatory network. Masitinib, a selective oral tyrosine kinase inhibitor, effectively inhibits the survival, migration and activity of mast cells. This exploratory study assessed the safety and clinical benefit of masitinib in the treatment of primary progressive MS (PPMS) or relapse-free secondary progressive MS (rfSPMS).
Multicenter, randomized, placebo-controlled, proof-of-concept trial. Masitinib was administered orally at 3 to 6 mg/kg/day for at least 12 months, with dose adjustment permitted in event of insufficient response with no toxicity. The primary response endpoint was the change relative to baseline in the multiple sclerosis functional composite score (MSFC). Clinical response was defined as an increase in MSFC score relative to baseline of > 100%.
Thirty-five patients were randomized to receive masitinib (N = 27) or placebo (N = 8). Masitinib was relatively well tolerated with the most common adverse events being asthenia, rash, nausea, edema, and diarrhea. The overall frequency of adverse events was similar to the placebo group, however, a higher incidence of severe and serious events was associated with masitinib treatment. Masitinib appeared to have a positive effect on MS-related impairment for PPMS and rfSPMS patients, as evidenced by an improvement in MSFC scores relative to baseline, compared with a worsening MSFC score in patients receiving placebo; +103% ± 189 versus -60% ± 190 at month-12, respectively. This positive, albeit non-statistically significant response was observed as early as month-3 and sustained through to month-18, with similar trends seen in the PPMS and rfSPMS subpopulations. A total of 7/22 (32%) assessable masitinib patients reported clinical response following 12 months of treatment (according to the modified intent-to-treat population, observed cases) compared with none in the placebo group. The Expanded Disability Status Scale remained stable for both treatment groups.
These data suggest that masitinib is of therapeutic benefit to PPMS and rfSPMS patients and could therefore represent an innovative avenue of treatment for this disease. This exploratory trial provides evidence that may support a larger placebo-controlled investigation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVETo evaluate the ability of intereye retinal thickness difference (IETD) measured by optical coherence tomography (OCT) to detect asymptomatic optic nerve involvement in clinically isolated ...syndrome (CIS).
METHODSWe conducted a cross-sectional study of patients who recently presented a CIS (≤4.5 months). All patients underwent OCT and brain/optic nerve MRI. Optic nerve involvement was defined clinically (episode of optic neuritis ON or not) and radiologically (optic nerve hypersignal on 3D double inversion recovery 3D-DIR). We evaluated the sensitivity and specificity of previously published IETD thresholds and report the observed optimal thresholds for identifying symptomatic optic nerve involvement but also for identifying asymptomatic optic nerve involvement (optic nerve hypersignal without ON history). Primary outcomes were ganglion cell–inner plexiform layer (GC-IPL) and peripapillary retinal nerve fiber layer IETD.
RESULTSThe study group consisted of 130 patients. In the CIS with ON group, 3D-DIR showed a hypersignal in all 41 symptomatic optic nerves and in 11 asymptomatic optic nerves. In the CIS without ON group, 3D-DIR showed a unilateral optic nerve hypersignal in 22 patients and a bilateral optic nerve hypersignal in 7 patients. For the detection of symptomatic and asymptomatic optic nerve lesion, GC-IPL IETD had better performance. We found an optimal GC-IPL IETD threshold ≥2.83 µm (sensitivity 88.2, specificity 83.3%) for the detection of symptomatic lesions and an optimal GC-IPL IETD ≥1.42 µm (sensitivity 89.3%, specificity 72.6%) for the detection of asymptomatic lesions.
CONCLUSIONSDetection of asymptomatic optic nerve lesions in CIS requires lower IETD thresholds than previously reported. GC-IPL IETD represents an alternative biomarker to MRI for the detection of asymptomatic optic nerve lesions.
CLASSIFICATION OF EVIDENCEThis study provides Class I evidence that OCT accurately identifies asymptomatic optic nerve involvement in patients with CIS.
Background:
Optic nerve involvement is not considered in dissemination in space (DIS) or time (DIT) of multiple sclerosis (MS) lesions.
Objectives:
To evaluate frequency of optic nerve involvement ...using three-dimensional (3D)-double inversion recovery (DIR) sequence in clinically isolated syndrome (CIS) and to measure its relationship with DIS and DIT (2010 and 2017 McDonald criteria).
Methods:
From November 2013 to August 2016, 57 CIS patients underwent 3T-magnetic resonance imaging (3T-MRI) including 3D-DIR sequence and optical coherence tomography (OCT) at 3 months after CIS. We assessed signal abnormalities of the optic nerves on DIR sequence and collected data for DIS and DIT criteria according to 2010 and 2017 McDonald criteria.
Results:
Among the 57 recruited patients, the presence of ⩾1 DIR hypersignal in optic nerve was observed in 36 (63%; 48 optic nerves) including asymptomatic hypersignal in 22 (38.5%; 25 optic nerves). Optic nerve involvement was significantly associated with DIT (p = 0.006) and MS according to 2010 criteria (p = 0.01) but was not significantly associated with presence of DIS criteria according to 2010 and 2017 McDonald criteria. We identified a significant (p < 0.001) temporal peripapillary retinal nerve fiber layer thinning on eyes with optic nerve involvement versus healthy controls.
Conclusions:
Optic nerve involvement is very frequent at the earliest clinical stage of MS. It is associated with the presence of asymptomatic gadolinium-enhancement and retinal axonal loss and may reflect the inflammatory disease activity level.
Few studies have investigated sustained B-cell depletion after long-term intravenous (IV) anti-CD20 B-cell depleting therapy (BCDT) in multiple sclerosis (MS) with respect to strict and/or minimal ...disease activity. The main objective of this study was to investigate how sustained B-cell depletion after BCDT influences clinical and radiological stability as defined by “no evidence of disease activity” (NEDA-3) and “minimal evidence of disease activity” (MEDA) status in MS patients at 12 and 18 months. Furthermore, we assessed the frequency of serious adverse events (SAE), and the influence of prior lymphocytopenia-inducing treatment (LIT) on lymphocyte subset counts and gammaglobulins in MS patients receiving long-term BCDT. We performed a retrospective, prospectively collected, study in a cohort of 192 MS patients of all clinical phenotypes treated by BCDT between January 2014 and September 2021. Overall, 84.2% and 96.9% of patients attained NEDA-3 and MEDA status at 18 months, respectively. Sustained CD19
+
depletion was observed in 85.8% of patients at 18 months. No significant difference was observed when comparing patients achieving either NEDA-3 or MEDA at 18 months and sustained B-cell depletion. Compared to baseline levels, IgM and IgG levels on BCDT significantly decreased at 6 months and 30 months, respectively. Patients receiving LIT prior to BCDT showed significant CD4
+
lymphocytopenia and lower IgG levels compared to non-LIT patients. Grade 3 or above SAEs were rare. As nearly all patients achieved MEDA at 18 months, we suggest tailoring IV BCDT after 18 months given the occurrence of lymphocytopenia, hypogammaglobulinemia, and SAE after this time point.
London et al. show that the asymptomatic optic nerve involvement detected on MRI in patients with clinically isolated syndrome drives the asymptomatic retinal axonal loss measured by optical ...coherence tomography. Moreover, the length of the optic nerve lesion correlates with retinal axonal loss and visual disability.
Abstract
In this study, we aimed to evaluate the association of asymptomatic optic nerve demyelinating lesion in patients presenting a clinically isolated syndrome with the asymptomatic retinal neuro-axonal loss previously reported at clinically isolated syndrome. We prospectively recruited 66 patients presenting a clinically isolated syndrome and 66 healthy control subjects matched according to age and gender. All patients underwent brain magnetic resonance imaging including 3D-double inversion recovery (DIR) sequence, optical coherence tomography examination and visual function evaluation, at 2.5-4.5 months after CIS. Evaluation criteria were presence and length of optic nerve DIR hypersignal, retinal layers (including ganglion cell inner plexiform layer and inner nuclear layer) thickness/volume, and low contrast monocular vision acuity (number of letters correctly identified). All clinically isolated syndrome eyes with past history of optic neuritis (CIS-ON) presented an optic nerve DIR hypersignal. We observed asymptomatic optic nerve DIR hypersignal in 22.2% of clinically isolated syndrome eyes without optic neuritis (CIS-NON). In comparison with healthy control, GCIPL volume (in mm3) was significantly lower in CIS-ON eyes β (95% confidence interval, CI) = −0.121 (−0.168 to −0.074); P < 0.0001, and to a lesser extent in CIS-NON β (95% CI) = −0.023 (−0.039 to −0.008); P = 0.004. In comparison to healthy controls, eyes with asymptomatic optic nerve DIR hypersignal presented significantly lower macular ganglion cell inner plexiform layer volume β (95% CI) = −0.043 (−0.068 to −0.019); P = 0.001, and eyes without did not β (95% CI) = −0.016 (−0.034 to 0.003); P = 0.083. Among CIS-NON, macular ganglion cell inner plexiform layer volume decrease was associated with asymptomatic optic nerve DIR hypersignal independently of optic radiations T2 lesions and primary visual cortex volumes (P = 0.012). Symptomatic optic nerve DIR hypersignal were significantly longer (13.8 ± 6.7 mm) than asymptomatic optic nerve hypersignal (10.0 ± 5.5 mm; P = 0.047). Length of optic nerve DIR hypersignal was significantly associated with thinner inner retinal layers (P ≤ 0.001), thicker inner nuclear layer (P = 0.017) and lower low contrast monocular vision acuity (P < 0.05). Compared to healthy control, low contrast monocular vision acuity was significantly lower in CIS-ON eyes (P < 0.0001) and CIS-NON eyes with (P = 0.03) or without asymptomatic optic nerve DIR hypersignal (P = 0.0005). Asymptomatic demyelinating optic nerve DIR hypersignal at the earliest clinical stage of multiple sclerosis is frequent and associated with asymptomatic retinal neuro-axonal loss reported at clinically isolated syndrome stage. Length of optic nerve DIR hypersignal is a biomarker of retinal neuro-axonal loss and visual disability at clinically isolated syndrome stage. Visual disability of clinically isolated syndrome eyes without clinical and subclinical optic nerve involvement might be due to missed optic nerve lesions on MRI. At the earliest clinical stage of multiple sclerosis, our results support considering optical coherence tomography as a window to the optic nerve rather than to the brain.
Recent studies in multiple sclerosis (MS) showed longer survival times from clinical onset than older hospital-based series. However estimated median time ranges widely, from 24 to 45 years, which ...makes huge difference for patients as this neurological disease mainly starts around age 20 to 40. Precise and up-to-date reference data about mortality in MS are crucial for patients and neurologists, but unavailable yet in France.
Estimate survival in MS patients and compare mortality with that of the French general population.
We conducted a multicenter observational study involving clinical longitudinal data from 30,413 eligible patients, linked to the national deaths register. Inclusion criteria were definite MS diagnosis and clinical onset prior to January, 1st 2009 in order to get a minimum of 1-year disease duration.
After removing between-center duplicates and applying inclusion criteria, the final population comprised 27,603 MS patients (F/M sex ratio 2.5, mean age at onset 33.0 years, 85.5% relapsing onset). During the follow-up period (mean 15.2 +/- 10.3 years), 1569 deaths (5.7%) were identified; half related to MS. Death rates were significantly higher in men, patients with later clinical onset, and in progressive MS. Overall excess mortality compared with the general population was moderate (Standardized Mortality Ratio 1.48, 95% confidence interval 1.41-1.55), but increased considerably after 20 years of disease (2.20 2.10-2.31).
This study revealed a moderate decrease in life expectancy in MS patients, and showed that the risk of dying is strongly correlated to disease duration and disability, highlighting the need for early actions that can slow disability progression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The key role of B cells in the pathophysiology of multiple sclerosis (MS) is supported by the presence of oligoclonal bands in the cerebrospinal fluid, by the association of meningeal ectopic B cell ...follicles with demyelination, axonal loss and reduction of astrocytes, as well as by the high efficacy of B lymphocyte depletion in controlling inflammatory parameters of MS. Here, we use a spontaneous model of experimental autoimmune encephalomyelitis (EAE) to study the clonality of the B cell response targeting myelin oligodendrocyte glycoprotein (MOG). In particular, 94% of SJL/j mice expressing an I-A
: MOG
specific transgenic T cell receptor (TCR
) spontaneously develop a chronic paralytic EAE between the age of 60-500 days. The immune response is triggered by the microbiota in the gut-associated lymphoid tissue, while there is evidence that the maturation of the autoimmune demyelinating response might occur in the cervical lymph nodes owing to local brain drainage. Using MOG-protein-tetramers we tracked the autoantigen-specific B cells and localized their enrichment to the cervical lymph nodes and among the brain immune infiltrate. MOG-specific IgG1 antibodies were detected in the serum of diseased TCR
mice and proved pathogenic upon adoptive transfer into disease-prone recipients. The ontogeny of the MOG-specific humoral response preceded disease onset coherent with their contribution to EAE initiation. This humoral response was, however, not sufficient for disease induction as MOG-antibodies could be detected at the age of 69 days in a model with an average age of onset of 197 days. To assess the MOG-specific B cell repertoire we FACS-sorted MOG-tetramer binding cells and clonally expand them
to sequence the paratopes of the IgG heavy chain and kappa light chains. Despite the fragility of clonally expanding MOG-tetramer binding effector B cells, our results indicate the selection of a common CDR-3 clonotype among the Igk light chains derived from both disease-free and diseased TCR
mice. Our study demonstrates the pre-clinical mobilization of the MOG-specific B cell response within the brain-draining cervical lymph nodes, and reiterates that MOG antibodies are a poor biomarker of disease onset and progression.
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