To assess efficacy and safety of rituximab (RTX) as induction therapy, maintenance of remission and treatment of relapses in a cohort of IgG4-related disease (IgG4-RD) patients.
Nationwide ...retrospective multicenter study of IgG4-RD patients treated with at least one course of RTX. Clinical, biological and radiological response, relapse rate and drug tolerance were analyzed. Kaplan-Meier curves were plotted and risk factors for relapse studied with a Cox regression model.
Among 156 IgG4-RD patients included in the French database, 33 received rituximab. Clinical response was noted in 29/31 (93.5%) symptomatic patients. Glucocorticoids withdrawal was achieved in 17 (51.5%) patients. During a mean follow-up of 24.8 ±21 months, 13/31 (41.9%) responder patients relapsed after a mean delay of 19 ±11 months after RTX. Active disease, as defined by an IgG4-RD Responder Index >9 before RTX, was significantly associated with relapse (HR = 3.68, 95% CI: 1.1, 12.6) (P = 0.04), whereas maintenance therapy with systematic (i.e. before occurrence of a relapse) RTX retreatment was associated with longer relapse-free survival (41 versus 21 months; P = 0.02). Eight severe infections occurred in 4 patients during follow-up (severe infections rate of 12.1/100 patient-years) and hypogammaglobulinemia ≤5 g/l in 3 patients.
RTX is effective for both induction therapy and treatment of relapses in IgG4-RD, but relapses are frequent after B-cell reconstitution. Maintenance therapy with systematic RTX infusions is associated with longer relapse-free survival and might represent a novel treatment strategy. Yet, the high rate of infections and the temporary effect of RTX might be hindrances to such strategy.
Objectives:
We aim to (1) determine the frequency and distinctive features of short myelitis (SM) and longitudinally extensive transverse myelitis (LETM) in a cohort of adults with myelin ...oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated myelitis and (2) determine baseline prognostic factors among MOG-Ab-positive patients whose disease started with myelitis.
Material and Methods:
We retrospectively analyzed clinical and paraclinical variables from a multicentric French cohort of adults with MOG-Ab-associated myelitis. At last follow-up, patients were classified into two groups according to the severity of the Expanded Disability Status Scale (EDSS) as ⩽2.5 or ⩾3.0.
Results:
Seventy-three patients with at least one episode of myelitis over disease course were included; among them, 28 (38.4%) presented with SM at the time of the first myelitis. Motor and sphincter involvement was less frequently observed in SM (51.9% and 48.2%, respectively) than in LETM patients (83.3% and 78.6%, respectively), p = 0.007 and p = 0.017; 61% of LETM patients displayed brain lesions compared to 28.6% in the SM group, p = 0.008, and the thoracic segment was more frequently involved in the LETM (82.2%) than in the SM group (39.3%), p < 0.001. EDSS at last follow-up was higher in LETM (median 3.0 (interquartile range: 2.0–4.0)) compared to SM patients (2.0, (1.0–3.0)), p = 0.042. Finally, a higher EDSS at onset was identified as the only independent risk factor for EDSS ⩾3.0 (odds ratio, 1.40, 95% confidence interval (CI): 1.01–1.95, p = 0.046).
Conclusion:
SM in MOG-Ab-associated disease is not rare. The severity at onset was the only independent factor related to the final prognosis in MOG-Ab-associated myelitis.
Adult-onset genetic leukoencephalopathies and leukodystrophies are increasingly recognized as a heterogeneous group of disorders with new diagnostic approaches and potential treatments. In the new ...era of genomics, the challenging interpretation of individual genetic variations requires an accurate phenotypic description and classification. Clinical and magnetic resonance imaging (MRI)-based approaches have been proposed to improve the diagnostic process of adult-onset leukoencephalopathies. Cerebral calcifications, when associated with white matter hyperintensities, are of major importance in the decision-making process to focus the diagnosis among the diversity of rare causes.
This literature review demonstrated that the morphologic features and topography of the calcifications observed in a careful combined analysis of computed tomographic and MRI scans may help indicate the diagnosis of adult-onset genetic leukoencephalopathies. Vascular genetic leukoencephalopathies are an important cause of leukoencephalopathy with calcifications. Among them, COL4A1-related disorders are frequently associated with spotlike calcifications in the basal ganglia. Adult-onset leukoencephalopathy with axonal spheroids, a probably underestimated disorder, is associated with a specific pattern of calcifications: small, symmetric, sparing the basal ganglia, and a stepping stone appearance in the frontal pericallosal region. Moreover, disorders primarily associated with basal ganglia calcifications, such as primary familial brain calcifications, can be associated with marked leukoencephalopathy.
The number of identified causes of adult-onset genetic leukoencephalopathies has recently increased. A diagnostic algorithm should take into account the pattern of calcifications to better target the genetic analyses.
Background
Assessing the multicenter variability of magnetization transfer ratio (MTR) measurements in the spinal cord of healthy controls is the first step toward investigating its clinical use as a ...biomarker.
Purpose
To analyze the between‐session, between‐participant, and between‐scanner variability of MTR measurements in automatically extracted regions of interest in the cervical cord of healthy controls.
Study Type
Control study.
Population
Forty‐four participants, distributed across five MRI scanners (all from the same manufacturer). Ten participants were scanned twice in the same scanner, and 10 others were scanned twice in two different scanners.
Field Strength/Sequence
3D‐gradient echo images, centered on C5, without and with magnetization transfer prepulse at 3T.
Assessment
We calculated the mean MTR for different vertebral levels in the whole cord (WC), as well as in the white matter and gray matter, and determined the between‐session, between‐participant, and between‐scanner variabilities.
Statistical Tests
Coefficients of variation and intraclass correlations (ICCs) for the different variabilities and their associated confidence intervals.
Results
The MTR measurements for Levels C4‐C6 (near the slab center) exhibited a mean value in WC of 34.6 pu and a pooled standard deviation of 0.9 pu. The between‐session coefficient of variation was estimated as 2.3% (ICC = 0.63), the between‐participant coefficient as 1.6% (ICC = 0.32), and the between‐scanner coefficient as 0.7% (ICC = 0.05). The resulting aggregate coefficient of variation was 2.9%, which was sufficiently low to detect an MTR reduction of 1 pu between groups of about 45 participants (Type‐I error rate: 0.05; Type‐II error rate: 0.10).
Data Conclusion
The good between‐scanner reproducibility and low overall variability in cervical spinal cord MTR measurements in a control population might pave the way for multicenter analyses in various neurological diseases with moderate cohort sizes.
Level of Evidence: 2
Technical Efficacy: Stage 2
J. Magn. Reson. Imaging 2019;49:1777–1785.
Background:
Epidemiological data reveal that 45% of persons with multiple sclerosis (PwMS) in France are more than 50 years. This population more than 50 is more susceptible to cancer, and this risk ...may be increased by frequent use of immunosuppressive drugs. Consequently, concerns have arisen about the potential increased risk of cancer in PwMS and how patients should be screened and managed in terms of cancer risk.
Objective:
To develop evidence-based recommendations to manage the coexistence of cancer and multiple sclerosis (MS).
Methods:
The French Group for Recommendations in MS collected articles from PubMed and university databases covering the period January 1975 through June 2022. The RAND/UCLA method was employed to achieve formal consensus. MS experts comprehensively reviewed the full-text articles and developed the initial recommendations. A group of multidisciplinary health care specialists then validated the final proposal.
Results:
Five key questions were addressed, encompassing various topics such as cancer screening before or after initiating a disease-modifying therapy (DMT), appropriate management of MS in the context of cancer, recommended follow-up for cancer in patients receiving a DMT, and the potential reintroduction of a DMT after initial cancer treatment. A strong consensus was reached for all 31 recommendations.
Conclusion:
These recommendations propose a strategic approach to managing cancer risk in PwMS.
Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular ...diagnosis of these diseases by sequencing a large cohort of undiagnosed families.
We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines.
We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation.
A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation.
Background
Steps towards the development of diagnostic criteria are needed for children with the radiologically isolated syndrome to identify children at risk of clinical demyelination.
Objectives
To ...evaluate the 2005 and 2016 MAGNIMS magnetic resonance imaging criteria for dissemination in space for multiple sclerosis, both alone and with oligoclonal bands in cerebrospinal fluid added, as predictors of a first clinical event consistent with central nervous system demyelination in children with radiologically isolated syndrome.
Methods
We analysed an international historical cohort of 61 children with radiologically isolated syndrome (≤18 years), defined using the 2010 magnetic resonance imaging dissemination in space criteria (Ped-RIS) who were followed longitudinally (mean 4.2 ± 4.7 years). All index scans also met the 2017 magnetic resonance imaging dissemination in space criteria.
Results
Diagnostic indices (95% confidence intervals) for the 2005 dissemination in space criteria, with and without oligoclonal bands, were: sensitivity 66.7% (38.4–88.2%) versus 72.7% (49.8–89.3%); specificity 83.3% (58.6–96.4%) versus 53.9% (37.2–69.9%). For the 2016 MAGNIMS dissemination in space criteria diagnostic indices were: sensitivity 76.5% (50.1–93.2%) versus 100% (84.6–100%); specificity 72.7% (49.8–89.3%) versus 25.6% (13.0–42.1%).
Conclusions
Oligoclonal bands increased the specificity of magnetic resonance imaging criteria in children with Ped-RIS. Clinicians should consider testing cerebrospinal fluid to improve diagnostic certainty. There is rationale to include cerebrospinal fluid analysis for biomarkers including oligoclonal bands in planned prospective studies to develop optimal diagnostic criteria for radiologically isolated syndrome in children.
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