Introduction
IgG4 antibodies against neurofascin (Nfasc155 and Nfasc140/186), contactin (CNTN1) and contactin-associated protein (Caspr1) are described in specific subtypes of chronic inflammatory ...demyelinating polyradiculoneuropathy (CIDP). Our objective was to assess, in a real-life practice, the incidence, the clinical features and the response to treatment of these forms of CIDP.
Methods
1500 sera of patients suspected of having CIDP from France, Belgium and Switzerland were prospectively tested using a flow cytometry technique. The characteristics of patients with antibodies against the node of Ranvier were compared to 100 seronegative CIDP from our department.
Results
IgG4 antibodies against Nfasc155, CNTN1, and Caspr1 were, respectively, detected in 15 (prevalence 1%), 10 (0.7%) and 2 (0.2%) sera. Antibodies specific of the Nfasc140/186 were not detected.
All subjects with antibodies against the node of Ranvier fulfilled diagnostic criteria for CIDP.
CIDP with anti-Nfasc155 were younger, had more sensory ataxia and postural tremor than seronegative CIDP. CIDP with anti-CNTN1 had more frequent subacute onset and facial paralysis, commoner renal involvement with membranous glomerulonephritis and greater disability, than seronegative CIDP. CIDP with anti-Caspr1 had more frequent respiratory failure and cranial nerve involvement but not more neuropathic pain than seronegative CIDP. Intravenous immunoglobulins were ineffective in most seropositive patients. Rituximab produced dramatic improvement in disability and decreased antibodies titres in 13 seropositive patients (8 with anti-Nfasc155 and 5 with anti-CNTN1 antibodies).
Conclusions
Although rare, anti-paranodal antibodies are clinically valuable, because they are associated with specific phenotypes and therapeutic response.
There is an unmet need for treatment options for generalised myasthenia gravis that are effective, targeted, well tolerated, and can be used in a broad population of patients. We aimed to assess the ...safety and efficacy of efgartigimod (ARGX-113), a human IgG1 antibody Fc fragment engineered to reduce pathogenic IgG autoantibody levels, in patients with generalised myasthenia gravis.
ADAPT was a randomised, double-blind, placebo-controlled, phase 3 trial done at 56 neuromuscular academic and community centres in 15 countries in North America, Europe, and Japan. Patients aged at least 18 years with generalised myasthenia gravis were eligible to participate in the study, regardless of anti-acetylcholine receptor antibody status, if they had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (>50% non-ocular), and were on a stable dose of at least one treatment for generalised myasthenia gravis. Patients were randomly assigned by interactive response technology (1:1) to efgartigimod (10 mg/kg) or matching placebo, administered as four infusions per cycle (one infusion per week), repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle. Patients, investigators, and clinical site staff were all masked to treatment allocation. The primary endpoint was proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responders (≥2-point MG-ADL improvement sustained for ≥4 weeks) in the first treatment cycle. The primary analysis was done in the modified intention-to-treat population of all acetylcholine receptor antibody-positive patients who had a valid baseline MG-ADL assessment and at least one post-baseline MG-ADL assessment. The safety analysis included all randomly assigned patients who received at least one dose or part dose of efgartigimod or placebo. This trial is registered at ClinicalTrials.gov (NCT03669588); an open-label extension is ongoing (ADAPT+, NCT03770403).
Between Sept 5, 2018, and Nov 26, 2019, 167 patients (84 in the efgartigimod group and 83 in the placebo group) were enrolled, randomly assigned, and treated. 129 (77%) were acetylcholine receptor antibody-positive. Of these patients, more of those in the efgartigimod group were MG-ADL responders (44 68% of 65) in cycle 1 than in the placebo group (19 30% of 64), with an odds ratio of 4·95 (95% CI 2·21–11·53, p<0·0001). 65 (77%) of 84 patients in the efgartigimod group and 70 (84%) of 83 in the placebo group had treatment-emergent adverse events, with the most frequent being headache (efgartigimod 24 29% vs placebo 23 28%) and nasopharyngitis (efgartigimod ten 12% vs placebo 15 18%). Four (5%) efgartigimod-treated patients and seven (8%) patients in the placebo group had a serious adverse event. Three patients in each treatment group (4%) discontinued treatment during the study. There were no deaths.
Efgartigimod was well tolerated and efficacious in patients with generalised myasthenia gravis. The individualised dosing based on clinical response was a unique feature of ADAPT, and translation to clinical practice with longer term safety and efficacy data will be further informed by the ongoing open-label extension.
argenx.
Background and Aim
Recreational use of nitrous oxide (N2O) has been associated with the development of severe nitrous oxide‐induced neuropathy (N2On). Follow‐up of these patients poses challenges, ...and their clinical progression remains largely unknown. The identification of prognostic factors is made difficult by the lack of standardized longitudinal assessments in most studies. The objective was to document the course of neuropathy through systematic follow‐up assessments in N2On patients to identify prognostic factors for persistent disability after 6 months.
Methods
We gathered demographic, clinical, biological, and electrophysiological data from N2On patients hospitalized in the Referral center in Marseille, both at baseline and during a standardized follow‐up assessment at 6 months.
Results
We retrospectively included 26 N2On patients (mean age 22.6 ± 4.4). Significant improvements were observed in all main clinical scores including Rankin, ONLS, and MRC testing (p < .01). Electrophysiological studies (EDX) revealed a predominantly motor neuropathy with marked reduction in CMAP in the lower limbs at baseline, and no significant improvement in motor parameters (p = .543). Rankin score at 6 months correlated with the initial weekly N2O consumption (r = .43, p = .03) and the CMAP sum score in the lower limbs at the first EDX (r = −.47, p = .02). Patients with and without myelitis showed similar Rankin and ONLS score after 6 months.
Interpretation
The clinical course generally improved favorably at 6 months with notable amelioration in the primary disability scores, sensory deficits, and ataxia. However, distal motor impairment associated with peripheral neuropathy persisted, with distal axonal loss emerging as the main prognostic factor for long‐term disability in these young patients.
Objective
The objective of this study is to evaluate the frequency and characteristics of facial involvement in inclusion body myositis (IBM) patients and to compare it to the one previously ...described in facioscapulohumeral dystrophy (FSHD) patients.
Methods
Thirty-two IBM patients were included and compared to 29 controls and 39 FSHD patients. All participants were recorded in a video as they performed a series of seven facial tasks. Five raters independently assessed facial weakness using both a qualitative evaluation and a semi-quantitative facial weakness score (FWS).
Results
IBM patients had higher FWS than controls (7.89 ± 7.56 vs 1.06 ± 0.88,
p
< 0.001). Twenty IBM patients (63%) had a facial weakness with a FWS above the maximum value for controls. All facial tasks were significantly more impaired in IBM patients compared to controls (
p
< 0.001), task 2 evaluating orbiculari oculi muscle weakness being the most affected. IBM patients with facial weakness reported more swallowing troubles than IBM patients without facial weakness (
p
= 0.03). FSHD patients displayed higher FWS than IBM patients (12.16 ± 8.37 vs 7.89 ± 7.56,
p
= 0.01) with more pronounced facial asymmetry (
p
= 0.01). FWS inter-rater ICC was 0.775.
Conclusion
This study enabled us to estimate the frequency of facial impairment in IBM in more than half of patients, to detail its characteristics and to compare them with those of FSHD patients. The standardized, semi-quantitative FWS is an interesting diagnostic help in IBM as it appeared more sensitive than qualitative evaluation to detect mild facial weakness.
Il est urgent d’établir une évaluation à court terme de l’efficacité des immunoglobulines intraveineuses (IgIV) dans la polyradiculonévrite inflammatoire démyélinisante chronique (PIDC).
Notre ...objectif était d’identifier des biomarqueurs liés à l’incapacité, hautement sensibles aux changements peu de temps après les perfusions d’IgIV.
Au total, 29 patients atteints de PIDC traités de façon chronique par IgIV ont été inclus. Plusieurs biomarqueurs cliniques, biologiques et électrophysiologiques ont été examinés pour identifier ceux qui étaient corrélés avec l’incapacité des patients mesurés par le RODS. Ensuite, les biomarqueurs sélectionnés ont été évalués avant et 21jours après les perfusions d’IgIV.
Le score ONLS, le score MRC, le grip test, le test de marche de 10 mètres, le test des 4 marches, la sommes des PGAM, le MUNIX, les latences distales motrices tibiales, la durée du PGAM du nerf fibulaire commun et les taux sériques des chaînes légères de neurofilament (NFL) étaient significativement corrélés à l’incapacité des patients. Des variations significatives n’ont été observées que pour le score ONLS (−18 %, p=0,01), le score MUNIX (+11 %, p=0,039) et les taux de NFL (−11 %, p=0,014), 21jours après les perfusions d’IgIV.
L’ONLS est sensible aux changements à court terme et sa place reste pertinente dans l’évaluation de la CIDP. La diminution rapide des taux de NFL montre que les immunoglobulines peuvent limiter la destruction axonale dans la PIDC en quelques jours. Le MUNIX peut être un outil précieux pour évaluer les patients atteints de PIDC lors de leur suivi.
Le score ONLS, le MUNIX et les taux de NFL sont liés à l’incapacité et sensibles aux changements peu de temps après une perfusion d’IgIV.
Introduction
Anti-MAG neuropathies are associated with an IgM monoclonal gammopathy of undetermined significance (MGUS) or with a malignant haemopathy. Our objective was to determine whether the ...presence of a haemopathy or somatic mutations of MYD88 and CXCR4 genes influences disease presentation and response to rituximab (RTX).
Methods
We included 79 patients (mean age 74 years, disease duration 9.68 years) who had a bone marrow aspiration with morphologic and immunophenotypic analysis. MYD88
L265P
and CXCR4 mutations were analysed in peripheral B cells.
Information collected included: inflammatory neuropathy cause and treatment sensory sum score (ISS), MRC testing, overall neuropathy limitation scale (ONLS), Rash-built Overall Disability Score (RODS), ataxia score, anti-MAG titres, peak IgM dosage, neurofilament light chain levels, motor and sensory amplitudes, motor unit index (MUNIX) and motor unit size index (MUSIX) sum scores. Efficacy of RTX was evaluated at 12 months in 26 patients.
Results
Malignant haematological disorders were discovered in 17 patients (22%): 13 Waldenstrom macroglobulinemia, 3 marginal zone lymphoma and one mantle cell lymphoma. MYD88
L265P
mutation was detected in 29/60 (48%) patients and CXCR4 in 1 single patient. Disease severity, biological and electrophysiological data and response to RTX were comparable in patients with MGUS/lymphoma and patients with/without MYD88
L265P
mutation. ISS was lower and MUSIX higher in patients improved by RTX.
Conclusions
MYD88
L265P
mutation and underlying haemopathies are not predictive of a more severe disease. However, in cases of resistant and progressive neuropathy, they provide an opportunity to prescribe newly available drugs such as Bruton tyrosine kinase inhibitors.
•Patients with antibodies against the node of Ranvier fulfil electrodiagnostic criteria for definite CIDP.•Patients with anti-CNTN1 and anti-NfascC155 antibodies have similar electrophysiological ...patterns.•Electrophysiological abnormalities are more marked in patients with antibodies.
Chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) with antibodies against neurofascin 155 (Nfasc155) or contactin-1 (CNTN1) have distinctive clinical features. Knowledge on their electrophysiological characteristics is still scarce. In this study, we are investigating whether these patients have specific electrophysiological characteristics.
The electrophysiological data from 13 patients with anti-Nfasc155 IgG4 antibodies, 9 with anti-CNTN1 IgG4 antibodies were compared with those of 40 consecutive CIDP patients without antibodies.
All the patients with antibodies against Nfasc155 or CNTN1 fulfilled the EFNS/PNS electrodiagnostic criteria for definite CIDP. There was no electrophysiological difference between patients with anti-CNTN1 and anti-Nfasc155 antibodies. Nerve conduction abnormalities were heterogeneously distributed along nerves trunks and roots. They were more pronounced than in CIDP without antibodies. Motor conduction velocity on median nerve <24 m/s or motor velocity on ulnar nerve <26 m/s or motor distal latency on ulnar nerve >7.4 ms were predictive of positive antibodies against the node of Ranvier with a sensitivity of 59% and a specificity of 93%.
Marked conduction abnormalities may suggest the presence of positive antibodies against the node of Ranvier.
Anti-Nfasc155 and anti-CNTN1 antibodies target the the paranodal axo-glial domain but are associated with nerve conduction abnormalities mimicking a “demyelinating” neuropathy.
Les neuropathies anti-MAG sont associées à une gammapathie monoclonale de signification indéterminée (MGUS) ou à une hémopathie maligne. Les symptômes de la maladie sont directement en lien ...l’activité pathogène de l’IgM produite.
Notre objectif est de déterminer si la présence d’une hémopathie maligne ou d’une mutation des gènes MYD88 et CXCR4 influence la présentation de la maladie et la réponse au rituximab (RTX) en monothérapie ou en combinaison avec une chimiothérapie.
Nous avons inclus 79 patients atteints de neuropathies anti-MAG. Les mutations MYD88L265P et CXCR4 ont été recherchées dans le sang des patients. Les données cliniques, biologiques et électrophysiologiques ont été collectées à l’inclusion. L’efficacité du traitement par RTX a été mesurée à 12 mois son administration.
Une hémopathie maligne a été diagnostiquée chez 17 patients (22 %). La mutation MYD88L265P et une mutation du gène CXCR4 ont été détectées chez respectivement 29/60 patients (48 %) et un patient. La présence d’une hémopathie ou d’une mutation MYD88L265P n’avaient aucune influence sur la présentation de la maladie ou la réponse au RTX. Les patients ayant répondu favorablement au RTX avaient des scores ISS plus faibles et des valeurs de MUSIX plus élevées que les patients non répondeurs (p=0,02).
Les caractéristiques phénotypiques de notre cohorte sont similaires à celles précédemment rapportées dans la littérature. Les mutations du gène MYD88 sont fréquemment retrouvées. Les mutations du gène CXCR4, sont rares. La recherche de ces mutations manque toutefois de sensibilité lorsqu’elle est faite dans le sang.
Le profil mutationnel MYD88L265P ou la présence d’une hémopathie maligne sous-jacente n’influent pas sur la neuropathie. La prévalence élevée de cette mutation constitue un argument pour l’utilisation d’inhibiteurs de la tyrosine kinase.
