Mikael Cohen

Therapeutic target of memory B cells depletion helps to tailor administration frequency of rituximab in myasthenia gravis

Rituximab (RTX) has demonstrated efficacy in limiting relapses in myasthenia gravis (MG). We investigated the interest of CD27+ memory B cell monitoring in patients as a biological marker of clinical relapse. Twenty-four patients have been treated with RTX (375mg/m(2)/week-month as an induction treatment). Maintenance treatment consisted with either systematic treatment every 3months or only when CD27+ memory B cells were detectable. After the induction treatment, the mean infusions were 1.3/year compared with 4/year. We suggest that RTX administration frequency can be decreased safely by monitoring the re-emerging CD27+ memory B cells.

Endermology: A treatment for injection-induced lipoatrophy in multiple sclerosis patients treated with sub cutaneous glatiramer acetate

OBJECTIVE To evaluate sessions of endermology (LPG) on patients with lipoatrophy, due to GA injections in an open-labelled study. BACKGROUND Glatiramer acetate (GA) is an immunomodulatory drug, with an excellent safety profile, that is currently used for treatment of multiple sclerosis and is administered as daily subcutaneous injections of 20 mg. The most common adverse effects, which occur in approximately 20-60% of the patients, include pain, inflammation and induration at the injection sites. Another adverse effect is frank panniculitis followed by localized lipoatrophy at the injection sites, which has been described in half of the patients receiving treatment with glatiramer acetate injections. No treatment has been found for established lipoatrophy. PATIENTS AND METHODS All patients underwent LPG twice a week during 30 min. A cycle of two months was initially proposed. If the patient was satisfied with the result, sessions were continued with one session per week until the 4th month. RESULTS Eight Patients treated with GA and presenting with lipoatrophy were prospectively recruited. None of them complained of any adverse events. After 8 weeks of treatment, all had a visible reduction of lipoatrophic area. MRI showed no major subcutaneous changes except for a reduction in and repartition of fatty tissues. CONCLUSION The LPG cellu M6 keymodule is a mechanotransduction machine that stimulates the skins surface in triggering cells to activate lipolysis and collagen production. It has never been used for treatment of lipoatrophy due to drug treatment or in specific diseases associated with lipoatrophy (diabetes, HIV). The prevention and management of lipoatrophy includes patient education, regular examination and manual palpation of all injection sites. LPG endermology can help patients to resolve this side effect and to continue immunomodulatory treatment.

Monitoring CD27+ memory B-cells in neuromyelitis optica spectrum disorders patients treated with rituximab: Results from a bicentric study

BACKGROUND Rituximab (RTX) is increasingly used in the treatment of neuromyelitis optica spectrum disorder (NMO-SD). Administration regimen is not consensual as there is no reliable biomarker of RTX efficacy. In most cases, after induction, RTX is administered systematically every 6months. OBJECTIVE To assess efficacy and safety of a maintenance regimen based on CD19+ CD27+ memory B-cell (mBc) detection. METHODS We conducted a study in two French centers, including patients with NMO-SD who received an induction therapy with RTX. We compared the number of administered infusions, relapses and EDSS depending on two maintenance schemes (S1: administration of 1g RTX infusion every 6months or S2: a scheme based on regular mBc detection. 1g RTX was administered if mBc was >0.05%) RESULTS: 40 patients were included (mean age: 40.2years, F/M sex ratio: 5/1). Aquaporin-4 antibodies were positive in 75% patients. Under S1 regimen, all patients received 2 infusions per year, whereas under S2, they received 1.62 infusion per year. The mean interval between infusions under S2 was 7.4months, without decrease of clinical efficacy. CONCLUSION In our study, mBc-based administration of RTX allowed personalizing treatment administration and in several cases to lower the cumulative dose without loss of efficacy.

Tear analysis as a tool to detect oligoclonal bands in radiologically isolated syndrome

BACKGROUND Although radiologically isolated syndrome (RIS) is a newly defined entity, incidental findings of T2 hypersignals on brain MRI can lead to misdiagnosis or useless investigations. The detection of oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) is a major indicator that helps in diagnosis of subclinical inflammatory disease of the central nervous system, but lumbar puncture still remains an invasive option. METHODS We have prospectively included patients with RIS, have compared the results of CSF and tear OCB detection by isoelectric focusing (IEF) and assessed concordance between OCB detection in tears and in CSF. Tears were collected using a Schirmer strip. RESULTS In 45 recruited RIS patients, OCBs were detected in CSF for 55% (25/45) and in tears for 50% (21/42) of samples. CONCLUSIONS We suggest that tear OCB detection may replace CSF OCB detection as a diagnostic tool in patients with RIS and be useful in follow-up.

Double-Blind Controlled Randomized Trial of Cyclophosphamide versus Methylprednisolone in Secondary Progressive Multiple Sclerosis.

Background Therapeutic options are limited in secondary progressive multiple sclerosis (SPMS). Open-label studies suggested efficacy of monthly IV cyclophosphamide (CPM) without induction for delaying progression but no randomized trial was conducted so far. Objective To compare CPM to methylprednisolone (MP) in SPMS. Methods Randomized, double-blind clinical trial on two parallel groups. Patient with SPMS, with a documented worsening of the Expanded Disability Status Scale (EDSS) score during the last year and an EDSS score between 4·0 and 6·5 were recruited and received one intravenous infusion of treatment (CPM: 750 mg /m2 body surface area—MP: 1g) every four weeks for one year, and every eight weeks for the second year. The primary endpoint was the time to EDSS deterioration, when confirmed sixteen weeks later, analyzed using a Cox model. Results Due to recruitment difficulties, the study was terminated prematurely after 138 patients were included (CPM, n = 72; MP, n = 66). In the CPM group, 33 patients stopped treatment prematurely, mainly due to tolerability, compared with 22 in the MP group. Primary endpoint: the hazard ratio for EDSS deterioration in the CPM in comparison with the MP group was 0.61 [95% CI: 0·31–1·22](p = 0·16). According to the secondary multistate model analysis, patients in the CPM group were 2.2 times more likely ([1·14–4.29]; p = 0.02) to discontinue treatment than those in the MP group and 2.7 times less likely (HR = 0.37, 95% CI: 0.17–0.84; p = 0.02) to experience disability progression when they did not stop treatment prematurely. Safety profile was as expected. Conclusion Although the primary end-point was negative, secondary analysis suggested that CPM decreases the risk of progression in SPMS, but its use may be limited by low tolerability. Trial Registration Clinicaltrials.gov NCT00241254

Solitary sclerosis: Experience from three French tertiary care centres

In all cases, the paraclinical investigations exclu-ded all potential differential diagnoses. All patients had extensive metabolic, infectious and immunological screening which was unremarkable. Neuro-myelitis optica (NMO) antibodies were negative for all patients. Visual Evoked Potentials (VEP) and Electromyography (EMG) were normal for all patients, as well as thoracic-abdominal pelvis computed tomography scan.

GIANT URTICARIA AND PERSISTENT NEUTRALIZING ANTIBODIES AFTER THE FIRST NATALIZUMAB INFUSION

Natalizumab (NTZ) (Biogen Idec/Elan) is a monoclonal immunoglobulin G antibody against alpha-4-integrin that is prescribed in France for patients with multiple sclerosis (MS) who have experienced at least one relapse during a 1-year therapy with interferon-β and an increase in the T2 lesion load, or in naive patients who have experienced at least 2 relapses and have MRI evidence of active disease defined by more than 9 T2 lesions and gadolinium enhancement. Common adverse events described with NTZ include infusion-induced reactions in 15% of patients and hypersensitivity reactions in 4% of patients during or within 1 hour after infusion.1,2 Hypersensitivity reactions commonly occur at the beginning of the treatment with a peak during the second and third infusion. Development of persistent anti-NTZ antibodies is reported in 6% of patients.3 We report the case of a patient who presented with a severe hypersensitivity reaction 8 days after the first infusion. She developed early and persistent anti-NTZ antibodies. ### Level of evidence. This article provides Class IV evidence that natalizumab is able to produce hypersensitivity reactions such as giant urticaria, laryngeal edema, dyspnea, and fever. This is a single observational study without controls. ### Case report. A 37-year-old patient was treated …

Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: The MOGADOR study

Objective To describe clinical and radiologic features associated with myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) in a large French nationwide adult cohort, to assess baseline prognostic features of MOG-Ab-associated diseases after a first acute demyelinating syndrome, and to evaluate the clinical value of MOG-Ab longitudinal analysis. Methods Clinical data were obtained from 197 MOG-Ab-positive patients ≥18 years of age. Complete imaging data were available in 108, and 54 serum samples were eligible for longitudinal evaluation. For survival analysis comparison, 169 aquaporin-4 antibody (AQP4-Ab)-positive patients from the NOMADMUS database were included. Results Median age at onset was 36.46 (range 18.0–76.8) years, and patients were predominantly white (92.9%) with male:female ratio, 1.1. Clinical phenotype at onset included optic neuritis or myelitis in 90.86%, isolated brainstem or encephalopathy syndromes in 6.6%, and a combination of syndromes in 2.5%. Distinctive brain MRI findings in MOG-Ab-positive patients were thalamic and pontine lesions. Cortical and leptomeningeal lesions were found in 16.3% and 6.1%, respectively. The probability of reaching a first relapse after 2 and 5 years was 44.8% and 61.8%, respectively. MOG-Ab-positive patients were at lower risk at presentation of further clinical relapse (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.26–0.79) compared to AQP4-Ab-positive individuals. MOG-Ab-positive individuals had a lower risk of reaching Disability Status Scale score of 3.0 (HR 0.46, 95% CI 0.22–0.94) and visual acuity of 20/100 (HR 0.23, 95% CI 0.07–0.72). Finally, MOG-Ab titers were higher at relapse than in remission (p = 0.009). Conclusion In adults, MOG-Ab-associated disease extends beyond clinical and radiologic abnormalities in the optic nerve and spinal cord. Despite the relapsing course, the overall visual and motor outcome is better compared with AQP4-Ab-positive patients.

Evaluation of quality of life and fatigue in radiologically isolated syndrome

BACKGROUND Radiologically isolated syndrome (RIS) is a new subtype entity described at the very left of the demyelinating disease spectrum, where spatial dissemination of T2-weighted lesions can be documented on MRI in subjects with no history of neurological symptoms. OBJECTIVES This study was a longitudinal assessment of health-related quality of life (HRQOL) and fatigue in RIS patients. METHODS Non-converted RIS patients were evaluated at the time of diagnosis, and at 1 and 2 years of follow-up; their scores were compared with scores in clinically isolated syndrome (CIS) patients and age-matched controls. RESULTS Sociodemographic characteristics were comparable at baseline. There was no statistical difference between RIS and CIS groups in terms of cerebrospinal fluid (CSF) positivity or T2 lesion load. For HRQOL evaluations, RIS patients scored the same as controls, while CIS patients scored lower. Fatigue was detectable in both RIS and CIS patients compared with baseline and with controls. Mental HRQOL scores decreased significantly for RIS patients during follow-up. CONCLUSION HRQOL impairment and fatigue were detectable during follow-up in both non-converted RIS and CIS patients.

False positivity of anti aquaporin-4 antibodies in natalizumab-treated patients

Background: Neuromyelitis optica spectrum disorders (NMOSD) represent a differential diagnosis of multiple sclerosis (MS). Detection of anti-aquaporin-4 antibodies (AQP4-Ab) is the strongest argument to confirm NMOSD. Diagnosing NMOSD is a major concern because specific MS disease modifying drugs can lead to neurological worsening. Objective: To report the case of two natalizumab (NTZ) treated patients who presented a false positive result for AQP4-Ab. Methods: A retrospective analysis of NTZ-treated patients who were tested positive for AQP4-Ab in our MS center. Results: Two patients treated by NTZ presented a false positive result. Conclusions: Clinicians should be aware of potential technical issues in detecting AQP4-Ab in NTZ-treated patients leading to false positive results.