Is It Too Early to Predict the Failure of Natalizumab in NMO?—Reply

Kleiter, Ingo; Hellwig, Kerstin; Berthele, Achim; Kümpfel, Tania; Linker, Ralf A.; Hartung, Hans‐Peter; Paul, Friedemann; Aktaş, Orhan; Group, for the Neuromyelitis Optica Study

doi:10.1001/archneurol.2012.1316

Cited by 7 publications

(6 citation statements)

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“…3 However, relapse prevention remains a challenging issue in NMO because established multiple sclerosis therapies such as interferons, natalizumab, and fingolimod have been reported to show little efficacy or even to be detrimental. [4][5][6] According to smaller case series or retrospective cohort studies, long-term immunosuppression with azathioprine 7 or mycophenolate mofetil 8 is recommended for mild NMO cases, with methotrexate being an alternative treatment option. 3,9 In patients with more severe NMO courses, rituximab 10 and mitoxantrone hydrochoride 11 have been reported to diminish the relapse frequency.…”

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confidence: 99%

Long-term Therapy With Interleukin 6 Receptor Blockade in Highly Active Neuromyelitis Optica Spectrum Disorder

et al. 2015

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IMPORTANCE Neuromyelitis optica (NMO) is characterized by disabling relapses of optic neuritis and myelitis and the presence of aquaporin 4 antibodies (AQP4-abs). Interleukin 6, which is significantly elevated in serum and cerebrospinal fluid of patients with NMO, induces AQP4-ab production by plasmablasts and represents a novel therapeutic target.OBJECTIVE To evaluate the long-term safety and efficacy of tocilizumab, a humanized antibody targeting the interleukin 6 receptor, in NMO and NMO spectrum disorder. DESIGN, SETTING, AND PARTICIPANTSRetrospective observational study with 10 to 51 months of follow-up between December 2010 and February 2015, in neurology departments at tertiary referral centers. Participants were 8 female patients of white race/ethnicity with highly active AQP4-ab-seropositive NMO (n = 6) and NMO spectrum disorder (n = 2) whose disease had been resistant to previous medications, including B-cell depletion, and who switched to tocilizumab (6-8 mg/kg of body weight per dose). MAIN OUTCOMES AND MEASURESAnnualized relapse rate, Expanded Disability Status Scale score, spinal cord and brain magnetic resonance imaging, AQP4-ab titers, pain levels (numerical rating scale), and adverse effects. RESULTSPatients were followed up for a mean (SD) of 30.9 (15.9) months after switching to tocilizumab. Two of eight patients received add-on therapy with monthly corticosteroid pulses (temporary) or azathioprine, respectively. During tocilizumab treatment, the median annualized relapse rate significantly decreased from 4.0 (interquartile range, 3.0-5.0) in the year before tocilizumab therapy to 0.4 (interquartile range, 0.0-0.8) (P = .008), and the median Expanded Disability Status Scale score significantly decreased from 7.3 (interquartile range, 5.4-8.4) to 5.5 (interquartile range, 2.6-6.5) (P = .03). Active magnetic resonance imaging lesions were seen in 6 of 8 patients at tocilizumab initiation and in 1 of 8 patients at the last magnetic resonance imaging. Three patients remained relapse free during tocilizumab treatment. In 5 patients, a total of 8 relapses occurred, 4 within the first 2½ months of therapy. Five attacks were associated with delayed tocilizumab administration (Ն40 days), and 6 attacks were associated with reduced tocilizumab dosage (6 vs 8 mg/kg). The AQP4-ab titers (P = .02) and pain levels (P = .02) dropped significantly during tocilizumab treatment. Adverse effects included moderate cholesterol elevation in 6 of 8 patients, infections in 4 of 8 patients, and deep venous thrombosis and neutropenia in one patient each. CONCLUSIONS AND RELEVANCEProlonged tocilizumab therapy may be safe and effective from early treatment phases onward for otherwise therapy-resistant highly active NMO and NMO spectrum disorder. Relapse patterns indicate that adherence to a regular therapeutic regimen with monthly infusions of tocilizumab (8 mg/kg) may increase efficacy.

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Long-term Therapy With Interleukin 6 Receptor Blockade in Highly Active Neuromyelitis Optica Spectrum Disorder

et al. 2015

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“…Taking also the previous literature into account, it is apparent that NAT is not beneficial for most patients with NMOSD. 6 – 8 , 19 – 24 A review of 19 patients published so far revealed that the majority of patients with NMOSD treated with NAT for at least 3 months deteriorated (table e-2). Moreover, early appearance of severe attacks with atypical cerebral manifestation was noted in a subset of NMO NAT patients.…”

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confidence: 99%

Aquaporin-4 antibodies in patients treated with natalizumab for suspected MS

Gahlen

Trampe

Haupeltshofer

et al. 2017

Neurol Neuroimmunol Neuroinflamm

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Objective:To evaluate (1) the frequency of aquaporin-4 antibody (AQP4-ab)-seropositive cases among patients treated with natalizumab (NAT) and previously diagnosed with MS (MSNAT) in a nationwide cohort, (2) the clinical course of NAT-treated AQP4-ab–seropositive neuromyelitis optica spectrum disorder (NMOSD) patients (NMONAT), (3) AQP4-ab titers in NMONAT and AQP4-ab–seropositive NMOSD treated with other immunotherapies (NMOIT), and (4) immune mechanisms influencing disease activity in NMONAT.Methods:MSNAT serum samples were retrospectively screened with a cell-based assay for AQP4-IgG and titers determined by ELISA. The annualized relapse rate (ARR) and disability progression were assessed. Serum levels of proinflammatory cytokines (interleukin [IL]-1β, IL-4, IL-6, IL-8, IL-10, IL-17, IL-21, and interferon [IFN]-γ) and the chemokine CXCL-10 of NMONAT patients identified in this (n = 4) and a previous study (n = 5) were measured by cytometric bead array and ELISA.Results:Of the 1,183 MSNAT patients (851 female, median 9 NAT infusions), only 4 (0.33%; 3 female, 1 male) had AQP4-IgG. Of these, 2 fulfilled the 2006 NMO criteria and all met the 2015 NMOSD criteria. The ARR was higher in NMONAT vs MSNAT (p = 0.0182). All 4 NMONAT patients had relapses and 2 had an increase of disability. AQP4-ab titers were higher in NMONAT (n = 9) vs NMOIT (n = 13; p = 0.0059). IL-8, IL-1β, and IFN-γ serum levels were significantly higher, and CXCL-10 was significantly lower in NMONAT vs NMOIT.Conclusions:Misdiagnosis of NMOSD with MS is rare. NAT was not able to control disease activity in NMONAT patients, who had higher serum levels of AQP4-IgG and proinflammatory cytokines than patients with NMOSD treated with other immunotherapies.

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“…The first study investigated the initial cohort of 175 NMO patients as to their demographic, clinical and imaging findings with regard to AQP4 serostatus [8]. In parallel, a subgroup of patients in this cohort was identified that was initially misdiagnosed as relapsing-remitting MS and were routinely put on a high-dose MS therapy with natalizumab [14]; despite this, the patients continued to exhibit persistent related disease activity [15,16]. This difficult diagnosis following a somewhat circuitous route was documented in an article on patients who initially underwent a spinal biopsy (which was in some cases not acceptably tolerated) for a suspect-ed malignant spinal tumor, but who in the end had apparent tumefactive longitudinal extensive transverse myelitis (LETM) [17].…”

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confidence: 99%

Neuroimmunological Registries in Germany

Thiel

Leypoldt

Röpke

et al. 2018

Neurology International Open

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Several neuroimmunological registries have been established in Germany during the last 10 years. The common aim is to investigate the course of different diseases, mainly under various therapeutic conditions, to identify predictive factors as well as the side effects of immunomodulating therapies. Six nationwide neuroimmunological registries will be presented in this article. The German Network for Research on Autoimmune Encephalitis (GENERATE) with more than 40 participating clinical centers and 570 documented patients (September 2016) collects data and biomaterials of autoimmune encephalitis with known and unknown antibodies. The registry coordinates and mediates between scientists and clinicians and acts as a platform for the development of guidelines and procedures. The neuromyelitis optica study group (NEMOS) has established a national registry for patients with neuromyelitis optica and neuromyelitis optica spectrum disorders. In addition to 22 academic hospitals, 17 regional hospitals and several practices are participating. Currently, 250 patients are enrolled. Moreover, NEMOS is now establishing a prospective patient cohort (NationNMO) within the competence network multiple sclerosis. Current research focuses on treatment strategies for relapses and interval therapy of neuromyelitis optica. The competence network multiple sclerosis has initiated a multi-center, prospective cohort study of patients with clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (MS) (NationMS), with the aim of long-term follow-up and clinical and paraclinical characterization of the patients. Between August 2010 and December 2014, 1,212 patients in 22 university und non-university centers were enrolled in the NationMS cohort. Standardized clinical data as well as biomaterial and MRI images were collected and stored. The German MS Society (DMSG, Bundesverband e.V.) established in 2001 a long-term project to obtain a consistent and reliable overview of MS patients in Germany. Since 2014 the registry has been revised comprehensively, with the main purpose of establishing a permanent data repository for healthcare research while ensuring the collection, storage and provision of data over decades and enabling the description of long-term outcomes. Currently, more than 170 German centers are participating and over 48,000 patients are enrolled in the registry. Since 2013, the competence network multiple sclerosis has established the immunotherapy registry REGIMS with the objective to obtain information on incidence, type and characteristics of adverse events of new immunomodulating therapies for patients with multiple sclerosis or clinical isolated syndrome. As of January 2017 more than 700 patients have been recruited from 36 active centers. The German Multiple Sclerosis and Pregnancy Registry aims to obtain safety information of disease modifying drug exposure during pregnancy. In addition to safety aspects, disease course during pregnancy and postpartum and the identification of predictors of disease activity are investigated. During the last ten years 1,500 pregnant MS patients were prospectively enrolled in the registry and at least 250 new pregnancies are followed every year. These six registries make an important epidemiological and scientific contribution. Numerous colleagues from clinics and practice support these registries. The objective is the closer understanding of the disease course, the influence of therapeutic decisions and thus the improvement of counseling and care.

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Is It Too Early to Predict the Failure of Natalizumab in NMO?—Reply

Cited by 7 publications

References 7 publications

Long-term Therapy With Interleukin 6 Receptor Blockade in Highly Active Neuromyelitis Optica Spectrum Disorder

Long-term Therapy With Interleukin 6 Receptor Blockade in Highly Active Neuromyelitis Optica Spectrum Disorder

Aquaporin-4 antibodies in patients treated with natalizumab for suspected MS

Neuroimmunological Registries in Germany

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