Long-term efficacy, tolerability and retention rate of azathioprine in 103 aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder patients: a multicentre retrospective observational study from the UK

Elsone, Liene; Kitley, J; Luppe, Sebastian; Lythgoe, Daniel; Mutch, Kerry; Jacob, Saiju; Brown, Rachel; Moss, Kathryn M.; McNeillis, Benjamin; Goh, Yee Yen; Leite, Maria Isabel; Robertson, Neil; Palace, Jackie; Jacob, Anu

doi:10.1177/1352458514525870

Cited by 111 publications

(69 citation statements)

References 41 publications

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“…While therapeutic interventions with immunosuppressive drugs can reduce the frequency of NMO relapses, 3,[7][8][9][10][11] individual patients in most studies did not respond sufficiently to treatment or experienced major adverse effects. Therefore, better preventive NMO therapies are desirable.…”

Section: Discussionmentioning

confidence: 96%

“…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: 98%

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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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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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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 98%

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

et al. 2015

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“…Nevertheless, high rates of discontinuation (46%) over time were also reported. 37 Rituximab (RTX). The recommended dose in children is 375 mg/m 2 weekly for 4 weeks, with additional IV infusions depending on the CD191 B-cell count to maintain immunosuppression.…”

Section: Coexisting Autoimmune Diseases and Autoantibodiesmentioning

confidence: 99%

Neuromyelitis optica spectrum disorders in children and adolescents

Tenembaum¹,

Chitnis²,

Nakashima³

et al. 2016

Neurology

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Neuromyelitis optica (NMO) is a severe autoimmune disease of the CNS characterized by recurrent inflammatory events primarily involving the optic nerves and spinal cord. NMO is infrequent in children, but early recognition is important to start adequate treatment. In this article, we review the evolving diagnostic criteria of NMO and provide an update on the clinical and neuroimaging spectrum of the disorder in pediatric patients, including current knowledge on immunopathogenesis and treatment recommendations for children with NMO. Although neuromyelitis optica (NMO) was previously considered a subtype of multiple sclerosis (MS), the identification of autoimmune antibodies (NMO-immunoglobulin G [IgG]) targeted against the aquaporin-4 (AQP4) water channel in the majority of adult patients identified NMO as a different autoimmune disease entity. 1,2The high specificity of AQP4-IgG for NMO has allowed the identification of seropositive patients with atypical presentations of the disease: NMO spectrum disorders (NMOSD). 3Although adults are predominantly affected, NMO/NMOSD has been increasingly recognized in children, who demonstrate a spectrum of disease attacks that often involve CNS areas beyond the optic nerves and spinal cord. 4 A comprehensive update on NMO/NMOSD in the pediatric population is provided in this article. DEMOGRAPHICS AND EPIDEMIOLOGYThe mean age at NMO presentation ranges from 32 to 45 years in major case series. Population-based studies from Europe, Asia, and South America suggest that the incidence of NMO ranges from 0.05 to 4/100,000/y and the prevalence from 0.52 to 4.4/100,000. 5 Nevertheless, most of these studies have not stratified data by pediatric or adult age at onset.5 Pediatric onset is relatively rare.In a comprehensive prevalence study from Cuba, a country with a multiracial population, NMO onset prior to the age of 20 years constituted 3.4% of all NMO cases with an overall prevalence rate of 0.12/100,000 persons. 6 In this study, diagnosis was based on the Wingerchuk et al. 7 1999 criteria, in which AQP4 antibody testing was not included.In a large study of patient samples collected at the Mayo Clinic, 5% of AQP4 antibody-positive patients were children (,18 years), with a mean age at clinical onset of 12 years, a clear female preponderance (7:1), mixed ethnic background, and a poorer prognosis compared with childhood MS. 4 In 3 prospective studies of children with a first demyelinating syndrome, 0.6% (2/302), 8 3.5% (3/86), 9 and 3.7% (3/81) 10 of patients were identified as having NMO over 3-6 years of follow-up. A similar study on 44 children with optic neuritis (ON) reported a final diagnosis of NMO in 7% of patients.

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“…AZA was discontinued in 38/ 99 patients, mostly for side effects and lack of efficacy. Another retrospective study of 103 patients with AQP4-IgG-positive NMOSD confirmed these findings, revealed a reduction of the median ARR in 89 % of patients (median of 1.5 pretreatment to 0 on AZA), and an improvement or stabilization of the EDSS in 78 % of patients, but again had a high discontinuation rate of AZA (46 %) [78]. A third retrospective study of 31 patients with AQP4-IgG-positive or AQP4-IgG-negative NMOSD described a reduction in the mean ARR from 2.26 to 0.63 with a failure rate in 53 % of patients, despite concomitant prednisone therapy [79].…”

Section: Azamentioning

confidence: 68%

“…Several studies including a total of almost 400 patients have shown that AZA reduces the ARR, sometimes associated with improvement of neurological disability [17,[74][75][76][77][78][79][80]. A retrospective study evaluating classical NMO and patients with AQP4-IgG-positive NMOSD reported a decrease in the mean ARR from 2.18 to 0.64 in 70 patients treated with AZA for >1 year, with or without concomitant corticosteroid therapy [77].…”

Section: Azamentioning

confidence: 99%

Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders

Kleiter

Gold

2016

Neurotherapeutics

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Neuromyelitis optica spectrum disorders (NMOSD) are important evolving entities, which have reached much attention in the recent years. NMOSD are characterized by inflammatory lesions in the optic nerves, spinal cord, and central parts of the brain, as well as an autoimmune process directed against aquaporin-4. As disability in NMOSD accumulates by inflammatory damage from attacks, both the treatment and prevention of attacks are decisive for the long-term outcome. NMOSD attacks are treated with highdose intravenous corticosteroids and apheresis therapies, in particular therapeutic plasma exchange. In cases of incomplete remission, escalation of attack treatment is recommended. Preventive therapy is immunosuppressive and should by commenced as early as possible. Apart from classical immunosuppressants such as azathioprine and mycophenolate mofetil, repurposed biologicals are increasingly used. B-cell depletion with rituximab and other agents, inhibition of the interleukin-6 receptor with tocilizumab, and blockade of complement-mediated damage by eculizumab all are promising therapeutic strategies evaluated in randomized controlled trials. In this review, we will discuss present and future immunotherapies for NMOSD and also consider combination of treatments, plasma, cellular and other therapies. Current advances in immunopathological knowledge are translated into innovative concepts and begin a new era of NMOSD therapy.

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Long-term efficacy, tolerability and retention rate of azathioprine in 103 aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder patients: a multicentre retrospective observational study from the UK

Abstract: AZA is a modestly effective treatment for NMO. However, many patients discontinue AZA over time and this seems to reflect poor tolerability more than lack of efficacy.

Cited by 111 publications

References 41 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

Neuromyelitis optica spectrum disorders in children and adolescents

Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders

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