Treatment Of Neuromyelitis Optica Research Articles

Immunogenicity dynamics and covariate effects after satralizumab administration predicted with a hidden Markov model.

Immunogenicity is the propensity of a therapeutic protein to generate an immune response to itself. While reporting of antidrug antibodies (ADAs) is increasing, model-based analysis of such data is seldom performed. Model-based characterization of factors affecting the emergence and dissipation of ADAs may inform drug development and/or improve understanding in clinical practice. This analysis aimed to predict ADA dynamics, including the potential influence of individual covariates, following subcutaneous satralizumab administration. Satralizumab is a humanized IgG2 monoclonal recycling IL-6 receptor antagonist antibody approved for treating neuromyelitis optica spectrum disorder (NMOSD). Longitudinal pharmacokinetic (PK) and ADA data from 154 NMOSD patients in two pivotal Phase 3 studies (NCT02028884, NCT02073279) and PK data from one Phase 1 study (SA-001JP) in 72 healthy volunteers were available for this analysis. An existing population PK model was adapted to derive steady-state concentration without ADA for each patient. A mixed hidden Markov model (mHMM) was developed whereby three different states were identified: one absorbing Markov state for non-ADA developer, and two dynamic and inter-connected Markov states-transient ADA negative and positive. Satralizumab exposure and body mass index impacted transition probabilities and, therefore, the likelihood of developing ADAs. In conclusion, the mHMM model was able to describe the time course of ADA development and identify patterns of ADA development in NMOSD patients following treatment with satralizumab, which may allow for the formulation of strategies to reduce the emergence or limit the impact of ADA in the clinical setting.

Neuromyelitis Optica with Negative AQP-4 Antibody

Abstract
 Introduction : Neuromyelitis Optica (NMO) or neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system that causes demyelination of the optic nerve and spinal cord. Approximately 75% of cases have antibodies against aquaporin 4 (AQP-4 Antibody).
 Case Illustration : A 42 years old male presented with progressing blurred vision in his right eye for 3 weeks. He described there was a black spot in his central vision which gradually enlarged to his peripheral vision, headache for 4 months, and transient tingling sensation and weakness on the left arm for 1 week. Positive RAPD in the right eye and signs of optic neuritis on funduscopy in Opthalmology examination. Campimetry examination revealed generalized depression in the right eye. The visual evoked potential (VEP) was consistent with right optic nerve demyelination. Spine MRI showed extensive transverse myelitis lesions >3 spinal cord hyperintensity on the level of C2-C6. However, the serum AQP-4 antibody was negative. The patient was treated with corticosteroid, and neuroprotector and was also being treated alongside the neurology department.
 Discussion : NMO is a rare autoimmune disease. NMO is characterized by segmented demyelination and inflammation of the spinal cord and the optic nerves which gives many ocular signs and symptoms like optic neuritis. A negative test result does not rule out the diagnosis of NMO. Brain and spine MRI plays an important role in diagnosing NMO. Treatment of NMO consists of corticosteroid and plasmapheresis or intravenous immunoglobulin.
 Conclusion : This case describes a diagnosis of NMO with a Negative AQP-4 antibody.

Rectifying global inequities in neuromyelitis optica diagnosis and treatment

The standard of care for patients with neuromyelitis optica (NMO) has become highly unequal globally. Sufficient data have been published to demonstrate that NMO is a disabling—and at times, fatal—disease needing preventive immunosuppressive treatment. Since 2019, there are multiple regulatory authority-approved disease-modifying therapies (DMTs) for aquaporin-4 antibody seropositive NMO for patients. Reframing the picture of NMO globally is now needed. When considered as a disease of high mortality when left untreated, parallel programs to those for cancer, HIV/AIDS, or tuberculosis can be considered. Nine collective goals for rectifying global inequities in NMO diagnosis and treatment are proposed.

Tocilizumab for Neuromyelitis Optica Spectrum Disorder


 Patients with neuromyelitis optica spectrum disorder treated with tocilizumab may experience decreased risks of relapse or disability progression compared to before treatment, but it is uncertain whether these changes can be entirely attributed to tocilizumab (TCZ) treatment.
 TCZ might be better than azathioprine for patients with neuromyelitis optica spectrum disorder in reducing relapse risk.
 TCZ might improve or have no impact on pain and fatigue measures for patients with neuromyelitis optica spectrum disorder.
 Adverse events were common during TCZ treatment, but patients treated with TCZ may experience adverse events at a similar or lower rate to those treated with azathioprine.
 One evidence-based guideline suggests that TCZ can be used as 1 of the second-line drugs to prevent long-term relapse for patients with neuromyelitis optica spectrum disorder who have no response to other immunosuppressants.
 We did not find any studies that compared TCZ to other immunosuppressants or any studies on the cost-effectiveness of TCZ for treating neuromyelitis optica spectrum disorder that met the inclusion criteria for this report.

Challenges in the diagnosis and treatment of neuromyelitis optica: A serial cases

The diagnosis of Neuromyelitis Optica spectrum disorder (NMOSD) can be challenging especially in patients with atypical presentations and unknown serostatus for aquaporin-4 antibodies (AQP4-Ab). We present three cases with different onset variations and relapsing episodes and aims to present and compare the clinical, radiological and evoked potential findings.

FTY720 Exacerbates Blood-Brain Barrier Dysfunction Induced by IgG Derived from Patients with NMO and MOG Disease.

Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibody-related disease (MOG disease) are inflammatory demyelinating diseases of the central nervous system (CNS). The disruption of the blood-brain barrier (BBB) is considered a key step in the pathogenesis of NMO and MOG disease. Although a previous report indicated that circulating immunoglobulin G (IgG) from NMO patients disrupts the BBB, the effect of IgG from patients with MOG disease has not been elucidated. In addition, it has been reported that some disease-modifying drugs for multiple sclerosis are harmful to NMO by an unknown mechanism. This study aimed to examine the effects of IgG from patients with NMO or MOG disease on BBB integrity. We also examined the effects of disease-modifying drugs (fingolimod [FTY720] and dimethyl fumarate [DMF]) on IgG-treated brain capillary endothelial cells. We used in vitro BBB models constructed with rat brain capillary endothelial cells (RBECs) to examine the effects on BBB function. The integrity of the RBECs was assessed by measuring transendothelial resistance (TEER) and cell viability. NMO or MOG-IgG treatment decreased TEER and cell viability in the endothelial monolayer model. Although FTY720 and DMF did not affect barrier function or cell viability under normal conditions, disease IgG-induced barrier dysfunctions were worsened by the presence of FTY720. These data indicate that circulating IgG in patients with NMO or MOG disease worsens BBB function. Furthermore, in patients with NMO or MOG disease treated with FTY720, changes in the integrity of the BBB were found to exacerbate the disease.

White matter abnormalities of the brain: similar to multiple sclerosis in adolescence

Also known as Devic's disease, neuromyelitis optica (NMO) is an autoimmune inflammatory disease that affects the central nervous system, considerably similar to multiple sclerosis (MS). This study aimed to compare the similarities of the clinical feature presented with similar cases found in the medical literature, addressing the symptoms, diagnosis, and treatment. This is a descriptive, retrospective, and qualitative study, done through the technique of direct observation. An adolescent male patient came to our service complaining of weakness in the lower limbs and urinary retention and, subsequently, urinary incontinence, during hospitalization. After undergoing magnetic resonance imaging of the skull, a large lesion with a demyelinating characteristic was evident through the T2 and FLAIR sequences, hyperintense in the white matter of the right cerebral hemisphere, with the exuberant enhancement of the contrasted image. Subsequently, he presented weakness in the left dimidium of the body, with progressive worsening in some days, with the impossibility of walking. The treatment was initiated with pulse therapy of methylprednisolone and interferon beta, obtaining an excellent clinical control of the disease. Thus, diagnostic confirmation was only possible thanks to the identification of a single brain white matter lesion through imaging and serological examination, which constituted a tool of great importance for the differential diagnosis that made it possible to exclude multiple sclerosis and allowed the establishment of timely treatment for neuromyelitis optica.

Longitudinally Extensive Transverse Myelitis in a Lupus-Neuromyelitis Optica Overlap.

Transverse myelitis is an inflammatory lesion of the spinal cord, occurring in different autoimmune, infectious, and traumatic diseases but is the hallmark of neuromyelitis optica (NMO), a rare neurologic autoimmune disease. Patients with systemic lupus erythematosus (SLE) may develop transverse myelitis as a neuropsychiatric complication of active disease; however, at times, NMO co-exists as an additional primary autoimmune condition in a SLE patient. Correct diagnosis of a SLE–NMO overlap is important not only for the different disease course and prognosis compared with SLE-related LETM, but especially for the emerging and highly specific NMO treatment options, not established for SLE-related LETM—such as anti-aquaporin 4 antibodies, anti-VEGF antibodies, complement modulation, or IVIg.

The evaluation of lymph node cell proliferation response by liposomes loaded with major histocompatibility complex class II binding aquaporin 4 antigen peptide.

Autoimmune responses to aquaporin 4 (AQP4) cause neuromyelitis optica (NMO); thus, specific immunotolerance to this self-antigen could represent a new NMO treatment. We generated the liposome-encapsulated AQP4 peptide 201-220 (p201-220) to induce immunotolerance. Liposomes were generated using phosphatidylserine and the polyglycidol species PG8MG. The in vivo tissue distribution of the liposomes was tested using an ex vivo imaging system. To confirm the antigen presentation capacity of PG8MG liposomes, dendritic cells were treated with PG8MG liposome-encapsulated AQP4 p201-220 (AQP4-PG8MG liposomes). Immunotolerance induction by AQP4-PG8MG liposomes was evaluated using the ex vivo cell proliferation of lymph node cells isolated from AQP4 p201-220-immunized AQP4-deficient mice. Fluorescent dye-labeled PG8MG liposomes were distributed to the lymph nodes. AQP4 p201-220 was presented on dendritic cells. AQP4-PG8MG liposomes were tended to suppress immune responses to AQP4 p201-220. Thus, the encapsulation of AQP4 peptides in PG8MG liposomes represents a new strategy for suppressing autoimmune responses to AQP4.

Safety and efficacy of mycophenolate mofetil in treating neuromyelitis optica spectrum disorders: a protocol for systematic review and meta-analysis

IntroductionNeuromyelitis optica spectrum disorders (NMOSD) is an inflammatory and heterogeneous astrocyte disorder of the central nervous system with the characteristic of higher incidence in women and Asian people. Most patients...

Modern Methods of Devic’s Disease Treatment

BACKGROUND: Neuromyelitis optica (NMO) (also known as opticomyelitis, Devic’s syndrome/disease) is an idiopathic inflammatory disorder of the central nervous system characterized by predominant involvement of the optic nerves, spinal cord, and extensive transverse myelitis. To date, there are no convincing clinical trials that would fully evaluate the efficacy and safety of drugs for the treatment and prevention of NMO exacerbation. Taking into account the malignant course that quickly leads to disability of young, economically active population, the issues of searching for effective methods of NMO treatment remain highly urgent.
 AIM: The purpose of the study was to examine available modern methods of treatment and prevention of NMO exacerbation, which have potential and require further detailed clinical trials to ensure possible application of these treatment options in clinical practice.
 MATERIALS AND METHODS: We have reviewed previously applied and modern methods of treatment. We have analyzed systematic reviews, clinical, randomized, and retrospective studies of scientific medical databases: PubMed, Cochrane, The Lancet, UpToDate, and reviews of world medical journals in Russian and English.
 CONCLUSIONS: The authors concluded that there is a sufficient number of drugs and combinations of methods of Devic’s disease treatment. We were interested in combinations of rituximab (RIT) and autologous stem cell transplantation, RIT and fetal hepatocyte transplantation, and RIT and strengthening the effect by plasmapheresis sessions. However, successful implementation of these methods in clinical practice requires conducting controlled clinical trials with a larger number of patients and longer follow-up periods.

Experience of Using Adrenocorticotropic Hormone in the Treatment of Patients With Acute Neuromyelitis Optica Who Failed Systemic Steroids: A Case Series

Neuromyelitis optica (NMO) has a complex pathology. Clinical symptoms, derived from damage to optic nerves and spinal cord, cause optic neuritis and/or longitudinally extensive myelitis. Treatment options are limited. We assessed adrenocorticotropic hormone (ACTH) use in patients developing exacerbations on systemic steroid treatment and declining other treatments. Patients with NMO who initiated intravenous methylprednisolone (IVMP) for exacerbations and experienced a subsequent exacerbation on monthly IVMP or had inadequate response to IVMP received ACTH 80 U/d intramuscularly for 7 days (for acute relapse), followed by 80 U every 2 weeks (for long taper down/maintenance). Every 1 to 3 months, relapse, Expanded Disability Status Scale, laboratory, and adverse event assessments were performed. Six patients (mean age: 48.6 years; NMO-suggestive clinical/imaging presentations; cerebral spinal fluid revealing no oligoclonal bands; aquaporin-4 positive [n = 5]) were identified: 5 experiencing subsequent exacerbations with monthly IVMP and 1 with inadequate response to IVMP. No relapses occurred during ACTH treatment or taper-down period, laboratory values indicated no safety concerns, and annual follow-up magnetic resonance imagings were stable. Adverse events were generally characterized as improved or unchanged versus with IVMP, although 1 patient reported transient edema (lower extremities) only during ACTH treatment. Potential treatment-related AEs included edema, acne, urinary tract infection, and insomnia and were reportedly less severe with ACTH treatment than IVMP. Adrenocorticotropic hormone treatment for acute NMO was associated with clinical improvement, suggesting that ACTH could have a role in treating acute NMO patients failing IVMP and declining other treatments. Fewer/less severe AEs were observed with ACTH versus IVMP. Larger, controlled clinical studies are needed.

C16 Peptide Promotes Vascular Growth and Reduces Inflammation in a Neuromyelitis Optica Model.

The goal of this study was to elucidate the mechanism of action of C16, a laminin-1 peptide that competes with αvβ3 for integrin binding, in treating neuromyelitis optica (NMO). A NMO rat model was established and specific inhibitors were used to investigate the effect of Tie2 kinase, integrin, and PI3K/Akt signaling pathways on C16 function in NMO using histological, immunohistochemical, immunofluorescence, Western blot, and ELISA assays. A total of 150 rats were divided into five groups: a control untreated group (n = 18) and four test groups (n = 33 per group) including vehicle-treated control, C16, Tie2 kinase inhibitor + C16, and PI3K/Akt inhibitor LY294002 + C16. We found that inhibiting Tie2 kinase resulted in partial loss of C16 peptide-mediated effects, while suppressing PI3K/Akt signaling reduced C16 peptide-mediated effects. In addition, activation of the αvβ3 integrin axis and Tie2 kinase promoted PI3K/Akt signaling. Our study showed that the Tie2-PI3K/Akt, Tie2 integrin, and integrin-PI3K/Akt signaling pathways regulate C16 peptide function in vascular growth and stabilization as well as inflammation in NMO.

Current Status and Prospects of Complement-Targeting Therapy for Neuromyelitis Optica

Neuromyelitis optica (NMO) is clinically characterized by severe optic neuritis and long myelitis; and is associated with aquaporin-4 immunoglobulin-G (AQP4-IgG), an autoantibody directed against aquaporin-4 (AQP4), which is an astrocytic water channel protein. Until recent years, the treatment of NMO has mainly focused on the suppression of lymphocytes and depletion of autoantibodies. However, several studies on the pathogehesis of the disease in human pathology, cultured cells, and animal models have revealed that astrocyte injury in NMO is mainly caused by the complement-dependent cytotoxicity following AQP4-IgG binding to AQP4. Moreover, complement-targeting therapy has recently been translated into practical applications in several hematological disorders. and similary, also in the cases of NMO. In this article, we review the relevance of the complement system in the pathogenesis of NMO. Additionally, we review the current status and prospects of the complement-targeting therapy for NMO, including the clinical trials of eculizumab and C1 inhibitor for NMO, and the experimental studies on C1 inhibition by monoclonal antibodies.

Diagnosis and Treatment of Neuromyelitis Optica in Ethiopia (P2.6-042)

Diagnosis and Treatment of Neuromyelitis Optica in Ethiopia (P2.6-042)

Monoclonal antibodies in neurology: current state and future development

Monoclonal antibodies are one of the most fastly developing areas of specific therapy for cancer, infectious, autoimmune and demyelinating diseases. The main targets of monoclonal antibodies in autoimmune and demyelinating diseases are T and B-lymphocytes, cytokines, complement, and adhesion molecules. In the field of neurodegenerative diseases, the largest number of studies has been carried out in patients with Alzheimer's disease, in which monoclonal antibodies are targeted to brain aggregates of beta-amyloid. This review presents new therapeutic approaches to the use of antibody fragments, with a focus of their new class, nanobodies. A special attention is paid to new anti-CD20 and anti-CD19 monoclonal antibody drugs in multiple sclerosis (ocrelizumab, ofatumumab) and neuromyelitis optica (inebilizumab). Ocrelizumab is the first medication that proved to be effective in primary progressive multiple sclerosis. There have been significant advances in the treatment of neuromyelitis optica: the first multicenter study of Inebilizumab (MEDI-551) is currently underway.

Hematopoietic Stem Cell Transplantation for CNS Autoimmune Disorders for Adults and Children: Long-Term Outcomes - Experience of the Russian Federation

Rationale. More than 70 000 of patients registered with multiple sclerosis (MS) registered in Russia annually. Some of adults and children with CNS autoimmune disorder (AD) require hematopoietic stem cell transplantation (HSCT). We analyzed long-term outcomes and late effects in adults and children with MS and neuromyelitis optica (NMO) after HSCT treated in three Russian centers.Patients and Methods. Sixteen children were treated in the Russian Children's Research Hospital in collaboration with Dmitry Rogachev Center: MS - 13, NMO - 3. MS: female (F) - 9, male (M)- 4; NMO: all females. MS median age - 16,8±1,6 y.o., median Expanded Disability Status Scale (EDSS) 6,16±0,2. NMO pts median age - 12,7±1,4 y.o. All patients had severe refractory disease. MS children received Cyclophosphomide and horse ATG, NMO - Treosulfan, Fludarabine, Rituximab and horse ATG. Nighty nine MS adults received HSCT in National Pirogov Medical Surgical Center with reduced-intensity BEAM-like conditioning regimen in mean age-35 y.o.; M:F=39:60; median EDSS = 3.5; disease status - 43 relapsing/remitting MS, 56 progressive MS. Thirty-two MS adult patients were transplanted in Raisa Gorbacheva Research Institute during 2 periods of time: 25 patients in 2000 - 2010 (mean age - 34,4 y.o., M:F=12:13, mean EDSS=4,3) with conditioning regimen BEAM and horse ATG and in 2018 (mean age - 36 y.o., M:F=3:4, mean EDSS=4.5) with conditioning regimen based on Cyclophosphomide and horse ATG.Results. Rapid improvement of EDSS registered in children - EDSS decreasing on 3,1±0,3 during first 60 days. Median follow-up - 52,1 ± 2,3 months (12-86 months). Two MS patients relapsed (clinical and MRI). Almost all NMO patients stopped the progression and improved neurologically (clinical and MRI) except 1 pt - died due to refractory ADV-infection. Median follow-up - 24,2±4,5 months (1- 62 months). MS patients late effects cardio-vascular - 5 pts, endocrine - 3 pts (all females). NMO patients late effects: cardio-vascular - 2 pts., late immune reconstitution - 1 pt. In Pirogov Medical Surgical Center group at 6 months post-transplant, neurological improvement or stabilization was observed in all the patients except one. Cumulative incidence of disease progression was 16.7 % at 8 years after HSCT. Sixty-four patients who did not progress during the first 3 years post-transplant and were monitored for more than 3 years were included in long-term outcome analysis. At the median long-term follow-up of 62 months, 47 % of patients improved by at least 0.5 points on the EDSS as compared to baseline and exhibited improvement during the entire period of follow-up; 45 % of patients were stable. In Raisa Gorbacheva Research Institute 50% of patients (group transplanted in 2000 - 2010) relapsed, group transplanted in 2018 - 4 patients were improved on therapy and 3 - stabilized.Conclusions. HSCT is used both for children and adults in Russia. It is successful approach for refractory MS and pediatric NMO treatment. In-time HSCT can significantly improve the outcome. Late effects can be found in these patients, so it's important to find it and give adequate rehabilitation. Thus, the risk/benefit ratio of HSCT in our population of these patients are very favorable. DisclosuresNo relevant conflicts of interest to declare.

Apheresis therapies for NMOSD attacks: A retrospective study of 207 therapeutic interventions.

ObjectiveTo analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR).MethodsThis retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody–seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome.ResultsTwo hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04–144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89–0.99, p = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76–631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03–21.62, p = 0.046).ConclusionsOur findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques.Classification of evidenceThis study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.

Efficacy and safety of mycophenolate mofetil in treating neuromyelitis optica spectrum disorder: a multicenter, prospective, self-control study in Guangzhou City

Objective: To evaluate the efficacy and safety of mycophenolate mofetil (MMF) in neuromyelitis optica spectrum disorder (NMOSD). Method: From September 2014 to February 2017, NMOSD patients with seropositive aquaporin4-IgG was enrolled through a multicenter, prospective study, and the annual recurrence rate (ARR), Expanded Disability Status Scale (EDSS) and MMF-related side effects before and after MMF treatment were compared. Results: Ninety patients were enrolled in the study. After being treated for a median of 12 months (1-30 months), the median ARR decreased from 1.1 pre-MMF to 0 post-MMF (P<0.001), and the median EDSS score decreased from 4.0 pre-MMF to 3.0 post-MMF (P<0.001). The EDSS score reduced significantly after 90 days' treatment (P<0.05). The main adverse events included the deranged liver enzymes (19%, 17/90), respiratory infection (11%, 10/90), urinary tract infection (6%, 5/90), varicella-zoster infection (6%, 5/90), anemia (6%, 5/90), leucopenia (6%, 5/90), diarrhea (2%, 2/90), hair loss (1%, 1/90); 11% (10/90) patients experienced severe adverse events, and 6% (5/90) patients discontinued MMF. Conclusions: MMF could significantly reduce the ARR and EDSS score of NMOSD. However, awareness on side effects should be raised.

Persistent microscopic active inflammatory lesions in the central nervous system of a patient with neuromyelitis optica treated with oral prednisolone for more than 40 years.

We have reported an autopsy case of neuromyelitis optica (NMO) that exhibited persisting active inflammatory lesions in the central nervous system (CNS) despite a 45-year-long treatment with oral corticosteroids. To our knowledge, our case had received the longest course of maintenance treatment. This case study suggests that the current treatment of NMO with immunosuppressive agents may offer a good prospect for improving life expectancy. On the other hand, it also suggest that microscopic active lesions which were clinically silent and difficult to detect by neurological examination or MRI studies may persist in the CNS in patients with NMO, despite prolonged and continuous immunosuppressive treatment.