Search

Purpose of Review: B-cell depletion therapy, including anti-CD20 and anti-CD19 therapies, is increasingly used for a variety of autoimmune and conditions, including those affecting the central nervous system. However, B-cell depletion therapy use can be complicated by adverse effects associated with administration and immunosuppression. This review aims to summarize the application of anti-CD20 and anti-CD19 therapies for the pediatric neurologist and neuroimmunologist., Recent Findings: Most existing literature come from clinical trials with adult patients, although more recent studies are now capturing the effects of these therapies in children. The most common side effects include infusion related reactions and increased infection risk from immunosuppression. Several strategies can mitigate infusion related reactions. Increased infections due to persistent hypogammaglobulinemia can benefit from replacement immunoglobulin. B-cell depletion therapies can be safe and effective in pediatric patients. Anticipation and mitigation of common adverse effects through primary prevention strategies, close monitoring, and appropriate symptomatic management can improve safety and tolerability., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Inebilizumab is one of the monoclonal antibodies approved as maintenance therapy for aquaporin-4 immunoglobulin G-seropositive neuromyelitis optica spectrum disorder (NMOSD). It is a humanized monoclonal antibody targeting cluster of differentiation 19 (CD19). Common adverse reactions include urinary tract infections, nasopharyngitis, arthralgia, infusion reactions, headaches and a decrease in immunoglobulin levels. Here, we present a case of an NMOSD patient who experienced transient hyperCKaemia after the use of inebilizumab. The adverse reactions of this very rare monoclonal antibody drug improved after discontinuation., (© The Author(s), 2024.)

Aim: To investigate the short-term efficacy and safety of inebilizumab for neuromyelitis optica spectrum disorders (NMOSD)., Methods: A total of 33 patients with NMOSD treated with inebilizumab (Group INB, n =15) or rituximab (Group RTX, n =18) in addition to high-dose glucocorticoids were included. Both groups underwent hormone shock therapy during the acute phase. Subsequently, Group INB received inebilizumab injections during the remission phase, while Group RTX received rituximab injections. A comparison of aquaporins 4 (AQP4) titer values, peripheral blood B lymphocyte counts, and visual function recovery was conducted before and 8wk after treatment. Additionally, adverse reactions and patient tolerability were analyzed after using inebilizumab treatment regimes., Results: Following inebilizumab treatment, there was a significantly improvement in the visual acuity of NMOSD patients ( P <0.05), accompanied by a notable decrease in AQP4 titer values and B lymphocyte ratio ( P <0.05). Moreover, inebilizumab treatment showed a partial effect in preventing optic nerve atrophy ( P <0.05). However, there were no significant differences in other therapeutic effects compared to rituximab, which has previously demonstrated substantial therapeutic efficacy ( P >0.05). Furthermore, inebilizumab exhibited higher safety levels than that of rituximab injections., Conclusion: The combination of inebilizumab and high-dose glucocorticoids proves to be effective. In comparison to rituximab injections, inebilizumab displays better tolerance and safety. Moreover, it demonstrates a partial effect in preventing optic nerve atrophy. Thus, it stands as an effective method to reduce the disability rates and improve the daily living ability of patients with NMOSD., Competing Interests: Conflicts of Interest: Lou CY, None; Wang Y, None; Xing JY, None; Ma T, None; Tao L, None; Wang XT, None; Wang RS, None., (International Journal of Ophthalmology Press.)

Patients with neuromyelitis optica spectrum disorder (NMOSD) coexisting with both Sjögren's syndrome (SS) and pancytopenia are exceptionally rare. There is no study on the treatment of such patients. We presented a case of AQP4-IgG seropositive refractory NMOSD patient combined with SS and pancytopenia with significant response to inebilizumab. In 2017 the 49-year-old female patient was diagnosed with SS and pancytopenia without any treatment. In August 2022, she had a sudden onset of lower limbs weakness, manifested as inability to walk, accompanied by urinary incontinence. After receiving methylprednisolone and cyclophosphamide, she regained the ability to walk. In February 2023, she suffered from weakness of both lower limbs again and paralyzed in bed, accompanied by retention of urine and stool, and loss of vision in both eyes. After receiving methylprednisolone and three plasmapheresis, the condition did not further worsen, but there was no remission. In March 2023, the patient was admitted to our hospital and was formally diagnosed with AQP4-IgG seropositive NMOSD combined with SS and pancytopenia. After receiving two 300 mg injections of inebilizumab, not only the symptoms of NMOSD improved significantly, but also the symptoms of concurrent SS and pancytopenia. In the cases of AQP4-IgG seropositive NMOSD who have recurrent episodes and are comorbid with other autoimmune disorders, inebilizumab may be a good choice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Gao, He and Zhang.)

Introduction: Anti-aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) is a complement-mediated autoimmune disease in which unpredictable and relapsing attacks on the central nervous system cause irreversible and accumulating damage. Comparative efficacy of new NMOSD therapies, such as ravulizumab, with established therapies is critical in making informed treatment decisions., Methods: Efficacy of ravulizumab relative to established AQP4-Ab+ NMOSD treatments, such as eculizumab, inebilizumab, and satralizumab, was evaluated in a Bayesian network meta-analysis (NMA). Data were extracted from trials identified by a systematic literature review. The final evidence base consisted of 17 publications representing five unique and global studies (PREVENT, N-MOmentum, SAkuraSky, SAkuraStar, and CHAMPION-NMOSD). The primary endpoint was time-to-first relapse; other outcomes included annualized relapse rates (ARRs)., Results: For patients receiving monotherapy (monoclonal antibody only), ravulizumab was associated with a lower risk of relapse than inebilizumab (hazard ratio [HR] 0.09, 95% credible interval [CrI] 0.02, 0.57) or satralizumab (HR 0.08, 95% CrI 0.01, 0.55) and was comparable to eculizumab (HR 0.86, 95% Crl 0.16, 4.52). Ravulizumab + immunosuppressive therapy (IST) was associated with a lower risk of relapse than satralizumab + IST (HR 0.15, 95% CrI 0.03, 0.78); the comparison with eculizumab + IST suggested no difference. No patients treated with inebilizumab received background IST and were thus excluded from analysis. The ARR with ravulizumab monotherapy was 98% lower compared with inebilizumab (rate ratio [RR] 0.02, 95% Crl 0.00, 0.38) and satralizumab (RR 0.02, 95% Crl 0.00, 0.42) monotherapies. The ARR with ravulizumab ± IST showed the strongest treatment-effect estimates compared with other interventions., Conclusion: In the absence of head-to-head randomized controlled trials, NMA results suggest ravulizumab, a C5 inhibitor, is likely to be more effective in preventing NMOSD relapse in patients with AQP4-Ab+ NMOSD when compared with other treatments having different methods of action., (© 2024. The Author(s).)

Neuromyelitis optica spectrum disorder (NMOSD) is a rare but debilitating autoimmune disease of the central nervous system (CNS) for which several biotherapies have recently been approved on the market. Historically, NMOSD disease-modifying treatments relied on wide-spectrum off-label immunosuppressants, such as azathioprine, mycophenolate mofetil, and cyclophosphamide. Since 2015, evidence has accumulated to support off-label biotherapies (rituximab and tocilizumab) and to approve satralizumab, inebilizumab, eculizumab, and ravulizumab. This next generation of drugs provides several targeted disease-modifying treatment options for NMOSD. Here, we review this modern panel. We first review the mechanistic rationales associated with their specific targets. We then review the pivotal evidence supporting their use in practice and their respective regimens. Lastly, we discuss the positioning of each therapeutic class. The current therapeutic options in NMOSD comprise three targeted mechanisms at different stages of a unique tissue-injury cascade: B-cell depleting, anti-cytokine, and anti-complement therapies. One drug has been approved on the market in each class. The current consensus proposes positioning the approved drugs as first-line treatments for newly-diagnosed patients and as alternative therapies in case of failure of historical treatment. Yet, there has been limited acceptance in practice due to high drug prices., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Immunoglobulin G4-related disease (IgG4-RD) is a debilitating multiorgan disease characterized by recurring flares leading to organ dysfunction, decreased quality of life, and mortality. Glucocorticoids, the standard of care for IgG4-RD, are associated with substantial treatment-related toxicity. Inebilizumab, an antibody directed against CD19, mediates the rapid and durable depletion of CD19 + B cells thought to be involved in IgG4-RD pathogenesis. We describe the first international, prospective, double-blind, placebo-controlled trial to evaluate the safety and efficacy of B-cell depletion for flare prevention in IgG4-RD (MITIGATE)., Methods: The study was designed by an international panel of physicians with expertise in IgG4-RD. Critical trial design decisions included the selection of participants, definition of clinically meaningful primary and secondary endpoints, accommodation of standard of care, and development of flare diagnostic criteria. The study is approved for conduct in 22 countries., Planned Outcomes: The primary efficacy endpoint is time from randomization to the occurrence of the first centrally adjudicated and investigator-treated disease flare during the 1-year randomized controlled period. A set of novel, organ-specific flare diagnostic criteria were developed specifically for this trial, incorporating symptoms and signs, laboratory findings, imaging study results, and pathology data. MITIGATE aims to accrue 39 flares for the primary endpoint, which provides sufficient power to detect a relative risk reduction of 65% in the inebilizumab group. It is anticipated that enrollment of 160 participants will achieve this goal. Additional endpoints include safety, annualized flare rate, flare-free complete remission, quality-of-life measures, and cumulative glucocorticoid use. MITIGATE represents the first randomized, double-blind, placebo-controlled trial of any treatment strategy conducted in IgG4-RD. Data from this study will provide insights into the natural history and pathophysiology of IgG4-RD and the efficacy and safety of B-cell depletion as a therapeutic avenue., Trial Registration: NCT04540497., (© 2023. The Author(s).)

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition for which three treatments have been approved since 2019: eculizumab, inebilizumab, and satralizumab. We conducted a survey of U.S. academic neuroimmunologists to assess adoption of these therapies and barriers to use. Thirty-three neuroimmunologists from 18 states completed the survey. Nearly all (88 %) reported using the novel NMOSD treatments (NNTs). They uncommonly switched clinically stable patients to NNTs (69 % switched none, 22 % switched 1-25 % of their patients). For newly diagnosed patients, NNT initiation rates varied. Following relapse, respondents were dichotomized, either switching 75-100 % of patients (60 %) or 0-25 % (40 %). Insurance and cost-related barriers were common., Competing Interests: Declaration of Competing Interest Olga Thon has received financial compensation for her participation in advisory boards and speakers’ bureaus from Horizon Therapeutics. None of the other authors have disclosures., (Copyright © 2023. Published by Elsevier B.V.)

Monoclonal antibody therapies mark the new era of targeted treatment for relapse prevention in aquaporin-4 (AQP4)-immunoglobulin G (IgG)-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD). For over a decade, rituximab, an anti-CD20 B-cell-depleting agent, had been the most effectiveness treatment for AQP4-IgG+NMOSD. Tocilizumab, an anti-interleukin-6 receptor, was also observed to be effective. In 2019, several randomized, placebo-controlled trials were completed that demonstrated the remarkable efficacy of eculizumab (anti-C5 complement inhibitor), inebilizumab (anti-CD19 B-cell-depleting agent), and satralizumab (anti-interleukin-6 receptor), leading to the Food and Drug Administration (FDA) approval of specific treatments for AQP4-IgG+NMOSD for the first time. Most recently, ravulizumab (anti-C5 complement inhibitor) was also shown to be highly efficacious in an open-label, external-controlled trial. Although only some patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) warrant immunotherapy, there is currently no FDA-approved treatment for relapse prevention in MOGAD. Observational studies showed that tocilizumab was associated with a decrease in relapses, whereas rituximab seemed to have less robust effectiveness in MOGAD compared to AQP4-IgG+NMOSD. Herein, we review the evidence on the efficacy and safety of each monoclonal antibody therapy used in AQP4-IgG+NMOSD and MOGAD, including special considerations in children and women of childbearing potential., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Saudi Journal of Ophthalmology.)

Background: The Italian National Health Service (INHS) has recently reimbursed the monoclonal antibody inebilizumab as a second line monotherapy after rituximab (RTX) use for neuromyelitis optica spectrum disorders (NMOSD) patients ≥ 18 years anti-aquaporin 4 antibody-immunoglobulin G positive, who experienced a relapse in the last year or cannot receive RTX, if incident patients. Other INHS-reimbursed drugs for NMOSD treatment are satralizumab, eculizumab and, off-label, besides RTX, ocrelizumab, tocilizumab, and immunosuppressants., Research Design and Methods: A 3-year (2023-2025) prevalence-based budget impact model following the INHS viewpoint compared the costs and the NMOSD attacks without (1st scenario) and with inebilizumab (2nd scenario). The epidemiology of NMOSD, and the INHS-funded healthcare resources (drugs and their administration; specialist visits; hospitalizations due to drug-related adverse events and NMOSD attacks) were obtained from the literature. One-way, threshold value and scenario sensitivity analyses investigated the robustness of the baseline findings., Results: During 2023-2025 inebilizumab saves the INHS €8,373,125.13 (1st scenario: €176,770,028.63; 2nd scenario: €168,396,903.50) and 12.74 NMOSD attacks (1st scenario: 213.94; 2nd scenario: 201.19). Sensitivity analyses confirmed the robustness of the baseline results., Conclusion: Inebilizumab reduces the INHS expenditure for NMOSD drugs. Future research should explore the cost-effectiveness of inebilizumab vs other NMOSD-targeting drugs in Italy.

Background: The N-MOmentum trial investigated safety and efficacy of inebilizumab in participants with neuromyelitis optica spectrum disorder (NMOSD)., Objective: Evaluate the attack identification process and adjudication committee (AC) performance in N-MOmentum., Methods: Adults ( n = 230) with NMOSD and Expanded Disability Status Scale score ⩽8 were randomized (3:1) to inebilizumab 300 mg or placebo. The randomized controlled period was 28 weeks or until adjudicated attack. Attacks were adjudicated according to 18 predefined criteria. Magnetic resonance imaging (MRI) and biomarker (serum glial fibrillary acidic protein [sGFAP]) analyses were performed., Results: A total of 64 participant-reported neurological events occurred; 51 (80%) were investigator-determined to be attacks. The AC confirmed 43 of the investigator-determined attacks (84%). There was high inter- and intra-AC-member agreement. In 25/64 events (39%) and 14/43 AC-adjudicated attacks (33%), MRI was reviewed during adjudication. Retrospective analysis revealed new domain-specific T1 and T2 MRI lesions in 90% of adjudicated attacks. Increased mean sGFAP concentrations (>2-fold change) from baseline were observed in 56% of adjudicated attacks versus 14% of investigator-determined attacks rejected by the AC and 31% of participant-reported events determined not to be attacks., Conclusion: AC adjudication of NMOSD attacks according to predefined criteria appears robust. MRI lesion correlates and sGFAP elevations were found in most adjudicated attacks.

Neuromyelitis Optica spectrum disorder (NMOSD) is a relapsing autoimmune disease of the central nervous system (CNS) where aquaporin-4 water channels are the antigenic target of the disease. The spectrum of the disease involves regions of the CNS where the water channel is widely expressed including the spinal cord, the optic nerve, dorsal medulla, brainstem, and thalamus/hypothalamus. Management of NMOSD includes acute as well as long term treatment. Acute symptoms are typically treated with intravenous corticosteroids and/or plasma exchange while long-term treatment involves the use of immunosuppression/immune modulation. The year 2019 is thought to be the "year of the NMOSD" as three new medications became available for this devastating disease. In this review, FDA approved NMOSD medications are discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sudhakar, Abusamra, Thandampallayam and Kini.)

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system mediated by antibodies targeting the aquaporin-4 (AQP4) water channel expressed on astrocytes. The binding of specific antibodies to AQP4 causes complement-dependent cytotoxicity, leading to inflammation and demyelination. Several recent phase 2 and 3 randomized placebo-controlled trials showed the efficacy and safety of monoclonal antibody therapies targeting B-cells, interleukin-6 receptor, and complement., Areas Covered: Current biologic treatments for NMOSD and developments therein, and unresolved issues in NMOSD treatment., Expert Opinion: New biologic treatments demonstrate high efficacy and good safety for patients with AQP4-IgG-positive NMOSD. The optimal therapeutics for seronegative NMOSD, pediatric patients, and female patients who are pregnant or wish to be are unclear, and further research is needed. Also, real-world studies of new biological agents and the data on the durability of their beneficial effects and their long-term safety are required. Effective rescue therapy for an acute attack is critical given permanent disability in NMOSD is attack-related, and biologic agents that treat acute attack are emerging. If such treatments are to become widely applied, studies on the most cost-effective treatment strategies are needed.

Optic neuritis, an optic nerve inflammatory disease presenting with acute unilateral or bilateral visual loss, is one of the core symptoms of neuromyelitis optica spectrum disorder (NMOSD). The diagnosis of NMOSD-related optic neuritis is challenging, and it is mainly based on clinical presentation, optical coherence tomography, magnetic resonance imaging scans, and the status of serum aquaporin-4 antibodies. In the pathogenesis, aquaporin-4 antibodies target astrocytes in the optic nerves, spinal cord and some specific regions of the brain eliciting a devastating autoimmune response. Current pharmacological interventions are directed against various steps within the immunological response, notably the terminal complement system, B-cells, and the pro-inflammatory cytokine Interleukin 6 (IL6). Conventional maintenance therapies were off-label uses of the unspecific immunosuppressants azathioprine and mycophenolate mofetil as well as the CD20 specific antibody rituximab and the IL6 receptor specific antibody tocilizumab. Recently, four phase III clinical trials demonstrated the safety and efficacy of the three novel biologics eculizumab, inebilizumab, and satralizumab. These monoclonal antibodies are directed against the complement system, CD19 B-cells and the IL6 receptor, respectively. All three have been approved for NMOSD in the US and several other countries worldwide and thus provide convincing treatment options., Competing Interests: The authors declare that there are no conflicts of interests of this paper., (Copyright: © 2022 Taiwan J Ophthalmol.)

Aims: Neuromyelitis optica spectrum disorders (NMOSD) is an autoantibody-mediated, B cell-driven disease. Inebilizumab is a humanized, affinity-optimized, afucosylated IgG1 κ monoclonal antibody that binds to the B-cell specific surface antigen CD19, resulting in rapid, profound and sustained depletion of circulating peripheral B cells in NMOSD subjects (pivotal study). The objective of this study was to conduct population modelling of B-cell response following inebilizumab treatment in adult subjects with NMOSD, and to assess the impact of drug exposure to outcome., Methods: A haematopoietic transit model was developed to describe the joint effects of reducing influx from pro-B cells and accelerating CD20 +  B-cell depletion in the blood by inebilizumab. Furthermore, the relationships between inebilizumab pharmacokinetic (PK) exposure and the primary efficacy endpoint and key secondary efficacy endpoints were evaluated., Results: At the 300-mg dose, there was no apparent relationship between efficacy (reduction in disease attack risk, risk of worsening from baseline in Expanded Disability Status Scale, cumulative total active MRI lesions, and the number of NMOSD-related in-patient hospitalizations) and PK exposure. Subjects with low, medium and high PK exposure had a similar hazard ratio of NMOSD attack vs. placebo group., Conclusion: The pharmacodynamic modelling confirmed effective depletion of B cells is achieved with a 300 mg intravenous dose of inebilizumab administered on Day 1 and Day 15 and every 6 months thereafter. The PK variability between patients had no apparent effect on clinical efficacy., (© 2022 Horizon Therapeutics. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on British Pharmacological Society.)

Neuromyelitis optica spectrum disorders (NMOSD) are rare neurologic autoimmune diseases that have a poor prognosis if left untreated. For many years, generic oral immunosuppressants and repurposed monoclonal antibodies that target the interleukin-6 pathway or B cells were the mainstays of drug treatment. Recently, these drug treatments have been complemented by new biologics developed and approved specifically for NMOSD. In principle, all of these drugs are effective, but treatment recommendations that take this into account are still pending. Instead, the choice of a drug may depend on other criteria such as drug safety or tolerability. In this review, we summarise current knowledge on the adverse effects of azathioprine, mycophenolate mofetil, rituximab, tocilizumab, eculizumab, satralizumab, and inebilizumab in NMOSD. Infections, cytopenias, and infusion-related reactions are most common, but the data are as heterogeneous as the manifestations are diverse. Nevertheless, knowledge of safety issues may facilitate treatment choices for individual patients.

Aquaporin-4 (AQP4)-IgG seropositive neuromyelitis optica spectrum disorders (AQP4-IgG seropositive NMOSD) and myelin oligodendrocyte glycoprotein (MOG)-IgG-associated disease (MOGAD) are inflammatory demyelinating disorders distinct from each other and from multiple sclerosis (MS).While anti-CD20 treatments can be used to treat MS and AQP4-IgG seropositive NMOSD, some MS medications are ineffective or could exacerbate AQP4-IgG seropositive NMOSD including beta-interferons, natalizumab, and fingolimod. AQP4-IgG seropositive NMOSD has a relapsing course in most cases, and preventative maintenance treatments should be started after the initial attack. Rituximab, eculizumab, inebilizumab, and satralizumab all have class 1 evidence for use in AQP4-IgG seropositive NMOSD, and the latter three have been approved by the US Food and Drug Administration (FDA). MOGAD is much more likely to be monophasic than AQP4-IgG seropositive NMOSD, and preventative therapy is usually reserved for those who have had a disease relapse. There is a lack of any class 1 evidence for MOGAD preventative treatment. Observational benefit has been suggested from oral immunosuppressants, intravenous immunoglobulin (IVIg), rituximab, and tocilizumab. Randomized placebo-controlled trials are urgently needed in this area., (© 2022. The American Society for Experimental NeuroTherapeutics, Inc.)

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease defined by attacks on the central nervous system that cause irreversible damage. Recent approval of NMOSD therapies warrants investigations of comparative efficacy to inform treatment decisions., Methods: A network meta-analysis (NMA) of all U.S. Food and Drug Administration-approved therapies (eculizumab, inebilizumab, and satralizumab) for adults with aquaporin-4 immunoglobulin G-positive (AQP4+) NMOSD was conducted via a systematic literature review (SLR) using data from randomized controlled trials (RCTs). Database searches of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were executed for the SLR. A fixed-effects proportional hazards Bayesian NMA was used to estimate relative treatment effects based on data extracted from RCTs identified during the SLR (search end date: 11 September 2020). Four unique RCTs (N-MOmentum, PREVENT, SAkuraSky, and SAkuraStar) were identified, and data from 29 publications were extracted for analysis. Network scenarios describing the most comparable patient population groups (such as by treatment settings) were evaluated in our analyses. Relative treatment effects were evaluated based on time-to-first relapse and were expressed as hazard ratios (HRs) with 95% credible intervals (CrIs)., Results: In patients treated with a monoclonal antibody only, eculizumab was associated with a lower risk of relapse compared with satralizumab (HR 0.10, 95% CrI 0.01, 0.65) and inebilizumab (HR 0.11, 95% CrI 0.02, 0.68). In patients treated with monoclonal antibody with or without background immunosuppressive therapy (IST), patients treated with eculizumab ± IST were also less likely to relapse than patients treated with satralizumab ± IST (HR 0.24, 95% CrI 0.06, 0.98)., Conclusion: The NMA results suggest that complement component 5 (C5) inhibition prevents NMOSD relapses more effectively than broader mechanisms of action., (© 2021. The Author(s).)

Background: The N-MOmentum trial, a double-blind, randomized, placebo-controlled, phase 2/3 study of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD), enrolled participants who were aquaporin-4-immunoglobulin G (AQP4-IgG)-seropositive (AQP4+) or -seronegative (AQP4-). This article reports AQP4- participant outcomes., Methods: AQP4-IgG serostatus was determined for all screened participants by a central laboratory, using a validated, fluorescence-observation cell-binding assay. Medical histories and screening data for AQP4- participants were assessed independently by an eligibility committee of three clinical experts during screening. Diagnosis of NMOSD was confirmed by majority decision using the 2006 neuromyelitis optica criteria. Myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) serology (using a clinically validated, flow cytometry assay) and annualized attack rates (AARs) were evaluated post hoc. Efficacy outcomes were assessed by comparing pre-study and on-study AARs in treated participants., Results: Only 18/50 AQP4- screened participants (36%) were initially considered eligible for randomization; 16 were randomized and received full treatment, 4 to placebo (1 MOG-IgG-seropositive [MOG+]) and 12 to inebilizumab (6 MOG+). The most common reason for failure to pass screening among prospective AQP4- participants was failure to fulfill the 2006 NMO MRI criteria. In inebilizumab-treated AQP4- participants, on-study AARs (95% confidence interval [CI]) calculated from treatment initiation (whether from randomization or when received at the start of the open-label period) to the end of study were lower than pre-study rates: for all AQP4- participants (n = 16), mean (95% CI) AAR was 0.048 (0.02-0.15) versus 1.70 (0.74-2.66), respectively. For the subset of AQP4-/MOG+ participants (n = 7), AAR was 0.043 (0.006-0.302) after treatment versus 1.93 (1.10-3.14) before the study. For the subset of AQP4-/MOG- participants (n = 9), post-treatment AAR was 0.051 (0.013-0.204) versus 1.60 (1.02-2.38). Three attacks occurred during the randomized controlled period in the AQP4- inebilizumab group and were of mild severity; no attacks occurred in the AQP4- placebo group. The low number of participants receiving placebo (n = 4) confounds direct comparison with the inebilizumab group. No attacks were seen in any AQP4- participant after the second infusion of inebilizumab. Inebilizumab was generally well tolerated by AQP4- participants and the adverse event profile observed was similar to that of AQP4+ participants., Conclusion: The high rate of rejection of AQP4- participants from enrollment into the study highlights the challenges of implementing the diagnostic criteria of AQP4- NMOSD. An apparent reduction of AAR in participants with AQP4- NMOSD who received inebilizumab warrants further investigation., (Copyright © 2021. Published by Elsevier B.V.)

Background: The B-cell-depleting agent rituximab (anti-CD20) was historically used to prevent attacks in neuromyelitis optica spectrum disorder (NMOSD). Inebilizumab, which targets and depletes CD19-expressing B cells, plasmablasts, and some plasma cells, received approval from the US Food and Drug Administration for treatment of NMOSD based on results from the randomized, placebo-controlled, phase 2/3 N-MOmentum trial. Because of their closely related mechanisms of action, consideration as to whether inebilizumab may be a suitable treatment option for patients with prior rituximab experience is important. This post hoc analysis of data from N-MOmentum assessed inebilizumab efficacy and tolerability in participants previously treated with rituximab., Methods: Adjudicated attacks, secondary efficacy outcomes, and treatment-emergent adverse events were assessed by prior rituximab use during a 6-month randomized control period and open-label period., Results: Seventeen participants in N-MOmentum had prior rituximab use, of whom 13 were randomly assigned to the inebilizumab treatment group. Seven of these participants had breakthrough attacks prior to enrollment (annualized attack rate, 0.78 attacks/person-year) despite rituximab use. While they were receiving inebilizumab in the randomized control period, 1 of 13 participants with prior rituximab use had an attack (hazard ratio vs all placebo, 0.16; 95% confidence interval: 0.02 1.20; p = 0.07). Two additional participants with prior rituximab use experienced attacks on inebilizumab during the open-label period, with an overall annualized attack rate of 0.08 (95% confidence interval: 0.02 0.34) attacks/person-year. This annualized attack rate was similar to that of participants without prior rituximab use (0.10 [95% confidence interval: 0.07 0.15]). None of the 7 participants who experienced attacks while taking rituximab experienced an attack while receiving inebilizumab. Two (12%) participants with prior rituximab use experienced serious treatment-emergent adverse events related to inebilizumab, with serious or grade ≥3 infections occurring in 3 (18%) participants each. No deaths or opportunistic infections were reported in this cohort., Conclusions: These findings support the efficacy of inebilizumab in participants with NMOSD who had previously been treated with rituximab. Infections occurred in nearly all study participants with prior rituximab exposure, highlighting a need for clinical vigilance in such individuals. Further studies are necessary to determine potential safety concerns of inebilizumab, including risk of infection, in rituximab-experienced patients. ClinicalTrials.gov identifier: NCT02200770., (Copyright © 2021. Published by Elsevier B.V.)

Background: In the N-MOmentum trial, the risk of an adjudicated neuromyelitis optica spectrum disorder (NMOSD) attack was significantly reduced with inebilizumab compared with placebo., Objective: To demonstrate the robustness of this finding, using pre-specified sensitivity and subgroup analyses., Methods: N-MOmentum is a prospective, randomized, placebo-controlled, double-masked trial of inebilizumab, an anti-CD19 monoclonal B-cell-depleting antibody, in patients with NMOSD. Pre-planned and post hoc analyses were performed to evaluate the primary endpoint across a range of attack definitions and demographic groups, as well as key secondary endpoints., Results: In the N-MOmentum trial (ClinicalTrials.gov: NCT02200770), 174 participants received inebilizumab and 56 received placebo. Attack risk for inebilizumab versus placebo was consistently and significantly reduced, regardless of attack definition, type of attack, baseline disability, ethnicity, treatment history, or disease course (all with hazard ratios < 0.4 favoring inebilizumab, p < 0.05). Analyses of secondary endpoints showed similar trends., Conclusion: N-MOmentum demonstrated that inebilizumab provides a robust reduction in the risk of NMOSD attacks regardless of attack evaluation method, attack type, patient demographics, or previous therapy.The N-MOmentum study is registered at ClinicalTrials.gov: NCT2200770.

Treatment and new evidences in neuromyelitis optica spectrum disorder Illés Zs, MD, PhD Ideggyogy Sz 2021;74(9-10):309-321. Neuromyelitis optica spectrum disorder (NMOSD) is associated with antibodies against AQP4 in about 80% of the cases. In about one-fourth of seronegative cases, antibodies against the MOG protein are present in the serum (MOG-antibody associated disease, MOGAD). This article discusses off-label azathioprine and mycophenolate mofetil in the treatment of NMOSD and reviews the evidence-based clinical aspects of B/plasma cell depletion, antagonization of IL-6 signaling and blocking the complement pathway. The review also summarizes basic aspects of NMOSD pregnancy focusing on treatment, and the different therapeutic approach in MOGAD. In the recent two years, phase 3 clinical trials provided class I evidence for the efficacy and safety of rituximab (anti-CD20), inebilizumab (anti-CD19), tocilizumab (anti-IL6R), satralizumab (anti-IL6R), and eculizumab (anti-C5) in combination with other immunosuppressants or in monotherapy. The treatment approach in MOGAD is complicated by the monophasic course in about half of the cases and by the potential disappearance of MOG antibody. The necessity of maintenance treatment in MOGAD should be decided after tapered oral steroid. Immunosuppression is recommended in NMOSD during pregnancy and lactation, and this should be considered for optimal selection of treatment in fertile female patients. The new monoclonal antibodies broadened treatment options NMOSD, and the treatment strategy of MOGAD has become more straightforward.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare relapsing autoimmune disease of the central nervous system that preferentially targets the optic nerves and spinal cord, leading to visual loss and impaired mobility. Until 2019, no medications were FDA-approved for NMOSD treatment, and standard of care was based on mostly empiric and retrospective data. Therapies that target B cells emerged as a treatment strategy due to their fundamental role in disease pathogenesis. We explore different monoclonal antibodies directed at either CD20+ or CD19+ B cells that may have utilization in the treatment of NMOSD, discussing what is known regarding their efficacy and safety., Competing Interests: Michael Levy has received consulting income from Horizon Therapeutics (manufacturer of inebilizumab), Genentech (manufacturer of rituximab), Alexion, UCB Pharmaceuticals and Mitsubishi Pharmaceuticals. He has also received grants from these companies funding research at Massachusetts General Hospital. Maureen A. Mealy works for Horizon Therapeutics, the manufacturer of inebilizumab. Her contribution to the manuscript herein does not necessarily represent the views of Horizon Therapeutics. The authors report no other potential conflicts of interest for this work., (© 2021 Levy and Mealy.)

Background: To update the efficacy and safety data of monoclonal antibodies for the treatment of neuromyelitis optica spectrum disorders (NMOSD) and explore the differences in the effect of treatment between patients seropositive and seronegative for AQP4-IgG., Methods: PubMed, Embase, and the Cochrane Library published up to July 2020 were searched for randomized controlled trials (RCTs) of monoclonal antibodies treatment (mAb) in patients with NMOSD. The primary outcome was the hazard ratio (HR) for relapse. The secondary outcomes included Expanded Disability Status Scale (EDSS) changes from baseline, adverse events (AEs), and serious adverse events (SAEs). A random-effects model was applied for the effect of heterogeneity among trials., Results: We included 603 patients (monoclonal antibody group, n =382, and control group, n =221) from seven RCTs. There were fewer relapses in the mAb group (HR=0.32, 95% CI: 0.23-0.46, p <0.001), as well as in the AQP4-IgG-seropositive patients (HR=0.18, 95% CI: 0.10-0.32, p <0.001), but not in AQP4-IgG-seronegative NMOSD. Similar results were observed when considering satralizumab only. The mAb had no impact on the changes in EDSS scores from baseline (WMD=-0.21, 95% CI: -0.50-0.09, p =0.176). The mAb did not lead to a higher frequency of AEs (OR=1.18, 95% CI: 0.70-1.98, p =0.529) or SAEs (OR=0.99, 95% CI: 0.63-1.56, p =0.975) compared with the control group., Conclusions: Compared to the control arm, monoclonal antibody therapy showed a significantly better outcome in restraining the HR for relapse among patients with NMOSD but insignificant effects in NMOSD patients with seronegative APQ4-IgG. The safety profile in each arm had no significant difference., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kong, Wang, Zheng, Cai, Hua and Li.)

Until recently, the use of preventative immunotherapy in neuromyelitis optica spectrum disorders (NMOSD) was based on observational studies and clinical experiences. Meanwhile, the first drugs, among others the monoclonal antibody inebilizumab, were approved for the treatment of aquaporin-4 (AQP4) antibody-positive NMOSD. Inebilizumab binds to the CD19 antigen on B cells and leads to B-cell depletion. The first two dosages of 300 mg inebilizumab are administered intravenously at an interval of 2 weeks followed by further infusions every 6 months. In the placebo-controlled pivotal phase II/III study N-MOmentum, inebilizumab significantly prolonged the time to a first adjudicated relapse in AQP4 antibody-positive patients compared with placebo. The most frequent side effects were infusion reactions, urinary and respiratory tract infections, and arthralgia. This review presents data on clinical and preclinical pharmacology, administration, safety aspects and clinical trials of inebilizumab., (Copyright 2021 Clarivate Analytics.)

Background: Neuromyelitis Optica spectrum disorder (NMOSD) is an inflammatory disease, which manifests mostly as recurrent episodes of optic neuritis or myelitis that cause important disability. Early diagnosis and prompt initiation of immunosuppressive therapy are crucial in reducing relapses, disability, and mortality. Even though, there are few prospective randomized controlled trials, several drugs have proved to be both effective and safe. Azathioprine and Rituximab represent the standard of care and are used as first-line treatment agents worldwide. However, recent studies have unveiled new therapies, such as monoclonal antibodies. To make treatment recommendations and management guidelines, it is imperative to define an appropriate standard of care., Methods: A systematic literature review was performed in MEDLINE, EMBASE, and LILACS databases using the following terms: "(NMO OR Devic OR Neuromyelitis Optica) AND (Azathioprine OR Prednisone OR Rituximab OR Tocilizumab OR Bortezomib OR Inebilizumab OR Eculizumab OR Satralizumab)" including both, randomized clinical trials and observational studies published between January 2006 and January 2021. The inclusion criteria comprised patients aged 18 or older, NMOSD diagnosis following the Wingerchuck criteria, two or more therapies been compared, and the evaluation of both efficacy and safety outcomes. All studies comparing treatment only with placebo were excluded. Quality was assessed according with the design of the study, and results were synthesized through comparative tables for each outcome evaluated, differentiating the results of randomized and non-randomized studies., Results: Thirteen studies with 1447 patients were included. Twelve studies evaluated the expanded disability status scale (EDSS) before and after treatment; in five of seven evaluating rituximab, it outperformed its comparators in improving the disability degree. Eleven studies assessed the annual relapse rate (ARR). Again, in six of seven evaluating rituximab, it was superior to other therapies. Time to relapse (TTR) was reported in five studies. The three studies that included Rituximab revealed a longer time to relapse in this arm of treatment. Finding were consistent in randomized and non-randomized studies. The new molecules Satralizumab, Eculizumab and Tocilizumab were evaluated in one study each, proving to be highly effective and safe. The safety profile analysis showed a higher number of adverse events for Azathioprine., Discussion: This systematic review demonstrates a superiority tendency of Rituximab upon the other treatments strengthening the available evidence about NMOSD management. Superiority in EDSS outcomes, annual relapse rate, time to first relapse and relapses during treatment time was evidenced in the Rituximab group compared to other medications, with lower rates of adverse events. New molecules Tocilizumab, Eculizumab and Satralizumab also showed superiority in the evaluated results, especially in the relapses during treatment time outcome, although with subtle differences in EDSS and ARR outcomes., Conclusion: Our results suggest that monoclonal antibodies are highly effective and safe for the treatment of NMOSD; Rituximab showed better performance on multiple outcomes and has more evidence available. New molecules: Eculizumab, Tocilizumab, Satralizumab are good options for treatment. Drugs like Azathioprine and Mycophenolate are effective, but with a worse risk-benefit ratio, therefore, they are useful alternatives in places that do not have access to monoclonal antibodies., (Copyright © 2021. Published by Elsevier B.V.)

The first description of neuromyelitis optica by Eugène Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica spectrum disorders (NMOSD) are now considered autoantibody-mediated autoimmune diseases, bringing the pivotal pathogenetic role of B cells and plasma cells into focus. Not long ago, there was no approved medication for this deleterious disease and off-label therapies were the only treatment options for affected patients. Within the last years, there has been a tremendous development of novel therapies with diverse treatment strategies: immunosuppression, B cell depletion, complement factor antagonism and interleukin-6 receptor blockage were shown to be effective and promising therapeutic interventions. This has led to the long-expected official approval of eculizumab in 2019 and inebilizumab in 2020. In this article, we review current pathogenetic concepts in NMOSD with a focus on the role of B cells and autoantibodies as major contributors to the propagation of these diseases. Lastly, by highlighting promising experimental and future treatment options, we aim to round up the current state of knowledge on the therapeutic arsenal in NMOSD.

Introduction: Treatment options for patients suffering from neuromyelitis optica spectrum disorders (NMOSD) so far have relied on off-label and empiric drugs. The first drug for the therapy of anti-aquaporin-4 (AQP4) antibody-seropositive NMOSD patients has been approved in 2019: the C5 complement inhibitor eculizumab. The interleukin-6 receptor inhibitor satralizumab and anti-CD19 antibody inebilizumab have published positive phase III trial results and await approval in the near future., Areas Covered: We sum up current treatment options and portray in detail the new developments in NMOSD drugs focusing on phase III clinical trials, followed by an overview of emerging drugs in less advanced clinical trial stages., Expert Opinion: Eculizumab's approval by the competent authorities marks a milestone in NMOSD treatment. Satralizumab and inebilizumab will most likely follow in approval given their presented results in efficacy and safety. All three drugs have shown efficacy in reducing relapse rates in NMOSD patients with anti-AQP4 antibodies. Although we will have even more evidence-based therapy options in the future, empirically used medications will keep their importance for now. The potential effect of new medications in AQP4 antibody-seronegative NMOSD and patients with an NMOSD phenotype and antibodies to myelin oligodendrocyte glycoprotein remains to be determined.

Introduction: Evidence-based treatment options for neuromyelitis optica spectrum disorders (NMOSD) patients are beginning to enter the market. Where previously, there was only the exclusive use of empiric and off-label immunosuppressants in this rare and devastating central nervous system autoimmune disease., Areas Covered: In accordance to expanding pathogenetic insights, drugs in phase II and III clinical trials are presented in the context of the current treatment situation for acute attacks and immunopreventative strategies in NMOSD. Some such drugs are the 2019-approved complement inhibitor eculizumab, other compounds in late development include its modified successor ravulizumab, IL-6 receptor antibody satralizumab, CD19 targeting antibody inebilizumab and the TACI-Fc fusion protein telitacicept., Expert Opinion: Moving from broad immunosuppression to tailored treatment strategies, the prospects for efficient NMOSD therapy are positive. For the first time in this disease, class I treatment evidence is available, but long-term data will be necessary to confirm the overall promising study results of the compounds close to approval. While drug development still centers around AQP4 antibody seropositive patients, current and future research requires consideration of possible diverging treatment demands for the smaller group of seronegative patients and patients with presence of MOG antibodies.

Background: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies., Aims: To review, from an Infectious Diseases perspective, the safety profile of agents targeting CD19, CD20 and CD52 and to suggest preventive recommendations., Sources: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family., Content: Although CD19-targeted agents (blinatumomab or inebilizumab) are not associated with an increased risk of infection, they may cause IgG hypogammaglobulinaemia and neutropenia. The requirement for prolonged intravenous infusion of blinatumomab may increase the risk of catheter-associated bloodstream infections. Infection remains the most common non-haematological adverse effect of anti-CD20 monoclonal antibodies, including severe respiratory tract infection, hepatitis B virus (HBV) reactivation and varicella-zoster virus infection. Screening for chronic or resolved HBV infection is recommended for patients receiving anti-CD20 monoclonal antibodies. Antiviral prophylaxis should be offered for 12-18 months to hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative/anti-hepatitis B core antibody (HBc)-positive patients. Anti-Pneumocystis prophylaxis should be considered in patients receiving concomitant chemotherapy, particularly steroids. Alemtuzumab (anti-CD52) increases the risk of infections, in particular among leukaemia and solid organ transplant patients. These populations benefit from anti-Pneumocystis prophylaxis, prevention strategies for cytomegalovirus infection, and screening for HBV, hepatitis C virus and tuberculosis. Antiviral prophylaxis for at least 6-12 months should be provided for HBsAg-positive patients., Implications: As there are limited clinical data for many of the reviewed agents, special attention must be given to promptly detect and report emerging infectious complications., (Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Mice transgenic for human CD19 have been an important animal model to help understand the role of this molecule in B lymphocyte function. Previously, no lifetime studies had been performed to understand the effects of this CD19 over expression on the survival or spontaneous pathology within the C57BL/6J background strain. We conducted a lifetime study with interim sacrifices to understand the transgenic effects on clinical signs, body weight, survival, and spontaneous pathology. Blood and urine samples were collected from select animals at various time points during the study for measurement of clinical pathology parameters and groups of animals were euthanized and examined at predetermined intervals. There was fair survival with some animals living to 108 weeks of age. Clinical pathology evaluations revealed a declining red cell mass with a regenerative anemia, increasing total white blood cell counts and decreasing glucose level. Total protein, albumin, and globulin levels increased to 52 weeks of age and then declined to or below baseline with advancing age. Increased urinary microalbumin levels correlated with the severity of a glomerulopathy at 76 and 84 weeks of age. Mean body weight increased through 70 weeks and then declined to weights similar to week 28 at 108 weeks. Macroscopic observations included pale kidneys, enlarged seminal vesicles, and enlarged spleens (at 108 weeks of age). The most common neoplasms in this study were bronchiolar alveolar adenomas in the lung, histiocytic sarcoma in several different tissues, and hepatocellular adenomas. The most common non-neoplastic lesions were renal glomerulopathy, and pulmonary lymphocytic infiltrates with increased numbers of alveolar macrophages.