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.

/pdf/adverse-events-in-nmosd-therapy-2msa72kk.pdf

Adverse Events in NMOSD Therapy

The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating, and categorizing indications for the evidence‐based use of therapeutic apheresis (TA) in human disease. In the Ninth Edition, the JCA Special Issue Writing Committee has incorporated systematic review and evidence‐based approaches in the grading of evidence and categorization of apheresis indications to make recommendations on the use of apheresis in a wide variety of diseases and conditions. This edition has largely maintained the general layout and concept of a fact sheet introduced in the Fourth Edition (2007). Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease or medical condition. The Ninth Edition of the JCA Special Issue comprises 91 fact sheets and 166 graded and categorized indications. This includes seven new fact sheets, nine new indications on existing fact sheets, and eight changes in the category for existing indications. The Ninth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.

Guidelines on the Use of Therapeutic Apheresis in Clinical Practice – Evidence‐Based Approach from the Writing Committee of the American Society for Apheresis: The Ninth Special Issue

Comparison on the effect of seven drugs to prevent relapses of neuromyelitis optica spectrum disorders: A modeling analysis of literature aggregate data.

Inebilizumab (Uplizna®) is a recently approved monoclonal antibody for use in adults with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody seropositive. Inebilizumab targets the B cell antigen CD19 and effectively depletes circulating B cells, thus suppressing inflammatory NMOSD attacks that are potentially disabling or life-threatening. It is approved as an intravenous infusion in several countries. In the pivotal phase 2/3 N-MOmentum trial, inebilizumab reduced the risk of NMOSD attacks compared with placebo, including in AQP4-antibody seropositive patients. Inebilizumab also significantly reduced the risk of disability score worsening, the number of NMOSD-related hospitalisations and MRI lesion count, but had no significant effect on low-contrast binocular vision. The treatment effect on relapse risk and disability scores was sustained in inebilizumab-treated patients for ≥ 4 years during the open-label extension. Inebilizumab was generally well tolerated, with the most common adverse events being urinary tract infection and arthralgia. Thus, inebilizumab is an effective treatment option for adults with AQP4-antibody seropositive NMOSD.Neuromyelitis optica spectrum disorder (NMOSD) is a chronic condition denoted by relapsing autoimmune attacks affecting the central nervous system, which may lead to accruing disability or death. It is frequently associated with anti-aquaporin-4 (AQP4) autoantibodies. In recent years, three new monoclonal antibody therapies have gained regulatory approval for the treatment of NMOSD. Inebilizumab (Uplizna®), a monoclonal antibody that targets B cells, is approved for use in AQP4-antibody seropositive adults as an intravenous infusion. Inebilizumab was effective at preventing NMOSD relapse compared with placebo in a pivotal phase 2/3 trial. It also prevented worsening of disability scores, and decreased the number of NMOSD-related hospitalisations and MRI lesions, but did not significantly improve low-contrast binocular vision. The clinical benefit of inebilizumab was maintained long-term (≥ 4 years in the open-label extension). Inebilizumab was generally well tolerated, with most adverse events being mild to moderate in severity. The most common adverse events were urinary tract infection and joint pain. Inebilizumab provides an effective option for preventing NMOSD attacks in adults who are AQP4-antibody seropositive. 

https://link.springer.com/content/pdf/10.1007/s40263-022-00949-7.pdf

Inebilizumab: A Review in Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica spectrum disorders (NMOSD) are characterized in the majority of cases by the presence of IgG1 autoantibodies against aquaporin 4 (AQP4) and myelin-oligodendrocyte glycoprotein (MOG), both capable of activating complement.We review evidence of complement involvement in NMOSD pathophysiology from pathological, in vitro, in vivo, human studies, and clinical trials.In AQP4 NMOSD, complement deposition is a prominent pathological feature, while in vitro and in vivo studies have demonstrated complement-dependent pathogenicity of AQP4 antibodies. Consistent with these studies, the anti-C5 monoclonal antibody eculizumab was remarkably effective and safe in a phase 2/3 trial of AQP4-NMOSD patents leading to FDA-approved indication. Several other anti-complement agents, either approved or in trials for other neuro-autoimmunities, like myasthenia, CIDP, and GBS, are also relevant to NMOSD generating an exciting group of evolving immunotherapies. Limited but compelling in vivo and in vitro data suggest that anti-complement therapeutics may be also applicable to a subset of MOG NMOSD patients with severe disease. Overall, anticomplement agents, along with the already approved anti-IL6 and anti-CD19 monoclonal antibodies sartralizumab and inebilizumab, are rapidly changing the therapeutic algorithm in NMOSD, a previously difficult-to-treat autoimmune neurological disorder. 

https://www.tandfonline.com/doi/pdf/10.1080/1744666X.2022.2105205?needAccess=true

The role of complement and complement therapeutics in neuromyelitis optica spectrum disorders

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. 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). 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). The NMA results suggest that complement component 5 (C5) inhibition prevents NMOSD relapses more effectively than broader mechanisms of action. Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease characterized by inflammation that damages the brain and spinal cord. Many patients with NMOSD produce antibodies against a protein called aquaporin-4 (AQP4+). In the past two years, three drugs (eculizumab, inebilizumab, and satralizumab) have been approved by the U.S. Food and Drug Administration for the treatment of adults with AQP4+ NMOSD. Comparing the efficacy of these three drugs would help physicians make treatment decisions for their patients. In the absence of clinical trials directly comparing these three drugs, we conducted a Bayesian network meta-analysis in order to allow for simultaneous comparisons of these three drugs and estimate relative treatment effects between any pair of interventions in a connected network. With a Bayesian methodology, it is also possible to estimate the probability of being the best treatment out of all other interventions in a connected network. While all three drugs are safe and shown to prevent relapses in placebo-controlled trials, the results of our analysis suggests that eculizumab was the most efficacious in preventing relapses when compared with inebilizumab or satralizumab. These findings may help to inform physicians and their patients when determining the best treatment option for preventing the occurrence of relapses in adults with AQP4+ NMOSD.

/pdf/network-meta-analysis-of-food-and-drug-administration-cwda3tsnck.pdf

Network Meta-analysis of Food and Drug Administration-approved Treatment Options for Adults with Aquaporin-4 Immunoglobulin G-positive Neuromyelitis Optica Spectrum Disorder.

Ina Zhang

Papers

Network Meta-analysis of Food and Drug Administration-approved Treatment Options for Adults with Aquaporin-4 Immunoglobulin G-positive Neuromyelitis Optica Spectrum Disorder.