Targeting Neuromyelitis Optica Pathogenesis: Results from Randomized Controlled Trials of Biologics.
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ABSTRACT:
SUBMITTER: Cacciaguerra L
PROVIDER: S-EPMC8608970 | biostudies-literature | 2021 Jul
REPOSITORIES: biostudies-literature
Publications
Targeting Neuromyelitis Optica Pathogenesis: Results from Randomized Controlled Trials of Biologics.
Cacciaguerra Laura L Tortorella Paola P Rocca Maria A MA Filippi Massimo M
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20210428 3
Advances in neuromyelitis optica spectrum disorder pathogenesis have allowed the development of targeted drugs. These treatments act on core elements of the disease, including the pro-inflammatory IL-6 pathway (tocilizumab and satralizumab), B cells (rituximab and inebilizumab), and complement (eculizumab). According to recent phase II-III trials, biologics significantly reduced the risk of relapses in aquaporin-4-seropositive patients, whereas results were less striking in the small cohorts of ...[more]
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Project description:OBJECTIVE:To determine whether Scrambler therapy is an effective, acceptable, and feasible treatment of persistent central neuropathic pain in patients with neuromyelitis optica spectrum disorder (NMOSD) and to explore the effect of Scrambler therapy on co-occurring symptoms. METHODS:We conducted a randomized single-blind, sham-controlled trial in patients with NMOSD who have central neuropathic pain using Scrambler therapy for 10 consecutive weekdays. Pain severity, pain interference, anxiety, depression, and sleep disturbance were assessed at baseline, at the end of treatment, and at the 30- and 60-day follow-up. RESULTS:Twenty-two patients (11 per arm) were enrolled in and completed this trial. The median baseline numeric rating scale (NRS) pain score decreased from 5.0 to 1.5 after 10 days of treatment with Scrambler therapy, whereas the median NRS score did not significantly decrease in the sham arm. Depression was also reduced in the treatment arm, and anxiety was decreased in a subset of patients who responded to treatment. These symptoms were not affected in the sham arm. The safety profiles were similar between groups. CONCLUSIONS:Scrambler therapy is an effective, feasible, and safe intervention for central neuropathic pain in patients with NMOSD. Decreasing pain with Scrambler therapy may additionally improve depression and anxiety. CLINICALTRIALSGOV IDENTIFIER:NCT03452176. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that Scrambler therapy significantly reduces pain in patients with NMOSD and persistent central neuropathic pain.
| S-EPMC7274926 | biostudies-literature
Project description:Background: Neuromyelitis optica spectrum disorder (NMOSD), an autoimmune inflammatory disorder of the central nervous system, often leads to vision loss or paralysis. This meta-analysis focused on the assessment of the monoclonal antibody therapy in NMOSD and compared different targets of monoclonal antibodies with each other in terms of efficacy and safety outcomes. Method: We searched through the databases of MEDLINE, EMBASE, Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov for randomized controlled trials (RCTs) evaluating monoclonal antibody therapy in NMOSD up to April 2020. Results: We identified seven randomized controlled trials (RCTs), including 775 patients (monoclonal antibody group, n = 485 and placebo group, n = 290). Monoclonal antibody therapy decreased relapse risk (RR 0.33, 95% CI 0.21–0.52, P < 0.00001), annualized relapse rate (ARR) (mean −0.28, 95% CI −0.35−0.20, P < 0.00001), expanded disability status scale score (EDSS) (mean −0.19, 95% CI −0.32−0.07, P = 0.002) and serious adverse events (RR 0.78, 95% CI 0.61–1.00, P = 0.05). However, we did not observe any significant difference in terms of adverse events or mortality. Further, the subgroup analysis demonstrated that the anti-complement protein C5 monoclonal antibody (eculizumab) might have a lower relapse risk (RR 0.07, 95% CI 0.02–0.23, P < 0.0001) in the AQP4 seropositive patients, and anti-interleukin-6 receptor monoclonal antibodies (satralizumab and tocilizumab) showed decreased EDSS score (mean −0.17, 95% CI −0.31−0.02, P = 0.02) more effectively than other monoclonal antibodies. Conclusions: Monoclonal antibodies were effective and safe in NMOSD. Different targets of monoclonal antibodies might have their own advantages.
| S-EPMC7773932 | biostudies-literature
Project description:Neuromyelitis optica (NMO) is an autoimmune 'aquaporinopathy' of the central nervous system that causes inflammatory demyelinating lesions primarily in spinal cord and optic nerve, leading to paralysis and blindness. NMO lesions show loss of aquaporin-4 (AQP4), GFAP and myelin, infiltration of granulocytes and macrophages, and perivascular deposition of activated complement. Most patients with NMO are seropositive for immunoglobulin autoantibodies (AQP4-IgG) against AQP4, the principal water channel of astrocytes. There is strong evidence that AQP4-IgG is pathogenic in NMO, probably by a mechanism involving complement-dependent astrocyte cytotoxicity, causing leukocyte infiltration, cytokine release and blood-brain barrier disruption, which leads to oligodendrocyte death, myelin loss and neuron death. Here, we review the evidence for this and alternative proposed NMO pathogenesis mechanisms, such as AQP4-IgG-induced internalization of AQP4 and glutamate transporters, complement-independent cell-mediated cytotoxicity, and AQP4-IgG inhibition of AQP4 water transport function. Based on the initiating pathogenic role of AQP4-IgG binding to astrocyte AQP4 in NMO, selective blocker therapies are under development in which AQP4-targeted monoclonal antibodies or small molecules block binding of AQP4-IgG to astrocytes and consequent downstream pathology.
| S-EPMC3676174 | biostudies-literature
Project description:Neuromyelitis optica (NMO) is an autoimmune demyelinating disease with pathogenic autoantibodies that act against the astrocyte water channel protein, i.e. aquaporin-4: the disease is associated with recurrent episodes of optic neuritis (ON) and transverse myelitis, often resulting in severe disability. The main goals in treatment of NMO include acute symptomatic therapy and long-term stabilization of symptoms by preventing relapse. In recent years, ongoing randomized controlled trials in NMO patients have studied evidence for treatment. Briefly, acute-stage management (with pulse therapy using corticosteroids and/or plasmapheresis) and maintenance therapy (including rituximab, mycophenolate mofetil, and azathioprine) have been recommended in some case series and retrospective studies. Because of the high prevalence of liver disease, all NMO patients in Taiwan should be screened for hepatitis B and C before treatment is initiated. Although immunosuppression and plasma exchange are the mainstays of therapy for NMO ON, several selective and potentially therapeutic strategies targeting specific steps in NMO pathogenesis including blockers of NMO-IgG binding and inhibitors of granulocyte function have been evaluated in recent years.
| S-EPMC6172906 | biostudies-other
Project description: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.MethodsPubMed, 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.ResultsWe 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.ConclusionsCompared 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.
| S-EPMC8329455 | biostudies-literature
Project description:IntroductionNeuromyelitis optica spectrum disorder (NMOSD) is characterized by central nervous system inflammation and demyelination. In AQP4-IgG seropositive NMOSD, circulating immunoglobulin G (IgG) autoantibodies against astrocyte water channel aquaporin-4 (AQP4) cause tissue injury. Compelling evidence supports a pathogenic role for complement activation following AQP4-IgG binding to AQP4. Clinical studies supported the approval of eculizumab, an inhibitor of C5 cleavage, in AQP4-IgG seropositive NMOSD.Areas coveredThis review covers in vitro, animal models, and human evidence for complement-dependent and complement-independent tissue injury in AQP4-IgG seropositive NMOSD. Complement targets are discussed, including complement proteins, regulators and anaphylatoxin receptors, and corresponding drug candidates.Expert opinionThough preclinical data support a central pathogenic role of complement activation in AQP4-IgG seropositive NMOSD, they do not resolve the relative contributions of complement-dependent vs. complement-independent disease mechanisms such as antibody-dependent cellular cytotoxicity, T cell effector mechanisms, and direct AQP4-IgG-induced cellular injury. The best evidence that complement-dependent mechanisms predominate in AQP4-IgG seropositive NMOSD comes from eculizumab clinical data. Various drug candidates targeting distinct complement effector mechanisms may offer improved safety and efficacy. However, notwithstanding the demonstrated efficacy of complement inhibition in AQP4-IgG seropositive NMOSD, the ultimate niche for complement inhibition is not clear given multiple drug options with alternative mechanisms of action.Abbreviations: AAV2, Adeno-associated virus 2; ADCC, antibody-dependent cellular cytotoxicity; ANCA, antineutrophilic cytoplasmic autoantibody; AQP4, aquaporin-4; AQP4-IgG, AQP4-immunoglobulin G; C1-INH, C1-esterase inhibitor; C3aR, C3a receptor; C4BP, C4 binding protein; C5aR, C5a receptor; CDC, complement-dependent cytotoxicity; CFHR1, complement factor H related 1; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; EndoS, endoglycosidase S; FHL-1, factor-H-like protein 1; GFAP, glial fibrillary acidic protein; Iba-1, ionized calcium-binding adaptor protein-1; IgG, immunoglobulin G; IVIG, intravenous human immunoglobulin G; MAC, membrane attack complex; MBL, maltose-binding lectin; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; NK cell, natural killer cell; NMOSD, neuromyelitis optica spectrum disorder; OAP, orthogonal arrays of particles; PNH, paroxysmal nocturnal hemoglobinuria.
| S-EPMC8316261 | biostudies-literature
Project description:Current management of neuromyelitis optica (NMO) is noncurative and only partially effective. Immunosuppressive or immunomodulatory agents are the mainstays of maintenance treatment. Safer, better-tolerated, and proven effective treatments are needed. The perceived rarity of NMO has impeded clinical trials for this disease. However, a diagnostic biomarker and recognition of a wider spectrum of NMO presentations has expanded the patient population from which study candidates might be recruited. Emerging insights into the pathogenesis of NMO have provided rationale for exploring new therapeutic targets. Academic, pharmaceutical, and regulatory communities are increasingly interested in meeting the unmet needs of patients with NMO. Clinical trials powered to yield unambiguous outcomes and designed to facilitate rapid evaluation of an expanding pipeline of experimental agents are needed. NMO-related disability occurs incrementally as a result of attacks; thus, limiting attack frequency and severity are critical treatment goals. Yet, the severity of NMO and perception that currently available agents are effective pose challenges to study design. We propose strategies for NMO clinical trials to evaluate agents targeting recovery from acute attacks and prevention of relapses, the 2 primary goals of NMO treatment. Aligning the interests of all stakeholders is an essential step to this end.
| S-EPMC4424131 | biostudies-literature
Project description:BackgroundDetection of aquaporin-4-specific immunoglobulin G (IgG) has expanded the spectrum of neuromyelitis optica (NMO). Rare reports of familial aggregation have suggested a component of genetic susceptibility but these reports mostly antedated the discovery of the NMO-IgG biomarker and recently updated diagnostic criteria.MethodsWe report a case series describing the demographic, clinical, neuroimaging, and NMO-IgG serologic status of 12 multiplex NMO pedigrees with a total of 25 affected individuals.ResultsTwenty-one patients (84%) were women. Families were Asian (n = 5), Latino (n = 4), white (n = 1), or African (n = 2). Apparent transmission was either maternal (n = 5) or paternal (n = 2). In 1 family, 3 individuals had NMO; in the others, 2 individuals were affected. Sibling pairs (n = 6), parent-child (n = 4), and aunt-niece (n = 3) pairs were observed. Nineteen patients (76%) were NMO-IgG positive. Twelve (48%) had clinical or serologic evidence of another autoimmune disease. Familial occurrence of NMO occurs in approximately 3% of patients with well-established diagnosis of NMO.ConclusionsA small proportion of patients with NMO have relatives with this condition, but familial occurrence is more common than would be expected from its frequency in the general population. Familial NMO is indistinguishable from sporadic NMO based on clinical symptoms, age at onset, sex distribution, and frequency of NMO-IgG detection. One or 2 generations were affected and affected individuals represented a small fraction of family members. Taken together, these data suggest complex genetic susceptibility in NMO.
| S-EPMC2918892 | biostudies-literature
Project description:Neuromyelitis optica (NMO) is an inflammatory disease characterized by recurrent attacks of optic neuritis and myelitis. It is generally accepted that autoantibodies against aquaporin 4 water channel protein play a pathogenic role in neuromyelitis optica. We have recently reported that plasmablasts are increased in the peripheral blood of this autoimmune disease, and are capable of producing autoantibodies against aquaporin 4. Here, we demonstrate that CD138(+)HLA-DR(+) plasmablasts, a subset of IgG-producing cells, are increased in the peripheral blood and are enriched among the cerebrospinal fluid (CSF) lymphocytes during the relapse of neuromyelitis optica. Notably, these CD138(+)HLA-DR(+) plasmablasts overexpress CXCR3, whose ligands are present in the cerebrospinal fluid during the relapse of neuromyelitis optica. These results led us to speculate that plasmablasts producing anti-aquaporin 4 autoantibodies might traffic toward the central nervous system (CNS). Furthermore, we performed single-cell sorting of plasmablasts from peripheral blood and CSF samples from NMO and sequenced the complementarity-determining regions (CDRs) of the IgG heavy chain expressed by the sorted plasmablast clones. There were high frequencies of mutations in the CDRs compared with framework regions, indicating that these plasmablast clones would represent a post-germinal center B-cell lineage. Consistent with the preceding results, the plasmablast clones from the peripheral blood shared the same CDR sequences with the clones from the CSF. These results indicate that IgG-producing plasmablasts, which are guided by helper T-cells, may migrate from the peripheral blood preferentially to the CSF. Since migratory plasmablasts could be involved in the inflammatory pathology of NMO, the B-cell subset and their migration might be an attractive therapeutic target.
| S-EPMC3858367 | biostudies-literature
Project description:IntroductionNeuromyelitis Optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS). NMO manifests as selective and severe attacks on axons and myelin of the optic nerve and spinal cord, resulting in necrotic cavities. The circadian rhythms are well demonstrated to profoundly impact cellular function, behavior, and disease. This study is aimed to explore the role and molecular basis of circadian rhythms in NMO.MethodsWe used an Aquaporin 4(AQP4) IgG-induced NMO cell model in isolated astrocytes. The expression of Cx43 and Bmal1 were detected by real-time PCR and Western Blot. TAT-Gap19 and DQP-1105 were used to inhibit Cx43 and glutamate receptor respectively. The knockdown of Bmal1 were performed with the shRNA containing adenovirus. The levels of glutamate, anterior visual pathway (AVP), and vasoactive intestinal peptide (VIP) were quantified by ELISA kits.ResultsWe found that Bmal1 and Clock, two essential components of the circadian clock, were significantly decreased in NMO astrocytes, which were reversed by Cx43 activation (linoleic acid) or glutamate. Moreover, the expression levels of Bmal1 and Clock were also decreased by Cx43 blockade (TAT-Gap19) or glutamate receptor inhibition (DQP-1105). Furthermore, adenovirus-mediated Bmal1 knockdown by shRNA (Ad-sh-Bmal1) dramatically decreased the levels of glutamate, AVP, and VIP from neurons, and significantly down-regulated the protein level of Cx43 in NMO astrocytes with Cx43 activation (linoleic acid) or glutamate treatment. However, Bmal1 knockdown did not alter these levels in normal astrocytes with Cx43 blockade (TAT-Gap19) or glutamate receptor inhibition (DQP-1105).DiscussionCollectively, these results suggest that Cx43-glutamate signaling would be a critical upstream regulator that contributes to the NMO-induced rhythmic damage in SCN astrocytes.
| S-EPMC9885795 | biostudies-literature