A 5-Year Follow-up of Rituximab Treatment in Patients With Neuromyelitis Optica Spectrum Disorder
TL;DR: Repeated treatment with rituximab in patients with NMOSD over a 5-period, using an individualized dosing schedule according to the frequency of reemerging CD27+ memory B cells, leads to a sustained clinical response with no new adverse events.
Abstract: Importance A previous 2-year analysis of repeated rituximab treatment in patients with neuromyelitis optica (NMO) revealed significant improvements in relapse rates and disability. We report the findings from the longest follow-up of rituximab treatment in NMO, which provide reassurance regarding the long-term efficacy and safety of rituximab in NMO. Objective To report the results of rituximab treatment in patients with relapsing NMO or NMO spectrum disorder (NMOSD) for a median of 60 months. Design, Setting, and Participants Retrospective case series in an institutional referral center for multiple sclerosis, including 30 patients with relapsing NMO or NMOSD. Interventions After induction therapy, a single infusion of rituximab (375 mg/m 2 ) as maintenance therapy was administered whenever the frequency of reemerging CD27 + memory B cells in peripheral blood mononuclear cells, as measured with flow cytometry, exceeded 0.05% in the first 2 years and 0.1% thereafter. Main Outcomes and Measures Annualized relapse rate (ARR), disability (Expanded Disability Status Scale score), change in anti–aquaporin 4 antibody, and safety of rituximab treatment. Results Of 30 patients, 26 (87%) exhibited a marked reduction in ARR over 5 years (mean [SD] pretreatment vs posttreatment ARR, 2.4 [1.5] vs 0.3 [1.0]). Eighteen patients (60%) became relapse free after rituximab treatment. In 28 patients (93%), the disability was either improved or stabilized after rituximab treatment. No serious adverse events leading to discontinuation were observed during follow-up. Conclusions and Relevance Repeated treatment with rituximab in patients with NMOSD over a 5-period, using an individualized dosing schedule according to the frequency of reemerging CD27 + memory B cells, leads to a sustained clinical response with no new adverse events.
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TL;DR: The Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings.
Abstract: Neuromyelitis optica (NMO, Devic's syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity Major progress has been made in the diagnosis and treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004 In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical presentation of NMO spectrum disorders (NMOSD) In addition, imaging techniques, particularly magnetic resonance imaging of the brain and spinal cord, are obligatory in the diagnostic workup It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage Therapy of NMO should be initiated early Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients Other immunosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals
528 citations
Cites background from "A 5-Year Follow-up of Rituximab Tre..."
...CD19/20positive B cells and/or CD27? memory cells may be used as surrogate markers for treatment monitoring and re-dosing [100, 102, 183, 185]....
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TL;DR: Current NMO treatments include general immunosuppressive agents, B-cell depletion, and plasma exchange, and therapeutic strategies targeting complement proteins, the IL-6 receptor, neutrophils, eosinophils and CD19—all initially developed for other indications—are under clinical evaluation for repurposing for NMO.
Abstract: Neuromyelitis optica (NMO) is an autoimmune disease of the CNS that is characterized by inflammatory demyelinating lesions in the spinal cord and optic nerve, potentially leading to paralysis and blindness. NMO can usually be distinguished from multiple sclerosis (MS) on the basis of seropositivity for IgG antibodies against the astrocytic water channel aquaporin-4 (AQP4). Differentiation from MS is crucial, because some MS treatments can exacerbate NMO. NMO pathogenesis involves AQP4-IgG antibody binding to astrocytic AQP4, which causes complement-dependent cytotoxicity and secondary inflammation with granulocyte and macrophage infiltration, blood-brain barrier disruption and oligodendrocyte injury. Current NMO treatments include general immunosuppressive agents, B-cell depletion, and plasma exchange. Therapeutic strategies targeting complement proteins, the IL-6 receptor, neutrophils, eosinophils and CD19--all initially developed for other indications--are under clinical evaluation for repurposing for NMO. Therapies in the preclinical phase include AQP4-blocking antibodies and AQP4-IgG enzymatic inactivation. Additional, albeit currently theoretical, treatment options include reduction of AQP4 expression, disruption of AQP4 orthogonal arrays, enhancement of complement inhibitor expression, restoration of the blood-brain barrier, and induction of immune tolerance. Despite the many therapeutic options in NMO, no controlled clinical trials in patients with this condition have been conducted to date.
219 citations
01 Apr 2017
TL;DR: Current understanding of the clinical aspects, pathophysiology, and treatment of NMOSD is reviewed.
Abstract: The understanding of neuromyelitis optica spectrum disorder (NMOSD) has evolved substantially since its initial description over a century ago. The discovery in 2004 of a pathogenic autoantibody biomarker targeting aquaporin 4 IgG revolutionized diagnosis and therapeutic development. Although NMOSD resembles multiple sclerosis (MS), differences were identified and articulated in the late 1990s. New diagnostic criteria incorporating the biomarker as well as better understanding of the clinical and radiologic features of NMOSD now permit accurate diagnosis and differentiation from MS. Aquaporin 4 IgG-associated NMOSD is now regarded as an immune astrocytopathy with lytic and nonlytic effects on astrocytes. A second autoantibody, myelin oligodendrocyte glycoprotein IgG, which targets myelin rather than astrocytes, leads to an NMOSD syndrome with clinical and radiologic features that overlap but are distinct from those of aquaporin 4 IgG-associated NMOSD and MS. We review current understanding of the clinical aspects, pathophysiology, and treatment of NMOSD.
216 citations
TL;DR: Evidence is provided that rituximab therapy reduces the frequency of NMOSD relapses and neurological disability in patients with NMOSDs, however, the safety profile suggests caution in prescribing ritUXimab as a first-line therapy.
Abstract: Importance Neuromyelitis optica spectrum disorders (NMOSDs) are autoimmune astrocytopathies characterized by predominant involvement of the optic nerves and spinal cord. In most patients, an IgG autoantibody binding to astrocytic aquaporin 4, the principal water channel of the central nervous system, is detected. Rituximab, a chimeric monoclonal antibody specific for the CD20 B-lymphocyte surface antigen, has been increasingly adopted as a first-line off-label treatment for patients with NMOSDs. Objective To perform a systematic review and a meta-analysis of the efficacy and safety of rituximab use in NMOSDs, considering the potential predictive factors related to patient response to rituximab in this disease. Evidence Review English-language studies published between January 1, 2000, and July 31, 2015, were searched in the MEDLINE, Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov databases. Patient characteristics, outcome measures, treatment regimens, and recorded adverse effects were extracted. Findings Forty-six studies were included in the systematic review. Twenty-five studies that included 2 or more patients with NMOSDs treated with rituximab were included in the meta-analysis. Differences in the annualized relapse rate ratio and Expanded Disability Status Scale score before and after rituximab therapy were the main efficacy measures. Safety outcomes included the proportion of deaths, withdrawals because of toxic effects, and adverse effects. Results Among 46 studies involving 438 patients (381 female and 56 male [sex was not specified in 1 patient]; mean age at the outset of treatment, 32 years [age range, 2-77 years]), rituximab therapy resulted in a mean (SE) 0.79 (0.15) (95% CI, −1.08 to −0.49) reduction in the mean annualized relapse rate ratio and a mean (SE) 0.64 (0.27) (95% CI, −1.18 to −0.10) reduction in the mean Expanded Disability Status Scale score. A significant correlation was observed between disease duration and the Expanded Disability Status Scale score. Adverse effects were recorded in 114 of 438 (26%) patients treated with rituximab. Specifically, 45 patients (10.3%) experienced infusion-related adverse effects, 40 patients (9.1%) had an infection, 20 patients (4.6%) developed persistent leukopenia, 2 patients (0.5%) were diagnosed as having posterior reversible encephalopathy, and 7 patients (1.6%) died. Conclusions and Relevance This systematic review and meta-analysis provides evidence that rituximab therapy reduces the frequency of NMOSD relapses and neurological disability in patients with NMOSDs. However, the safety profile suggests caution in prescribing rituximab as a first-line therapy.
212 citations
TL;DR: Prolonged tocilizumab therapy may be safe and effective from early treatment phases onward for otherwise therapy-resistant highly active NMO and NMO spectrum disorder.
Abstract: Importance Neuromyelitis optica (NMO) is characterized by disabling relapses of optic neuritis and myelitis and the presence of aquaporin 4 antibodies (AQP4-abs). Interleukin 6, which is significantly elevated in serum and cerebrospinal fluid of patients with NMO, induces AQP4-ab production by plasmablasts and represents a novel therapeutic target. Objective To evaluate the long-term safety and efficacy of tocilizumab, a humanized antibody targeting the interleukin 6 receptor, in NMO and NMO spectrum disorder. Design, Setting, and Participants Retrospective observational study with 10 to 51 months of follow-up between December 2010 and February 2015, in neurology departments at tertiary referral centers. Participants were 8 female patients of white race/ethnicity with highly active AQP4-ab–seropositive NMO (n = 6) and NMO spectrum disorder (n = 2) whose disease had been resistant to previous medications, including B-cell depletion, and who switched to tocilizumab (6-8 mg/kg of body weight per dose). Main Outcomes and Measures Annualized relapse rate, Expanded Disability Status Scale score, spinal cord and brain magnetic resonance imaging, AQP4-ab titers, pain levels (numerical rating scale), and adverse effects. Results Patients were followed up for a mean (SD) of 30.9 (15.9) months after switching to tocilizumab. Two of eight patients received add-on therapy with monthly corticosteroid pulses (temporary) or azathioprine, respectively. During tocilizumab treatment, the median annualized relapse rate significantly decreased from 4.0 (interquartile range, 3.0-5.0) in the year before tocilizumab therapy to 0.4 (interquartile range, 0.0-0.8) ( P = .008), and the median Expanded Disability Status Scale score significantly decreased from 7.3 (interquartile range, 5.4-8.4) to 5.5 (interquartile range, 2.6-6.5) ( P = .03). Active magnetic resonance imaging lesions were seen in 6 of 8 patients at tocilizumab initiation and in 1 of 8 patients at the last magnetic resonance imaging. Three patients remained relapse free during tocilizumab treatment. In 5 patients, a total of 8 relapses occurred, 4 within the first 2½ months of therapy. Five attacks were associated with delayed tocilizumab administration (≥40 days), and 6 attacks were associated with reduced tocilizumab dosage (6 vs 8 mg/kg). The AQP4-ab titers ( P = .02) and pain levels ( P = .02) dropped significantly during tocilizumab treatment. Adverse effects included moderate cholesterol elevation in 6 of 8 patients, infections in 4 of 8 patients, and deep venous thrombosis and neutropenia in one patient each. Conclusions and Relevance Prolonged tocilizumab therapy may be safe and effective from early treatment phases onward for otherwise therapy-resistant highly active NMO and NMO spectrum disorder. Relapse patterns indicate that adherence to a regular therapeutic regimen with monthly infusions of tocilizumab (8 mg/kg) may increase efficacy.
182 citations
References
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TL;DR: Revised diagnostic criteria for definite neuromyelitis optica (NMO) that require optic neuritis, myelitis, and at least two of three supportive criteria: MRI evidence of a contiguous spinal cord lesion 3 or more segments in length, onset brain MRI nondiagnostic for multiple sclerosis, or NMO-IgG seropositivity.
Abstract: Background: The authors previously proposed diagnostic criteria for neuromyelitis optica (NMO) that facilitate its distinction from prototypic multiple sclerosis (MS) However, some patients with otherwise typical NMO have additional symptoms not attributable to optic nerve or spinal cord inflammation or have MS-like brain MRI lesions Furthermore, some patients are misclassified as NMO by the authors’ earlier proposed criteria despite having a subsequent course indistinguishable from prototypic MS A serum autoantibody marker, NMO-IgG, is highly specific for NMO The authors propose revised NMO diagnostic criteria that incorporate NMO-IgG status Methods: Using final clinical diagnosis (NMO or MS) as the reference standard, the authors calculated sensitivity and specificity for each criterion and various combinations using a sample of 96 patients with NMO and 33 with MS The authors used likelihood ratios and logistic regression analysis to develop the most practical and informative diagnostic model Results: Fourteen patients with NMO (146%) had extra-optic-spinal CNS symptoms NMO-IgG seropositivity was 76% sensitive and 94% specific for NMO The best diagnostic combination was 99% sensitive and 90% specific for NMO and consisted of at least two of three elements: longitudinally extensive cord lesion, onset brain MRI nondiagnostic for MS, or NMO-IgG seropositivity Conclusions: The authors propose revised diagnostic criteria for definite neuromyelitis optica (NMO) that require optic neuritis, myelitis, and at least two of three supportive criteria: MRI evidence of a contiguous spinal cord lesion 3 or more segments in length, onset brain MRI nondiagnostic for multiple sclerosis, or NMO-IgG seropositivity CNS involvement beyond the optic nerves and spinal cord is compatible with NMO
2,442 citations
TL;DR: It is shown that NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier, which may represent the first example of a novel class of autoimmune channelopathy.
Abstract: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that selectively affects optic nerves and spinal cord. It is considered a severe variant of multiple sclerosis (MS), and frequently is misdiagnosed as MS, but prognosis and optimal treatments differ. A serum immunoglobulin G autoantibody (NMO-IgG) serves as a specific marker for NMO. Here we show that NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier. NMO may represent the first example of a novel class of autoimmune channelopathy.
2,024 citations
"A 5-Year Follow-up of Rituximab Tre..." refers methods in this paper
...8 In brief, patients were required to have (1) a diagnosis of NMO (according to the 2006 diagnostic criteria9) or NMOSD10 and (2) at least 1 relapse during the 12 months before the start of rituximab therapy....
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...Two regimens were used as induction treatment: (1) 375 mg/m2 infused once weekly for 4 weeks (n = 16) and (2) 1000 mg infused twice at a 2-week interval (n = 14)....
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TL;DR: Data suggest that autoantibodies to aquaporin 4 derived from peripheral B cells cause the activation of complement, inflammatory demyelination, and necrosis that is seen in neuromyelitis optica.
Abstract: Summary Neuromyelitis optica (also known as Devic's disease) is an idiopathic, severe, demyelinating disease of the central nervous system that preferentially affects the optic nerve and spinal cord. Neuromyelitis optica has a worldwide distribution, poor prognosis, and has long been thought of as a variant of multiple sclerosis; however, clinical, laboratory, immunological, and pathological characteristics that distinguish it from multiple sclerosis are now recognised. The presence of a highly specific serum autoantibody marker (NMO-IgG) further differentiates neuromyelitis optica from multiple sclerosis and has helped to define a neuromyelitis optica spectrum of disorders. NMO-IgG reacts with the water channel aquaporin 4. Data suggest that autoantibodies to aquaporin 4 derived from peripheral B cells cause the activation of complement, inflammatory demyelination, and necrosis that is seen in neuromyelitis optica. The knowledge gained from further assessment of the exact role of NMO-IgG in the pathogenesis of neuromyelitis optica will provide a foundation for rational therapeutic trials for this rapidly disabling disease.
1,928 citations
Utrecht University1, Leiden University2, University of Crete3, Humboldt University of Berlin4, University of Genoa5, University of Paris6, University of Leeds7, Hospital for Special Surgery8, University of Santiago de Compostela9, University of Erlangen-Nuremberg10, University of Toronto11, University of Glasgow12, Autonomous University of Madrid13
TL;DR: The 10 recommendations are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA based on evidence and expert opinion.
Abstract: Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension. Such targets have not been defined for rheumatoid arthritis (RA).
1,676 citations
Journal Article•
TL;DR: In this article, a task force of rheumatologists and a patient developed a set of recommendations on the basis of evidence derived from a systematic literature review and expert opinion; these were subsequently discussed, amended and voted upon by >60 experts from various regions of the world in a Delphi-like procedure.
Abstract: Background Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension. Such targets have not been defined for rheumatoid arthritis (RA). Objective To develop recommendations for achieving optimal therapeutic outcomes in RA. Methods A task force of rheumatologists and a patient developed a set of recommendations on the basis of evidence derived from a systematic literature review and expert opinion; these were subsequently discussed, amended and voted upon by >60 experts from various regions of the world in a Delphi-like procedure. Levels of evidence, strength of recommendations and levels of agreement were derived. Results The treat-to-target activity resulted in 10 recommendations. The treatment aim was defined as remission with low disease activity being an alternative goal in patients with long-standing disease. Regular follow-up (every 1–3 months during active disease) with appropriate therapeutic adaptation to reach the desired state within 3 to a maximum of 6 months was recommended. Follow-up examinations ought to employ composite measures of disease activity which include joint counts. Additional items provide further details for particular aspects of the disease. Levels of agreement were very high for many of these recommendations (≥9/10). Conclusion The 10 recommendations are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA based on evidence and expert opinion.
1,580 citations