Neuromyelitis optica spectrum disorders (NMOSD) and systemic lupus erythematosus (SLE): Dangerous duo

Neuromyelitis optica spectrum disorders (NMOSD) and transverse myelitis (TM) are auto-antibody mediated chronic inflammatory demyelinating central nervous system (CNS) diseases.1 NMOSD and TM are characterized by severe and recurrent episodes of immune-mediated demyelination and axonal damage mainly involving optic nerves and spinal cord. NMOSD may be idiopathic or can occur in conjunction with other systemic diseases and may overlap with autoimmune rheumatic diseases including systemic lupus erythematosus (SLE).1 NMOSD has received attention in the past years because of the significant progress made in the understanding of the pathogenesis and in the identification of targets of therapy for the disease.2-4 NMOSD is a rare disease worldwide. The prevalence is about 0.52–4.4 per 100 000 with an incidence of about 0.05–0.4 per 100 000.5 African ethnicity has the highest incidence and prevalence of NMOSD, whereas white ethnicity has the lowest.5, 6 All ages (3–90 years) can be affected but the median age of onset is approximately 39 years and 70% to 90% of patients with NMOSD are women.6 NMOSD, may be looked at as an autoimmune astrocytopathic disease rather than solely an inflammatory demyelinating CNS disease.7 It is characterized by CNS damage directed primarily to astrocytes and the presence of serum antibodies that bind to the astrocytic water channel protein aquaporin 4 (AQP4) at the endfeet of astrocytes.7 NMOSD most commonly affects areas with high levels of AQP4 expression, such as the optic nerve, spinal cord and brain.7-9 NMOSD transverse myelitis (NMOSD-TM) is a longitudinally extending transverse myelitis (LETM) extending over 3 or more vertebral segments and is very often followed by pain and tonic spasms.10 Bladder, bowel and/or erectile dysfunction are commonly associated with TM.10 NMOSD optic neuritis (NMOSD-ON) may be bilateral, simultaneous or sequential, severe, irreversible, and can eventually cause blindness.11 In addition to ON and TM, NMOSD can result in an array of symptoms (headache, nausea, vomiting, symptomatic narcolepsy, intractable hiccups) associated with lesions in the nervous system at sites that highly express AQP4 (the water channel that is the target of NMO) and /or have a leaky blood–brain barrier.11 Neuromyelitis Optica (NMO) was first described in 1894 by Eugene Devic who reported a monophasic disease with severe, bilateral optic neuritis (ON) and TM.2 Scientific understanding of NMOSD has since advanced rapidly. In 1999 the first clinical diagnostic criteria were proposed to differentiate NMOSD from multiple sclerosis. In the year 2004 the antibody (biomarker) NMO-IgG antibody was identified and in 2005 the target antigen, aquaporin 4 (AQP4), expressed on the end feet of CNS astrocytes, was identified. In 2007 the term "NMOSD" was introduced and in 2015 the diagnostic criteria were broadened so that one attack qualifies for a diagnosis and classification based on the clinical presentation and antibody status.2-4 In NMOSD, pathophysiology is mediated by the AQP4 immunoglobulins (IgGs) that enter the CNS via the blood–brain barrier (BBB) and selectively bind to the astrocytic water channel protein aquaporin 4 (AQP4) at the endfeet of astrocytes [Figure 1].1, 4 AQP4 normally maintains water homeostasis and helps mediate waste protein clearance. AQP4-antibody is mainly of the immunoglogulin G1 (IgG) type which activates complement efficiently.1, 4, 7, 8 Complement activation (C5a, C5b,) leads to increased BBB permeability with recruitment of proinflammatory leucocytes promoted by C5a. The recruited leucocytes, namely macrophages, neutrophils, eosinophils, and natural killer cells bring about astrocyte and neuronal damage and death mainly by C5b, which forms part of the membrane attack complex. AQP4-antibody complement-mediated cytotoxicity is a major mechanism to damage AQP4-expressing astrocytes.1, 4, 7, 9 Astrocytic damage (together with myelin and neuron damage) in NMOSD can also occur in other ways: through antibody-dependent cellular cytotoxicity, activated mature B cells which synthesize antibodies against AQP-4 and induce the production of interleukin-6 (IL-6) that facilitates the disruption of the blood–brain barrier (BBB) and promotes B cell survival. IL-6 supporting plasmablasts promote AQP4-IgG release, through AQP4-reactive T cells and via inflammatory cytokines mainly T helper cell 17 (Th17)-related (Figure 1).1, 4, 7, 9 An impaired innate immune system may promote naive T cell transformation into Th17 cells and stimulate B cell differentiation to plasmablasts and then to plasma cells which produce AQP4-IgG.1, 4, 7-9 Furthermore, AQP4-binding antibodies impair glutamate transport by down-regulating excitatory amino acid transporter 2 (EAAT2) which is primarily responsible for the clearance of extracellular glutamate to prevent neuronal excitotoxicity and hyperexcitability.1, 4, 8 Death of astrocytes results in loss of support for surrounding neurones and oligodendrocytes. Demyelination is a secondary event occurring because of losses in glial astrocytes (Figure 1).1, 4, 7-9 About 1 in 4 patients with NMOSD have Sjogren's syndrome, SLE, myasthenia gravis, or other coexisting autoimmune disease.12 The pathophysiological link between SLE and NMO has not yet been established completely, some studies estimated that the chances of a patient having both SLE and NMO were far less than 1 in 1 00000.6, 12 SLE is a chronic multi-system, immune-mediated disease characterized by autoreactivity of the innate and adaptive immune systems, leading to autoantibody production and immune complex deposition within tissues.13, 14 Neuropsychiatric lupus involvement is one of the most complex and heterogenous manifestations of SLE. Although the survival and prognosis of SLE have improved substantially in recent decades, neuropsychiatric lupus (NPSLE) remains one of the main causes of morbidity, mortality, and lower health-related quality of life, only surpassed by lupus nephritis. About 30% of NP events are attributed to SLE.13-16 NPSLE events, none of which are specific to SLE, (inflammatory, immune-mediated, neurotoxic, or vascular, that is, thrombotic/ischaemic or both simultaneously) usually occur within the first 2 years following the first SLE manifestations.13, 14, 16 Studies have shown that patients with NPSLE have a tenfold and a threefold higher mortality compared to the general population and to those without NPSLE, respectively.13, 15, 16 Myelitis in SLE can present either as acute transverse myelitis consisting of spinal cord lesions of one to two spinal segments or rarely as longitudinally extensive transverse myelitis extending to three or more vertebral segments.10 Although neuropsychiatric complications of lupus may occur in up to 60% of patients, longitudinally extensive transverse myelitis (LETM) is uncommon and has been reported in only 1% to 2% of patients with SLE in some large case series and may present with motor, sensory, or autonomic deficits below the level of spinal inflammation, leading to significant morbidity.10, 17 Myelitis can be the presenting SLE manifestation. Patients with systemic lupus erythematosus (SLE) may develop transverse myelitis as a neuropsychiatric complication of active disease; however, at times, NMO co-exists as an additional primary autoimmune condition in a SLE patient.10, 12, 13, 16, 17 There still remains skepticism around whether they are manifestations of systemic autoimmune diseases or distinct clinical diagnostic entities that may occur at a higher frequency in patients with underlying autoimmune rheumatic diseases. In light of the severe relapsing course of NMOSD and the accrual damage and debility with each attack that leads to increased morbidity and mortality, it is essential to know how to manage these patients adequately. Moreover, these immune-mediated CNS demyelinating diseases, pose a diagnostic and therapeutic challenge and create a dilemma in clinical practice as there is still no standard treatment protocol. Accordingly, an extensive workup (see proposed algorithm -Figure 2) is required to exclude NPSLE mimickers including: infections, adverse effects of therapy (eg glucocorticoids), anti-phospholipid syndrome, cognitive dysfunction, delirium, depression, pychosis, myasthenia gravis, optic neuritis, aseptic meningitis, cerebrovascular disease, chorea, seizure, headache and neuropathy.17-19 The occurrence in a patient with known autoimmune rheumatologic disease of ON or a TM syndrome, especially LETM, should make one suspect NMO and proceed to prompt immediate evaluation for NMO, including serological testing for AQP4 autoantibodies. An AQP4 autoantibody-positive test result clinches the diagnosis of NMO coexisting with autoimmune rheumatologic disease. At least 2 potential mechanisms could underlie the co-association of NMO with systemic autoimmune rheumatic disease. Firstly, common genetic and /or environmental factors predisposing to autoimmune rheumatic disease could explain the co-occurrence.1, 4, 7-9, 17 Secondly, the initial autoimmune rheumatic disease may contribute (via inflammatory mediators and autoantibodies) to the disruption of the BBB allowing the AQP4 autoantibodies to gain access to the CNS and lead to the clinical manifestations of NMO.1, 4, 7-9 The coexistence of NMO and SLE remains rare and explicit evidence-based guidelines for the management of such cases are still lacking. It is essential to develop a clinically workable approach in the management of such, albeit rare, yet critical cases. It is crucial that rheumatologists and physicians in general be able to timely and accurately diagnose patients with ARDs, particularly SLE, presenting with CNS manifestations and to distinguish between SLE-related CNS manifestations and NMO with coexisting SLE (Table 1).17-19 The correct diagnosis is essential so as to intervene promptly with immunosuppression as the ultimate goal is to prevent further damage, relapses, and damage accrual (as debility accrues with each attack) which leads to severe disability with significant morbidity and mortality. Elevated anti-dsDNA antibody Hypocomplementemia Antiphospholipid antibody-positive In the differential diagnosis and work-up of such patients, the following should be considered: differentiating spinal cord syndromes in SLE patients, including lupus myelitis, NMO, and multiple sclerosis (MS), which can be challenging (Table 1).17-19 Gadolinium-enhanced magnetic resonance imaging (MRI) excludes compression, and detects T2-hyperintense lesions. Cerebrospinal fluid (CSF) analysis detects inflammation/rules out infection. Brain MRI in the presence of other concomitant CNS manifestation helps in the differential diagnosis for MS and NMO-IgG if NMO is suspected (ON, LETM).17-19 Aquaporin4 autoantibody seropositive LETM is associated with a high risk of relapse within 1 year in patients with comorbid NMO and SLE.17-19 The many relapses characterizing NMOSD necessitate long-term immunosuppression with several agents making these patients susceptible to recurrent infections and adding more to the disease burden and the challenges faced by the clinicians and patients alike.1, 4, 6 Early, accurate diagnosis is critical as untreated, 50% of patients with NMOSD become blind (ON) and/or become paralyzed (TM) requiring wheelchairs.1, 4, 8, 9 Furthermore, more than 30% die within 5 years of their first attack.1-6 Correct diagnosis of NMO coexisting with SLE is thus, the prelude to optimal therapy and optimal treatment outcomes. Timely accurate diagnosis is essential not only for the different disease courses and prognosis compared with SLE-related LETM but also because these patients may benefit from treatment tailored specifically to NMOSD. Time to treatment is also critical; delays in treating NMOSD can be devastating as damage from attacks is cumulative and severe. Also, inappropriate or incorrect treatment has high consequences, for instance, if misdiagnosed as MS, and MS disease-modifying agents such as fingolimod, natalizumab, alemtuzumab, dimethylfumarate, and IFN-β are administered, catastrophic consequences would result.20 There are no specific recommendations for the treatment of NMO/SLE overlapping cases, only expert opinion, therefore, head-to-head randomized trials to compare the efficacy of the different immunosuppressive agents are highly needed to set up a standardized treatment algorithm and optimize the management of NMOSD. The goals of treatment to achieve optimal outcomes include treatment of acute attacks, maintenance therapy, and prevention of relapse. There is no curative agent available for NMOSD, so ongoing treatment is necessary as well as careful, continued monitoring for adequacy and efficacy of treatment is essential. When a patient presents with an acute attack of NMOSD, the key goal is to minimize the amount of irreversible damage done as most of the disability resulting from NMO occurs at the time of the attack. It is critical to treat patients as well as to promote recovery and restore functionality to the greatest extent possible. For acute attacks, treatment with high doses of intravenous corticosteroids-1000 mg intravenous methylprednisolone (IVMP) for 5 days is necessary and because of the high rate of relapses, it is recommended that patients be put on a prolonged taper of oral steroids.21 If a patient does not get an adequate response from high doses of corticosteroids, there is good evidence mostly from observational studies that plasma exchange (PLEX) may rescue at least 50% of patients who continue to have disability after corticosteroids.21, 22 The simultaneous use of IVMP and PLEX seems to be the most effective acute therapy, particularly in TM.21 PLEX removes up to 99% of circulating antibodies after 5–7 cycles and may also remove other inflammatory factors/components that contribute to the disability.21, 22 Patients treated with PLEX within a few days of their symptoms fare much better than those who get treatment after a few weeks.21, 22 In one study, paraplegia occurred after 3 spinal attacks, whereas blindness occurred after 1.5 optic attacks.22 If patients fail PLEX there are some other potential options including intravenous immunoglobulin (IVIG) and other immunosuppressants such as cyclophosphamide even though the evidence of benefit of these agents is much lower.21, 22 Another key element in management is preventing relapse (an NMOSD relapse has been characterized as a "neuro-immunological stroke", with a poor prognosis for recovery) as by suppressing the attacks, it is quite likely that we will advert the vast majority of accrued disability that occurs in NMO. The primary treatment goal, in NMOSD patients, is prevention with immunosuppressive therapy or the use of a monoclonal antibody such as rituximab (RTX).23 The most commonly used drugs are azathioprine (AZA), mycophenolate mofetil (MMF), and RTX. In recent years, research has confirmed the effectiveness and safety of AZA, MMF, and RTX in the treatment of NMOSD.4, 21, 24 Moreover, AZA and MMF have been widely used, while corticosteroids, mitoxantrone, cyclosporine, and cyclophosphamide can also be considered.1, 4, 21 Table 2 depicts the most common maintenance medications used for NMOSD. Azathioprine Target dose: 2.5–3.0 mg/kg daily Route: Oral Side effects: GIT symptoms, hypersensitivity reaction, excessive bone marrow suppression, hepatotoxicity, malignancy (long-term use). Latency to full biological effect 4–6 months immunosuppressive bridge required typically with oral corticosteroids Prednisone Target dose: 15–60 mg/d Route: Oral Side effects: Hyperglycaemia, hypertension, gastric irritation, fluid retention, weight gain Stable dose of at least 30 mg/d until azathioprine or mycophenolate become fully effective, then taper over a course of 6 months Methotrexate Second-line treatment in NMOSD Target dose:15–25 mg weekly Route: Oral Side effects: hepatotoxicity, bone marrow suppression, teratogenic, pneumonitis, GIT upset Supplement with folate, 1 mg/d Avoid nonsteroidal anti-inflammatory drugs Mycophenolate Target dose: 750–1500 mg twice daily Route: Oral Side effects: GIT symptoms, headache, excessive bone marrow suppression, teratogenicity, photosensitivity Latency to full biological effect 4–6 months immunosuppressive bridge required typically with oral corticosteroids Reduce dose if WBC <3.0 × 109/L Mitoxantrone Second-line treatment in NMOSD Target dose:12 mg/m2 every 3 months; maximum cumulative dose 140 mg/m2 Route: Oral Side effects: Cardiotoxicity related to cumulative dose, excessive bone marrow suppression, and treatment-related acute leukemia Off-label Rituximab Considered as First-line treatment in NMOSD Dosing: 1000 mg given twice, 14 days apart. Each course may be administered 6 months or based on reemergence of CD19+ B cells Route: IV Side effects: sepsis, infections, leukopenia Mechanism of action: Chimeric mouse/human monoclonal antibody against CD20, a surface antigen expressed on B cells; its targeting results in B cell depletion Efficacy: Rituximab has been shown to have a preventive effect against relapse in NMOSD patients; in one trial rituximab use led to an 84% relapse-free rate after 28 months of rituximab treatment Advantages of Rituximab use: Rapid onset of action; B cell depletion occurs within 2 weeks of course completion and adherence can be easily tracked Off-label Tocilizumab Considered as Second-line treatment in NMOSD Dosing: 8 mg/kg every 4 weeks Route: IV Mechanism of action: Humanized monoclonal antibody against the IL-6 receptor. IL-6 signaling disruption→reduced AQP4-IgG production. Inhibition of proinflammatory T cell differentiation and decreased blood–brain permeability Efficacy: In a head-to-head trial of tocilizumab and azathioprine, tocilizumab was shown to have a greater therapeutic efficacy–89% on tocilizumab compared to 56% on azathioprine was relapse-free at the end of the trial. Tocilizumab was also associated with less adverse effects Treatments remained "empiric" as randomized clinical trials have only recently been conducted.1, 21, 24 Since 2019, the therapeutic landscape for NMOSD has been transformed with the introduction of more targeted therapy and with the FDA approval of 3 new drugs namely Eculizumab (terminal complement protein C5 inhibitor), Inebilizumab (CD-19 directed cytolytic antibody) and Satralizumab (IL-6 inhibitor) all demonstrating robust benefits in preventing relapses.1, 4, 25 Modulation of the complement system in the treatment of NMOSD was proposed with Eculizumab which was the first FDA-approved treatment for adults with AQP4 antibody-positive NMOSD.25, 26 Eculizumab is a monoclonal antibody (an anti-C5 complement inhibitor) that specifically binds to the complement component C5, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-C9.25, 26 Eculizumab thus works downstream and inhibits AQP4 antibody-induced terminal complement C5b-C9 deposition and the formation of the membrane attack complex.26 The Eculizumab trial or prevention of relapses in neuromyelitis optica (PREVENT) study showed that Eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 IgG-positive (AQP4+) NMOSD; it reduced the risk of relapse by 94% in patients compared to placebo (hazard ratio [HR] 0.06, 95% CI 0.02–0.20; p < .001) and the risk reduction persisted at 48 (98% in Eculizumab vs 63% in placebo group) and 144 weeks (96% in Eculizumab vs 45% in placebo group).27 Recently, in a phase III randomized trial a C5 no relapses occurred in the patients on as compared to the relapses that occurred in patients from the on placebo a monoclonal antibody to specifically bind to the surface antigen leads to the depletion of B cells to NMOSD with B and cell with antibody production which reduces the risk of further thus works In the Inebilizumab trial or MRI imaging into attack criteria for neuromyelitis optica spectrum (NMOSD) of the treated patients compared with of resulting in a reduction in adjudicated relapse risk 95% CI p < There was significant depletion in circulating after 8 at all time with Inebilizumab 30 levels of IL-6 in CNS fluid from patients with NMOSD may the use of IL-6 Satralizumab is a monoclonal antibody against the IL-6 by the IL-6 the differentiation of T cells into Th17 cells and in plasmablasts from antibodies against Satralizumab also targets inflammation, thus at multiple There are 2 Satralizumab the in with immunosuppressive and The study, showed a reduction in 95% CI p for treated patients The of treated patients were relapse-free at 48 weeks of and at weeks of The study a reduction in 95% CI p 30% of patients 50% of At 48 of patients were relapse-free of Furthermore, of treated patients 50% of remained relapse-free at In a both a reduction in the risk of attack in AQP4 antibody-positive patients was into therapeutic in NMOSD targeting Th17 cells and the cell bone marrow an a of a of which is and recently the trial of antigen therapy in NMOSD.25, It is to that these have no efficacy for the treatment of neuropsychiatric which the of the of LETM in SLE Furthermore, the 3 FDA agents are very adding an additional burden to The vast majority of NMOSD patients the would thus be of these medications as they would not be able to The less in clinical practice is For NMO patients on the then of how they should in not to to agents to be effective in relapse expert is, that since 90% of relapses occur within 5 years, therefore, 5 years relapse-free on RTX or agent may as evidence for disease without the for to an 24 the AQP4 autoantibody seropositive LETM is associated with a high risk of relapse within 1 year in patients with comorbid NMO and 4, The many relapses characterizing NMOSD necessitate long-term immunosuppression with several agents making these patients susceptible to recurrent infections and thus adding more to the disease burden and the challenges faced by clinicians and patients associated with poor increased relapse and relapse age years, African infections, of severe having a high AQP4 extensive LETM, symptoms at recurrent myelitis within 1 spinal cord and of The key are that SLE and coexisting NMO are that can be clinically expressed in patients with a to should these to extensive and clinical and serological evaluation of patients with of CNS disease, rheumatologic disease, or serological of the will and prompt and of treatment and of specific drugs drugs used for MS that can lead to catastrophic Myelitis is a rare complication of SLE which may lead to significant morbidity, and thus it is to differentiate it from presenting that may occur in patients with SLE as NMO and of NMO as a distinct diagnostic in patients with SLE is in that of prompt targeted treatment may to the many relapses that NMOSD long-term immunosuppression with several SLE patients are susceptible to recurrent infections adding to the disease should thus, manage relapses and to the of recurrent infections by prolonged differential diagnosis and treatment will the of such Furthermore, is that and and is required to identification of of patients with NMO and SLE and to of NMO for patients presenting with a first CNS event such as In the studies and the of a standardized for patients with SLE that LETM and NMO could to develop an effective treatment and targeted management for which may with SLE. studies of patients with coexisting NMO and rheumatologic diseases as are In studies in patients with overlap syndromes and with CNS manifestations of systemic autoimmune and rheumatologic diseases may better these and diagnostic and therapeutic on that or even prevent the disability resulting from attacks are greater will be needed to and for all with NMOSD. have to the recent and is not for or in other All have the All have no of and have no The that support the of study are available from the