Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood-brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive 'stage-dependent' investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM+) helper T (TH) 17/cytotoxic T (TC) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3+) regulatory T (Treg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103+ tissue-resident memory T (TRM) cells with long-lasting inflammatory potential, are detected under "standby" conditions in all stages. Furthermore, CD103+ TRM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM+ TH17/TC17 cells, and CD103+ TRM cells, as well as promoting the expansion of FOXP3+ Treg cells, may be effective in treating and preventing relapses of NMOSD.

Acute respiratory failure caused by brainstem demyelinating lesions in an older patient with an atypical relapsing autoimmune disorder.

An 84-year-old man presented with somnolence, dysphagia, and right hemiplegia, all occurring within a month, approximately one year after initial admission due to subacute, transient cognitive decline suggestive of acute disseminated encephalomyelitis involving the cerebral white matter. Serial magnetic resonance imaging (MRI) studies over that period revealed three high-intensity signal lesions on fluid-attenuated inversion recovery images, appearing in chronological order in the left upper and left lower medulla oblongata and left pontine base. Despite some clinical improvement following methylprednisolone pulse therapy, the patient died of respiratory failure. Autopsy revealed four fresh, well-defined lesions in the brainstem, three of which corresponded to the lesions detected radiologically. The remaining lesion was located in the dorsal medulla oblongata and involved the right solitary nucleus. This might have appeared at a later disease stage, eventually causing respiratory failure. Histologically, all four lesions showed loss of myelin, preservation of axons, and infiltration of lymphocytes, predominantly CD8-positive T cells, consistent with the histological features of autoimmune demyelinating diseases, particularly the confluent demyelination observed in the early and acute phases of multiple sclerosis (MS). In the cerebral white matter, autoimmune demyelination appeared superimposed on ischemic changes, consistent with the cerebrospinal fluid (CSF) and MRI findings on initial admission. No anti-AQP4 or MOG antibodies or those potentially causing autoimmune encephalitis/demyelination were detected in either the serum or CSF. Despite several similarities to MS, such as the relapsing-remitting disease course and lesion histology, the entire clinicopathological picture in the present patient, especially the advanced age at onset and development of brainstem lesions in close proximity within a short time frame, did not fit those of MS or other autoimmune diseases that are currently established. The present results suggest that exceptionally older individuals can be affected by an as yet unknown inflammatory demyelinating disease of the CNS.

[Tumefactive demyelinating lesion (TDL)].

Tumefactive demyelinating lesion(TDL)is defined as a large lesion, size >2 cm, mass effect, perilesional edema and/or ring enhancement. TDL could occur in multiple sclerosis(MS), neuromyelitis optica spectrum disorder(NMOSD), acute disseminated encephalomyelitis(ADEM)or other immunological diseases. Non-invasive methods including MR imaging and assay of several autoantibodies(e.g. aquaporin-4 autoantibodies)are recommended when each TDL is identified. The radiological findings on MRI are characterized by size >2 cm, mass effect, perilesional edema, T2 weighted hypointense rim, peripheral diffusion restriction, open ring enhancement, vascular enhancement, and central vein sign. When atypical clinical and radiological presentations are present in patients with TDL, diagnosis may necessitate brain biopsy due to exclude alternative pathology(e.g. primary central nervous system lymphoma). Because treatments and outcomes for patients with TDL are dependent on each disease etiology including MS, NMOSD, ADEM or others, we should always clarify the entire picture behind the disease.

Neuromyelitis optica spectrum disorder with massive basal ganglia involvement: a case report.

BACKGROUND: Occurrence of basal ganglia involvement in neuromyelitis optica spectrum disorders (NMOSD) has rarely been reported and none documented pathologically. CASE PRESENTATION: A 73-year-old female was clinically diagnosed with a NMOSD based on the clinical and radiological features and positive serum autoantibodies to AQP4. One month before her death, she became acutely ill with disturbed consciousness and right hemiparesis, and was diagnosed and treated as having basal ganglia infarction based on the brain CT. She made a partial recovery but later died from heart failure. At autopsy, the corresponding basal ganglia process revealed a large fresh area of necrosis. Histologically, several pathological signatures of NMOSD could be recognized in the lesion, including inflammatory cell infiltrations by B and T lymphocytes, perivascular complement and fibrinogen deposition, and the appearance of numerous phagocytosed corpora amylacea within the infiltrating macrophages. CONCLUSIONS: The present case illustrates that basal ganglia may be directly involved in the pathological processes of NMOSD, although the possibility of modification of the lesions by superimposed regional ischemia could not be excluded.

Recent transition of medical cost and relapse rate of multiple sclerosis in Japan based on analysis of a health insurance claims database.

BACKGROUND: In this study, we aimed to understand the trends in total and itemized medical expenses, especially of disease-modifying therapy (DMT), for multiple sclerosis (MS) in Japan through an analysis of health insurance claims data. METHODS: We analyzed a database containing health insurance claims data from hospitals that have adopted the Diagnosis Procedure Combination/Per-Diem Payment System in Japan. According to an algorithm based on diagnosis codes, data for all patients diagnosed with MS from April 2008 to July 2016 were extracted. Medical costs, rate of each medical treatment, and rate of relapses were analyzed by calendar-year. Medical costs in the month of relapse were compared with average medical costs per month of all MS patients by a cross-sectional analysis. RESULTS: Four thousand three hundred seventy-four MS patients were identified in the database. Total medical cost per patient per month (PPPM) increased from ¥87,640 (US$787.7 or €723.0 as of May 2017) to ¥102,846 (US$924.4 or €848.4) during the study period. This increment was mainly attributed to the growth in cost of outpatient DMT prescriptions, which increased from ¥23,039 (US$207.1 or €190.1) to ¥51,351 (US$461.5 or €423.6). In contrast, the rate of hospitalizations and relapses PPPM decreased during the study period (from 0.053 to 0.030, and 0.032 to 0.019, respectively). Medical costs in the month of relapse (¥424,661, US$3816.8 or €3503.1) were 3.57 times higher than the average monthly costs for all MS patients (¥119,021, US$1069.8 or €981.8), with the majority comprising hospitalization cost. CONCLUSION: Concomitant with the increased usage of DMT, the total medical cost for treating MS is increasing in Japan. However, rates of relapse and hospitalization have shown a decreasing trend. Although this study does not show the direct causality between DMT and reduction of relapse rates/fewer hospitalizations among MS patients, a reduction in hospital costs has been revealed concomitantly with the increasing prevalence of DMT.

Clinicopathological features in anterior visual pathway in neuromyelitis optica.

OBJECTIVE: Neuromyelitis optica spectrum disorder (NMOsd) is an autoimmune disorder of the central nervous system characterized by aquaporin-4 (AQP4) autoantibodies. The aim of this study was to elucidate the characteristics of involvement of the anterior visual pathway (AVP) and neurodegeneration via glia-neuron interaction in NMOsd. METHODS: Thirty Japanese patients with serologically verified NMOsd were assessed with a neuro-ophthalmological study. Using 27 tissue blocks from 13 other cases of NMOsd, we performed neuropathological analysis of glial and neuroaxonal involvement in the AVP. RESULTS: The AVP involvement in NMOsd was characterized by the following, compared to multiple sclerosis: (1) longitudinally extensive optic neuritis (ON); (2) more severe visual impairment and worse prognosis for ON; (3) unique AQP4 dynamics, including loss of AQP4 immunoreactivity on astrocytes with complement activation in ON lesions, loss of AQP4 immunoreactivity on Müller cells with no deposition of complement in the retinas, and densely packed AQP4 immunoreactivity on astrocytes in gliosis of secondary anterograde/retrograde degeneration in the optic nerves and retinal nerve fiber layer (RNFL); and (4) more severe neurodegeneration, including axonal accumulation of degenerative mitochondria and transient receptor potential melastatin 4 channel with complement-dependent astrocyte pathology in ON lesions, mild loss of horizontal cells, and RNFL thinning and loss of ganglion cells with abundance of AQP4(+) astrocytes, indicating secondary retrograde degeneration after ON. INTERPRETATION: Severe and widespread neuroaxonal damage and unique dynamics of astrocytes/Müller cells with alterations of AQP4 were prominent in the AVP and may be associated with poor visual function and prognosis in NMOsd.

Neurodegeneration in multiple sclerosis and neuromyelitis optica.

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are autoimmune demyelinating diseases of the central nervous system (CNS), having distinct immunological and pathological features. They have two pathogenic components, 'inflammation' and 'neurodegeneration', with different degrees of severity and pathogenetic mechanisms. The target antigen of autoimmunity in NMO is the water channel aquaporin-4 (AQP4), and antibodies directed against this antigen result in astrocyte damage. MS is a disease primarily affecting myelin and oligodendrocytes, but thus far, no MS-specific autoantigen has been identified. The distinct inflammatory processes in these diseases may trigger cascades of events leading to disease-specific neurodegeneration. Damage of the CNS tissue appears to be amplified by mechanisms that are in part shared by the two conditions and involve oxidative burst activation in microglia/macrophages, mitochondrial damage and axonal energy failure, Wallerian degeneration and meningeal inflammation. However, they appear to differ regarding the nature of the inflammatory response, the type and extent of cortical injury, and the type of astrocyte reaction and damage. Here, we provide a detailed comparison of the pathology between MS and NMO, which may help to define shared and disease-specific mechanisms of neurodegeneration in these diseases.

Efficacy of intravenous methylprednisolone pulse therapy in patients with multiple sclerosis and neuromyelitis optica.

BACKGROUND: No large-scale studies have compared the efficacy of intravenous methylprednisolone pulse therapy (IVMP) for multiple sclerosis (MS) and neuromyelitis optica (NMO). OBJECTIVE: To explain differences in treatment responses of MS and NMO patients to IVMP. METHODS: Changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1 week of IVMP completion were obtained in 2010 at 28 institutions, and retrospectively collated from 271 MS (478 courses) and 73 NMO (118 courses) cases. RESULTS: In MS patients, decreased EDSS score was significant after the first (-0.8 ± 0.9), second (-0.7 ± 0.9), and third (-0.7 ± 0.8) courses (p < 0.05), but not after the fourth (-0.3 ± 0.7) and fifth (-0.5 ± 0.6). However, decreased EDSS score was only significant after the first course (-0.5 ± 1.5, p < 0.05) in NMO patients. EDSS score was significantly decreased in MS compared with NMO patients at the first course (p < 0.05), but not thereafter. Model analysis for EDSS score improvement at the first course, adjusting for covariates, showed significantly greater decreases in MS compared with NMO patients (p < 0.05). CONCLUSION: IVMP is effective in MS from the first to third courses, and in NMO at the first course. Additionally, IVMP is more efficacious in MS than NMO patients, even at the first course.

Hypertrophic pachymeningitis: significance of myeloperoxidase anti-neutrophil cytoplasmic antibody.

The aim of this study was to elucidate the characteristics, pathogenesis and treatment strategy of hypertrophic pachymeningitis that is associated with myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA). We retrospectively investigated clinical, radiological, immunological and pathological profiles of 36 patients with immune-mediated or idiopathic hypertrophic pachymeningitis, including 17 patients with myeloperoxidase-ANCA, four patients with proteinase 3-ANCA, six patients with other immune-mediated disorders, and nine patients with 'idiopathic' variety. Myeloperoxidase-ANCA-positive hypertrophic pachymeningitis was characterized by: (i) an elderly female predominance; (ii) 82% of patients diagnosed with granulomatosis with polyangiitis (previously known as Wegener's granulomatosis) according to Watts' algorithm; (iii) a high frequency of patients with lesions limited to the dura mater and upper airways, developing headaches, chronic sinusitis, otitis media or mastoiditis; (iv) a low frequency of patients with the 'classical or generalized form' of granulomatosis with polyangiitis involving the entire upper and lower airways and kidney, or progressing to generalized disease, in contrast to proteinase 3-ANCA-positive hypertrophic pachymeningitis; (v) less severe neurological damage according to the modified Rankin Scale and low disease activity according to the Birmingham Vasculitis Activity Score compared with proteinase 3-ANCA-positive hypertrophic pachymeningitis; (vi) increased levels of CXCL10, CXCL8 and interleukin 6 in cerebrospinal fluids, and increased numbers of T cells, neutrophils, eosinophils, plasma cells and monocytes/macrophages in autopsied or biopsied dura mater with pachymeningitis, suggesting TH1-predominant granulomatous lesions in hypertrophic pachymeningitis, as previously reported in pulmonary or renal lesions of granulomatosis with polyangiitis; and (vii) greater efficacy of combination therapy with prednisolone and cyclophosphamide compared with monotherapy with prednisolone. Proteinase 3-ANCA may be considered a marker for more severe neurological damage, higher disease activity and a higher frequency of the generalized form compared with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. However, categorization into 'granulomatosis with polyangiitis' according to Watts' algorithm and immunological or pathological features were common in both proteinase 3- and myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. These data indicate that most patients with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis should be categorized as having the central nervous system-limited form of ANCA-associated vasculitis, consistent with the concept of ophthalmic-, pulmonary- or renal-limited vasculitis.

Significance of gray matter brain lesions in multiple sclerosis and neuromyelitis optica.

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are the two main autoimmune diseases of the CNS. In patients with NMO, the target antigen is aquaporin-4 (AQP4), the most abundant water channel protein in the CNS. AQP4 is mainly expressed on astrocytic endfoot processes at the blood-brain barrier and in subpial and subendymal regions. MS and NMO are distinct diseases, but they have some common clinical features: both have long been considered autoimmune diseases that primarily affect the white matter (WM). However, because WM demyelination by itself cannot explain the full extent of the clinical disabilities, including cognitive decline in patients with MS and NMO, renewed interest in gray matter (GM) pathology in MS and NMO is emerging. Important hallmarks of WM and GM lesions in MS and NMO may differentially influence neuronal degeneration and demyelination in the brain and spinal cord, given different detrimental effects, including cytokine diffusion, disruption of water homeostasis associated with or without AQP4 (the target antigen in NMO) dynamics, or other unidentified mechanisms. An increase in knowledge of the structure of GM and WM lesions in MS and NMO will result in more targeted therapeutic approaches to these two diseases.

Cognitive impairment and cortical degeneration in neuromyelitis optica.

OBJECTIVE: Neuromyelitis optica spectrum disorder (NMOsd) is an inflammatory and demyelinating syndrome characterized by optic neuritis and myelitis. Several magnetization transfer magnetic resonance imaging (MRI) studies have revealed abnormalities in normal-appearing gray matter in NMOsd. The aim of this study is to elucidate the characteristics and pathogenesis of cognitive impairment and neurodegeneration in NMOsd brains. METHODS: Fourteen Japanese patients with serologically verified NMOsd, 17 patients with multiple sclerosis (MS), and 37 healthy controls were assessed with the Rao's Brief Repeatable Battery of Neuropsychological Tests (BRBN). Using 128 tissue blocks from 6 other cases of NMOsd, 3 cases of MS, and 4 controls without central nervous system involvement, we performed quantitative analysis of cortical neuronal loss and layer-specific changes in NMOsd. RESULTS: In BRBN assessments, 57% of NMOsd patients and 47% of MS patients had impaired performance on at least 3 cognitive tests. Cognitive impairment in NMOsd was common even in the limited form of disease, indicating that NMOsd may progress insidiously from early stages of disease. Neuropathological assessments showed neuronal loss in cortical layers II, III, and IV, with nonlytic reaction of aquaporin-4 (AQP4)-negative astrocytes in layer I, massive activated microglia in layer II, and meningeal inflammation in NMOsd brains. All NMO cases showed no evidence of cortical demyelination. INTERPRETATION: We demonstrate cognitive impairment and substantial cortical neuronal loss with unique AQP4 dynamics in astrocytes in NMOsd. These data indicate pathological processes consisting not only of inflammatory demyelinating events characterized by pattern-specific loss of AQP4 immunoreactivity but also cortical neurodegeneration in NMOsd brains.

Apathy/depression, but not subjective fatigue, is related with cognitive dysfunction in patients with multiple sclerosis.

BACKGROUND: Cognitive impairment could affect quality of life for patients with multiple sclerosis (MS), and cognitive function may be correlated with several factors such as depression and fatigue. This study aimed to evaluate cognitive function in Japanese patients with MS and the association between cognitive function and apathy, fatigue, and depression. METHODS: The Brief Repeatable Battery of Neuropsychological tests (BRB-N) was performed in 184 Japanese patients with MS and 163 healthy controls matched for age, gender, and education. The Apathy Scale (AS), Fatigue Questionnaire (FQ), and Beck Depression Inventory Second Edition (BDI-II) were used to evaluate apathy, fatigue, and depression, respectively. Student's t-test was used to compare MS patients and healthy controls. Correlations between two factors were assessed using the Pearson correlation test, and multiple regression analysis was used to evaluate how much each factor affected the BRB-N score. RESULTS: In all BRB-N tests, patients with MS scored significantly lower than controls, and the effect size of symbol digit modalities test was the highest among the 9 tests of the BRB-N. Patients with MS had higher AS (p < 0.001), FQ (p < 0.0001), and BDI-II (p < 0.0001) scores than controls. In patients with MS, scores on most of the BRB-N tests correlated with scores on the AS and BDI-II; however, there was little correlation between scores on the BRB-N tests and those on the FQ. CONCLUSIONS: Cognitive function was impaired, particularly information-processing speed, and decreased cognitive function was correlated with apathy and depression in Japanese patients with MS. Despite the association between cognitive variables and depression/apathy, cognitive function was impaired beyond the effect of depression and apathy. However, subjective fatigue is not related with cognitive impairment. Taken together, this suggests that different therapeutic approaches are needed to improve subjective fatigue and cognition, and thereby quality of life, in patients with MS.

Can anti-AQP4 antibody damage the blood-brain barrier?

BACKGROUND: Aquaporin 4 (AQP4) is a water-channel protein predominantly expressed in astrocyte end feet that make up the blood-brain barrier (BBB). Recently, anti-AQP4 antibody has been identified as a specific biomarker of neuromyelitis optica (NMO). However, whether anti-AQP4 antibodies damage the BBB is unclear. METHODS: We evaluated BBB damage in patients with NMO and multiple sclerosis by measuring albumin leakage (AL) and studied its correlation with anti-AQP4 antibody. RESULTS: No obvious difference in AL was observed between patients with and without anti-AQP4 antibodies. In the multivariate analysis, anti-AQP4 antibody was not associated with BBB damage. Of the anti-AQP4-positive patients, 58.0% had normal AL values, and the degree of BBB damage was unrelated to the anti-AQP4 antibody titer. In addition, 41.9% of anti-AQP4-positive patients showed no gadolinium enhancement of the MRI. CONCLUSION: These results indicate that the presence of anti-AQP4 antibody alone in plasma is insufficient to disrupt the BBB.

[Characteristic features of radiological findings in multiple sclerosis and neuromyelitis optica].

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are the two main autoimmune and inflammatory diseases of the central nervous system (CNS), and conventional magnetic resonance imaging (MRI) is a currently-established tool in the diagnosis of these two diseases. More recently, the utility of both conventional MRI and advanced MR techniques including structural, metabolic and functional MRI have provided new surrogate markers of clinical activity and prognosis. This review focuses on the current knowledge of the details of radiological examination in two distinct diseases, MS and NMO, and clarifies that each has unique characteristic features of radiological and pathological modalities in the CNS. However, advanced MR techniques still need to be fully evaluated and validated by pathological studies.

Effect of Infliximab on Chronic Progressive Neuro-Behçet's Disease: Influence of the Timing of Introduction on the Patient Outcome.

Objectives Chronic progressive neuro-Behcet's disease (CPNB) is characterized by progressive deterioration leading to disability. Methotrexate (MTX) has been shown to have beneficial effects on CPNB. However, while infliximab has been found to be effective for patients with inadequate responses to MTX, the appropriate timing for the introduction of infliximab remains unclear. We explored the effects of intervals before the introduction of infliximab on the functional outcome. Methods A retrospective analysis was performed for patients with CPNB who received infliximab and were followed up until October 2015. Functional disability was rated by the Steinbrocker functional classification as used in rheumatoid arthritis. Correlations between the outcomes and intervals before the introduction of infliximab were then analyzed by Spearman's rank correlation test. Patients Eleven patients with CPNB [8 men, 3 women, age 35.2±9.3 years old (mean±standard deviation)] who met the international classification criteria for Behcet's disease were included. Results All 11 patients had received MTX prior to infliximab. The intervals from the onset to the introduction of infliximab and the follow-up periods were 26.6±35.1 months and 65.2±43.6 months [mean±standard deviation], respectively. Among the 11 patients, 2 still showed progression after the introduction of infliximab. The functional disability grades after infliximab treatment were significantly correlated with the intervals from the onset of CPNB to the introduction of infliximab (r=0.6177, p=0.0476). Conclusion The results indicate that the delayed introduction of infliximab leads to irreversible functional disability in CPNB. Thus, it is recommended that infliximab be administered as soon as possible for CPNB patients with inadequate responses to MTX.

Safety and Effectiveness of Satralizumab in Japanese Patients with Neuromyelitis Optica Spectrum Disorder: A 6-month Interim Analysis of Post-marketing Surveillance.

INTRODUCTION: Satralizumab, an anti-interleukin-6 receptor antibody, is approved in Japan for relapse prevention in neuromyelitis optica spectrum disorder (NMOSD) and is undergoing post-marketing surveillance (PMS) of clinical use. We aimed to describe the real-world safety and effectiveness of satralizumab in Japanese patients with NMOSD. METHODS: This is an ongoing PMS (planned completion: February 2027). This 6-month interim analysis assessed the safety and effectiveness of satralizumab in Japanese patients with NMOSD using data collected from August 2020 to July 2021. RESULTS: Among 570 patients who participated, 523 (91.75%) were female and the mean ± standard deviation (SD) age was 52.4 ± 14.1 years. At baseline, NMOSD expanded disability status scale mean ± SD was 4.19 ± 2.19; 490 (85.96%) patients used glucocorticoids and 277 (48.59%) patients used immunosuppressants concomitantly. Of 570 satralizumab-treated patients, 85 (14.91%) had discontinued satralizumab treatment at 6 months. For the overall adverse drug reactions (ADRs), 76.22 (66.07-87.48) events/100 person-years occurred in 118 (20.70%) patients, and infections occurred in 28 (4.91%) patients. Serious infections occurred in 18 (3.15%) patients, with an event rate of 9.05 (5.80-13.47) events/100 person-years. Of the 24 events of serious infections, respiratory tract infections (29.17%; 7) and urinary tract infections (25.00%; 6) were the most common serious infection events. One fatal ADR (septic shock) suspected to be related to satralizumab was reported. The mean ± SD glucocorticoid dose reduced from 12.28 ± 10.17 mg/day at the index date to 8.11 ± 7.30 mg/day at 6 months. The Kaplan-Meier cumulative relapse-free rate (95% confidence interval) was 94.59% (92.25-96.23) at 6 months. CONCLUSION: In this study, satralizumab was found to be safe, well tolerated, and effective in patients with NMOSD in routine clinical practice. The results are consistent with those of previous clinical trials. The safety and effectiveness of satralizumab in Japanese patients with NMOSD will be analyzed over the 6-year surveillance period. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000041047.

Clinical practice guidelines for multiple sclerosis, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein antibody-associated disease 2023 in Japan.

BACKGROUND: The previous Japanese clinical practice guidelines for multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) were published in 2017. Recently, for the first time in 6 years, the MS and NMOSD guideline development committee revised the Japanese guidelines for MS, NMOSD, and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). METHODS: The committee utilized the Grading of Recommendations Assessment, Development, and Evaluation system based on the "Minds Handbook for Clinical Practice Guideline Development 2020 Ver. 3.0″ with a focus on clinical questions (CQs). The committee also discussed clinical issues other than CQs, categorizing them as a question-and-answer (Q&A) section, including "issues on which experts' opinions agree to a certain extent" and "issues that are important but not included in the CQ". RESULTS: The committee identified 3, 1, and 1 key CQs related to MS, NMOSD, and MOGAD, respectively, and presented recommendations. A Q&A session regarding disease-modifying therapies and relapse prevention therapies for MS, NMOSD, and MOGAD was conducted. The revised guidelines were published in September 2023. CONCLUSIONS: The Japanese guidelines for clinical practice on MS, NMOSD, and MOGAD were updated. Treatment strategies for MS, NMOSD, and MOGAD are changing, and these updated guidelines may assist with treatment decisions for these diseases in clinical practice.

Relapse of multiple sclerosis in a patient retaining CCR7-expressing T cells in CSF under fingolimod therapy.

Fingolimod acts as a functional antagonist of the sphingosine-1-phosphate receptor, and it traps lymphocytes in secondary lymphoid organs and precludes their migration into the central nervous system. We report the case of a patient who suffered a relatively severe relapse of multiple sclerosis (MS) during the initial 3 months of fingolimod therapy, with retention of CCR7 expression on CD4(+) T cells in the cerebrospinal fluid (CSF) despite decreased numbers of lymphocytes and decreased expression of CCR7 on CD4(+) T cells in the blood. These data suggest that fingolimod may cause differential effects on the CSF and blood lymphocytes of patients with MS during the initial months of therapy.

Health-related quality of life in Japanese patients with multiple sclerosis.

OBJECTIVES: Neurological disabilities, especially physical issues, can adversely affect the daily lives of people with multiple sclerosis (MS) and negatively impact their health-related quality of life (HRQOL). On the other hand, physical and psychiatric symptoms are variable in people with MS, and QOL can be influenced by cultural and educational background. This study aimed to evaluate the association of HRQOL with disabilities, fatigue, and depression in Japanese subjects with MS. METHODS: Evaluation of HRQOL, fatigue, and depression was performed in 184 Japanese individuals with MS, using the Functional Assessment of MS (FAMS), Fatigue Severity Scale (FSS), and Beck Depression Inventory-Second Edition (BDI-II), respectively. RESULTS: Multiple linear regression analysis demonstrated negative correlations of the Expanded Disability Status Scale (EDSS) with scores on the FAMS subscales of mobility, symptoms, thinking and fatigue, total FAMS, and additional concerns. The FSS score had negative correlations with mobility, symptoms, emotional well-being, thinking and fatigue, total FAMS, and additional concerns. There were negative correlations between BDI-II scores and all items of FAMS. CONCLUSIONS: HRQOL had relatively close correlations with disabilities and fatigue, and depression had an especially close relationship with HRQOL.

Semiquantitative measurement of aquaporin-4 antibodies as a possible surrogate marker of neuromyelitis optica spectrum disorders with systemic autoimmune diseases.

OBJECTIVES: To assess the association between serum aquaporin-4 (AQP4) autoantibodies and neuromyelitis optica spectrum disorders (NMOSDs) associated with systemic autoimmune diseases. METHODS: We retrospectively studied 626 hospitalized patients with systemic lupus erythematosus (SLE) or Sjögren's syndrome (SS). We collected serum samples from those patients with suspected NMOSDs (i.e., myelitis or optic neuritis) at the time of onset and thereafter. AQP4 antibodies were measured by a cell-based indirect immunofluorescence assay using AQP4-transfected HEK-293 cells in a semi-quantitative manner. RESULTS: Sera from 6 patients with suspected NMOSDs and SLE (n = 3) or SS (n = 3) were evaluated. Among these, 2 patients' sera samples, i.e., 1 with SLE and 1 with SS, were positive for AQP4 antibodies. There was an inverse relationship between disease amelioration and antibody titer in one NMOSD patient, whereas the antibody titer remained high in the other NMOSD patient, whose clinical manifestations of NMOSDs did not improve despite intensive immunosuppressive treatments. CONCLUSIONS: These results indicate that serum AQP4 antibodies are present in some SLE/SS patients with myelitis/optic neuritis and might be associated with clinical outcomes. The semi-quantitative measurement of the AQP4 antibody might be a possible surrogate marker in patients with NMOSDs associated with systemic autoimmune diseases.