Tatsuro Misu

JC virus (JCV) reactivation causing progressive multifocal leukoencephalopathy (PML) is a complication in patients with multiple sclerosis (MS) treated with disease-modifying therapies (DMTs). Although natalizumab (NTZ) is most frequently involved, PML also occurs less commonly with sphingosine-1-phosphate receptor modulators (S1P-RM), dimethyl fumarate (DMF), and ocrelizumab. This study aimed to identify factors predicting worse outcomes, focusing on the influence of PML-immune reconstitution inflammatory syndrome (PML-IRIS), plasma exchange (PlEx), corticosteroids, and DMT reintroduction. This retrospective multicenter cohort study analyzed patients with MS who had JCV-associated pathology (PML or granule cell neuronopathy) from 42 centers (2009-2022). The primary outcome was disability at 12 months, measured by the modified Rankin Scale (mRS). Multivariable analyses identified predictors of poor outcomes, PML-IRIS development, and recurrent MS activity. Of 96 identified patients, 94 were analyzed. Most cases occurred under NTZ (77%), followed by S1P-RM (22%) and DMF (1%). Twelve-month survival was 91.5%, with a median mRS of 3 [IQR: 2-4]. Multivariable analysis showed that higher pre-PML disability (OR: 1.95 [95% CI 1.46-2.60], p < 0.001), elevated CSF JCV viral load (OR: 2.45 [95% CI 1.55-3.87], p < 0.001), and symptomatic presentation at onset (OR: 3.93 [95% CI 1.23-12.55], p = 0.021) were associated with worse outcomes. Conversely, PML-IRIS was associated with better outcomes (OR: 0.28 [95% CI 0.09-0.86], p = 0.025). PlEx and corticosteroid use had no negative effect. This study provides valuable insights into the management of iatrogenic PML in patients with MS. The findings may guide clinicians in making informed decisions, particularly regarding the use of PlEx, corticosteroids, and the management of PML-IRIS.

Eculizumab and ravulizumab [complement component 5 inhibitor therapies (C5ITs)] and satralizumab (interleukin-6 receptor inhibitor) are approved for treatment of anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (NMOSD) in Japan. Here, we evaluate real-world treatment adherence and persistence with C5IT and satralizumab in patients with NMOSD in Japan. In this retrospective observational study, data (January 2016 to May 2024) from the Japan Medical Data Vision database were used to assess treatment adherence [number of treated days, proportion of days covered (PDC), continuous multiple-interval measure of gaps (CMG), observed versus expected doses ratio (OvEDR)] and persistence (proportion of patients without treatment discontinuation) during the 1-year follow-up after treatment initiation. Of 206 patients, 49 (23.8%) received C5IT and 157 (76.2%) received satralizumab. Patients receiving C5IT were younger than those receiving satralizumab [mean (SD) 51.0 years (11.3) vs. 56.2 years (13.8)], P = 0.009]. Comedication rates were similar at baseline and through follow-up. Median (Q1, Q3) treatment duration was 351.0 (336.0, 356.0) days for C5IT and 337.0 (316.0, 347.0) days for satralizumab. Significantly greater adherence was observed in the C5IT cohort than the satralizumab cohort [median (Q1, Q3) 96.2% (92.1%, 97.5%) vs. 92.3% (86.6%, 95.1%), P < 0.001 for PDC; 3.8% (2.5%, 7.9%) vs. 7.7% (4.9%, 13.4%), P < 0.001 for CMG; 94.7% (82.8%, 98.2%) vs. 86.7% (80.0%, 93.3%), P = 0.001 for OvEDR]. C5IT was associated with greater treatment persistence than satralizumab when evaluated using gaps ≥ 3 times (main analysis; 98.0% vs. 87.9%, P = 0.043) and ≥ 2.5 times (sensitivity analysis; 93.9% vs. 87.3%, P = 0.21) the normal dosing interval to define discontinuation. In this real-world study, treatment adherence and persistence were higher in patients with NMOSD receiving C5IT than satralizumab in Japan. Further prospective and larger studies of adherence and persistence in NMOSD are needed.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disease mainly driven by aquaporin-4 antibodies (AQP4-IgG). During an attack, AQP4-IgG activates the complement system, leading to astrocyte destruction, inflammation, neuronal damage, and thus devastating and often irreversible neurologic deficits. Terminal complement inhibitors such as eculizumab and ravulizumab effectively prevent relapses, yet their therapeutic potential in stopping ongoing complement-mediated injury during acute attacks remains insufficiently explored. We conducted a multinational retrospective case series across NMOSD-specialized centers in 6 countries, analyzing 33 AQP4-IgG-positive patients (mean age: 48.1 years; 28 women) treated with component 5 (C5) inhibition during or shortly after acute relapse (mean 20.1 days from symptom onset; range 2-62). Eculizumab was used in 25 patients and ravulizumab in 8. Two additional patients were excluded because of delayed treatment initiation beyond 62 days. Lesion locations included myelitis (57.6%) and optic neuritis (30.3%). Expanded Disability Status Scale scores worsened from a pre-relapse median of 0 (interquartile range [IQR] 0-2) to a nadir of 6.5 (IQR 3.5-8), improving to 3.5 (IQR 3-6.5) at 1-3 months and 2.5 (IQR 2-6) at 6 months. All patients stabilized clinically; 20 continued C5 inhibition as attack-preventing therapy. Good, moderate, and poor/absent recovery were observed in 15, 11, and 7 patients, respectively. Earlier treatment was associated with better outcomes: treatment within 21 days yielded an odds ratio of 1.58 (95% CI 0.32-8.52) for good response. Plasma exchange was administered in 57.6% and was associated with higher overall response rates, but not with good response alone. These findings highlight the potential of complement inhibition as a treatment option for acute NMOSD attacks, particularly in patients with insufficient response to standard therapies. Given the absence of clinical worsening and the encouraging course observed in most of the patients, further investigation into the role of C5 inhibition in acute attack management is warranted. This retrospective case series provides Class IV evidence that the C5 complement inhibitors eculizumab or ravulizumab may improve disability in patients with NMOSD when given during or shortly after acute relapse.

In this study, blood cell counts and serum C3, C4, and CH50 values at baseline and after more than 6-month drug use were measured to elucidate changes in blood cells and complements during relapse prevention therapies for aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD). A total of 70 patients with AQP4+ NMOSD (87% female, median age 56 years) were enrolled. They were divided into the following treatment groups: glucocorticoids and/or immunosuppressants (GC/IS, n = 22), inebilizumab/rituximab (anti-CD19/20, n = 13), satralizumab (anti-IL-6R, n = 22), and eculizumab/ravulizumab (anti-C5, n = 13). At baseline, the blood counts and complement levels did not differ among the groups. At follow-up, the neutrophil and platelet counts in the anti-IL-6R group decreased from those at baseline (p < 0.0001 and p < 0.001, respectively). Compared with the GC/IS, anti-CD19/20, and anti-C5 groups, the anti-IL-6R group had lower levels of C3 (p < 0.0001, p < 0.01, and p < 0.05, respectively) and C4 (p < 0.0001, p < 0.01, p < 0.001, respectively). Furthermore, the anti-C5 group had significantly lower CH50 levels than the GC/IS, anti-CD19/20, and anti-IL-6R groups (p < 0.0001, p < 0.0001, p < 0.05, respectively). In addition, the anti-IL-6R group had lower CH50 levels than the GC/IS and anti-CD19/20 groups (p < 0.001 and p < 0.05, respectively). The present study demonstrated that anti-IL-6R therapy broadly and mildly suppressed the complement system and decreased the neutrophil and platelet counts. It also showed that anti-C5 therapy strongly suppressed total complement activity but did not affect the C3 and C4 levels or blood counts. These findings may have implications for the mode of action of the drugs and the risk of adverse drug reactions, including infections.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is characterized by the predominance of optic neuritis, myelitis, acute disseminated encephalomyelitis (ADEM), and cortical encephalitis, and can be diagnosed by the presence of pathogenic immunoglobulin G (IgG) antibodies targeting the extracellular domain of MOG in the serum and cerebrospinal fluid (CSF). Initially considered a variant of multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), it is now widely recognized as a separate entity, supported by converging evidence from serological, pathological, and clinical studies. Patients with MOGAD often exhibit better recovery from acute attacks; however, their clinical and pathological features vary based on the immunological role of MOG-IgG via antibody- or complement-mediated perivenous demyelinating pathology, in addition to MOG-specific cellular immunity, resulting in heterogeneous demyelinated lesions from vanishing benign forms to tissue necrosis, even though MOGAD is not a mild disease. The key is the immunological mechanism of devastating lesion coalescence and long-term degenerating mechanisms, which may still accrue, particularly in the relapsing, progressing, and aggressive clinical course of encephalomyelitis. The warning features of the severe clinical forms are: (1) fulminant acute multifocal lesions or multiphasic ADEM transitioning to diffuse (Schilder-type) or tumefactive lesions; (2) cortical or subcortical lesions related to brain atrophy and/or refractory epilepsy (Rasmussen-type); (3) longitudinally extended spinal cord lesions severely affected with residual symptoms. In addition, it is cautious for patients refractory to acute stage early 1st treatment including intravenous methylprednisolone treatment and apheresis with residual symptoms and relapse activity with immunoglobulin and other 2nd line treatments including B cell depletion therapy. Persistent MOG-IgG high titration, intrathecal production of MOG-IgG, and suggestive markers of higher disease activity, such as cerebrospinal fluid interleukin-6 and complement C5b-9, could be identified as promising markers of higher disease activity, worsening of disability, and poor prognosis, and used to identify signs of escalating treatment strategies. It is promising of currently ongoing investigational antibodies against anti-interleukin-6 receptor and the neonatal Fc receptor. Moreover, due to possible refractory issues such as the intrathecal production of autoantibody and the involvement of complement in the worsening of the lesion, further developments of other mechanisms of action such as chimeric antigen receptor T-cell (CAR-T) and anti-complement therapies are warranted in the future.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is characterized by the predominance of optic neuritis, myelitis, acute disseminated encephalomyelitis, and cortical encephalitis, which can be diagnosed by the presence of pathogenic immunoglobulin G (IgG) antibodies targeting the extracellular domain of MOG in the serum and cerebrospinal fluid (CSF). Initially considered a variant of multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), it is now widely recognized as a separate entity, supported by converging evidence from serological, pathological, and clinical studies. Pa-tients with MOGAD often exhibit better recovery from acute attacks, but their clinical and pathological features vary based on the immunological role of MOG-IgG via antibody-mediated or complement-mediated perivenous demyelinating pathology in addition to MOG-specific cellular immunity, resulting in heterogeneous demyelinated lesions from vanishing benign form to tissue necrosis. The key is the immunological mechanism of devastating lesion coalescence and long-term degenerating mechanisms, which may still accrue, particularly in the relapsing, progressing, and aggressive clinical course of encephalomyelitis. The warning features of the severe forms are: 1. fulminant acute multifocal lesions transitioning to diffuse or tumefactive lesions; 2. cortical lesions related to status epilepsy; 3. Longitudinally extended spinal cord lesions not well subsided. Persistent MOG-IgG high-titration, intrathecal production of MOG-IgG, and suggestive markers of higher disease activity like cerebrospinal fluid inter-leukin-6 and complement C5b-9 could be identified as promising markers of higher disease activity, disability worsening, and poor prognosis, for identifying sign of escalating treatment strategies.

To clarify T-cell responses in myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), we cultured the peripheral blood mononuclear cells of 24 patients with MOGAD and 20 with aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorders (NMOSD), and those of 17 healthy controls (HCs), in the presence of fourteen MOG peptides covering the full-length MOG, five AQP4 peptides, two myelin basic protein peptides, or two proteolipid protein peptides. Then, we measured T-cell activation markers, such as cell surface CD69 and the intracellular production of granulocyte–macrophage colony-stimulating factor (GM-CSF) and interferon-γ in CD4-positive T-cells, with a flow cytometer. The expression of CD69 in response to MOG p16–40 and MOG p181–205 was significantly higher (Stimulation Index > 2) in MOGAD than in HCs. Also, CD69 for AQP4 p21–40, AQP4 p211–230, and MOG p166–190 were significantly increased in NMOSD than in HCs. Intracellular GM-CSF production responding to MOG p16–40 was significantly higher in MOGAD than in HCs (p < 0.05), although intracellular interferon-γ was not elevated. None of the responses to the other peptides were different between the groups. The present study showed subtle CD4-positive T-cell activation elicited by some MOG peptides alone in patients with MOGAD. Further studies of cytokines or other stimulation and alternative assay markers and metrics are needed to delineate the immunopathological roles of T-cells in MOGAD.

Background/Objectives: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-related neurological disease that primarily affects the optic nerve and spinal cord. According to current international consensus guidelines for NMOSD, confirming the presence of aquaporin-4 immunoglobulin G antibody (AQP4-IgG) is one of the most important diagnostic criteria because AQP4-IgG is a significant diagnostic biomarker of NMOSD. Several assays are currently available for detecting AQP4-IgG, including cell-based assays (CBAs) and enzyme-linked immunosorbent assays (ELISAs). However, each assay has certain disadvantages, including insufficient sensitivity and specificity, the need for sophisticated techniques, and semi-quantitative results. Methods: We developed a fully automated chemiluminescent enzyme immunoassay (CLEIA) to detect AQP4-IgG (AQP4-CLEIA). This assay utilizes the recombinant antigen purified from the newly generated AQP4-M23 stably expressing Chinese hamster ovary cell line and an anti-AQP4 monoclonal antibody as a calibrator. Results: In analytical performance studies, the assay demonstrates good precision and linearity over the entire measurement range. Moreover, this assay showed no high-dose hook effect and interference from endogenous substances. In clinical validation studies, patients with AQP4-IgG positive NMOSD, multiple sclerosis, or myelin oligodendrocyte glycoprotein antibody-associated disorder and healthy individuals were tested. A cutoff value of 10.0 U/mL was determined by receiver operating characteristic curves based on the results of a microscopic live CBA. The sensitivity and specificity for AQP4-IgG-positive NMOSD were 97.0% and 100.0%, respectively, at the cutoff value. Conclusions: The results suggest that AQP4-CLEIA is a convenient automated method for measuring AQP4-IgG titers in hospitals and clinical laboratories, offering an effective alternative to the gold-standard CBA.

In myelin oligodendrocyte glycoprotein IgG-associated disease (MOGAD) and aquaporin-4 IgG+ neuromyelitis optica spectrum disorder (AQP4+NMOSD), the autoantibodies are mainly composed of IgG1, and complement-dependent cytotoxicity is a primary pathomechanism in AQP4+NMOSD. We aimed to evaluate the CSF complement activation in MOGAD. CSF-C3a, CSF-C4a, CSF-C5a, and CSF-C5b-9 levels during the acute phase before treatment in patients with MOGAD (n = 12), AQP4+NMOSD (n = 11), multiple sclerosis (MS) (n = 5), and noninflammatory neurologic disease (n = 2) were measured. CSF-C3a and CSF-C5a levels were significantly higher in MOGAD (mean ± SD, 5,629 ± 1,079 pg/mL and 2,930 ± 435.8 pg/mL) and AQP4+NMOSD (6,017 ± 3,937 pg/mL and 2,544 ± 1,231 pg/mL) than in MS (1,507 ± 1,286 pg/mL and 193.8 ± 0.53 pg/mL). CSF-C3a, CSF-C4a, and CSF-C5a did not differ between MOGAD and AQP4+NMOSD while CSF-C5b-9 (membrane attack complex, MAC) levels were significantly lower in MOGAD (17.4 ± 27.9 ng/mL) than in AQP4+NMOSD (62.5 ± 45.1 ng/mL, p = 0.0019). Patients with MOGAD with severer attacks (Expanded Disability Status Scale [EDSS] ≥ 3.5) had higher C5b-9 levels (34.0 ± 38.4 ng/m) than those with milder attacks (EDSS ≤3.0, 0.9 ± 0.7 ng/mL, p = 0.044). The complement pathway is activated in both MOGAD and AQP4+NMOSD, but MAC formation is lower in MOGAD, particularly in those with mild attacks, than in AQP4+NMOSD. These findings may have pathogenetic and therapeutic implications in MOGAD.