Objective Myelin oligodendrocyte glycoprotein–immunoglobulin G (MOG-IgG) associated disorder (MOGAD) often manifests with recurrent CNS demyelinating attacks. The optimal treatment for reducing relapses is unknown. To help determine the efficacy of long-term immunotherapy in preventing relapse in patients with MOGAD, we conducted a multicenter retrospective study to determine the rate of relapses on various treatments. Methods We determined the frequency of relapses in patients receiving various forms of long-term immunotherapy for MOGAD. Inclusion criteria were history of ≥1 CNS demyelinating attacks, MOG-IgG seropositivity, and immunotherapy for ≥6 months. Patients were reviewed for CNS demyelinating attacks before and during long-term immunotherapy. Results Seventy patients were included. The median age at initial CNS demyelinating attack was 29 years (range 3–61 years; 33% <18 years), and 59% were female. The median annualized relapse rate (ARR) before treatment was 1.6. On maintenance immunotherapy, the proportion of patients with relapse was as follows: mycophenolate mofetil 74% (14 of 19; ARR 0.67), rituximab 61% (22 of 36; ARR 0.59), azathioprine 59% (13 of 22; ARR 0.2), and IV immunoglobulin (IVIG) 20% (2 of 10; ARR 0). The overall median ARR on these 4 treatments was 0.3. All 9 patients treated with multiple sclerosis (MS) disease-modifying agents had a breakthrough relapse on treatment (ARR 1.5). Conclusion This large retrospective multicenter study of patients with MOGAD suggests that maintenance immunotherapy reduces recurrent CNS demyelinating attacks, with the lowest ARR being associated with maintenance IVIG therapy. Traditional MS disease-modifying agents appear to be ineffective. Prospective randomized controlled studies are required to validate these conclusions.

Objective To determine if autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) could be a salvage therapy for neuromyelitis optica spectrum disorder (NMOSD). Methods Thirteen patients were enrolled in a prospective open-label cohort study (11 NMOSD aquaporin-4–immunoglobulin G [AQP4-IgG]–positive, 1 NMOSD without AQP4, and 1 NMOSD AQP4-IgG-positive with neuropsychiatric systemic lupus erythematosus [SLE]). Following stem cell mobilization with cyclophosphamide (2 g/m²) and filgrastim, patients were treated with cyclophosphamide (200 mg/kg) divided as 50 mg/kg IV on day −5 to day −2, rATG (thymoglobulin) given IV at 0.5 mg/kg on day −5, 1 mg/kg on day −4, and 1.5 mg/kg on days −3, −2, and −1 (total dose 6 mg/kg), and rituximab 500 mg IV on days −6 and +1. Unselected peripheral blood stem cells were infused on day 0. AQP4-IgG antibody status was determined by Clinical Laboratory Improvement Amendments–validated ELISA or flow cytometry assays. Cell-killing activity was measured using a flow cytometry–based complement assay. Results Median follow-up was 57 months. The patient with coexistent SLE died of complications of active lupus 10 months after HSCT. For the 12 patients with NMOSD without other active coexisting autoimmune diseases, 11 patients are more than 5 years post-transplant, and 80% are relapse-free off all immunosuppression (p < 0.001). At 1 and 5 years after HSCT, Expanded Disability Status Scale score improved from a baseline mean of 4.4 to 3.3 (p < 0.01) at 5 years. The Neurologic Rating Scale score improved after HSCT from a baseline mean of 69.5 to 85.7 at 5 years (p < 0.01). The Short Form–36 health survey for quality of life total score improved from mean 34.2 to 62.1 (p = 0.001) at 5 years. In the 11 patients whose baseline AQP4-IgG serostatus was positive, 9 patients became seronegative by the immunofluorescence or cell-binding assays available at the time; complement activating and cell-killing ability of patient serum was switched off in 6 of 7 patients with before and after HSCT testing. Two patients remained AQP4-IgG-seropositive (with persistent complement activating and cell-killing ability) and relapsed within 2 years of HSCT. No patient with seronegative conversion relapsed. Conclusion Prolonged drug-free remission with AQP4-IgG seroconversion to negative following nonmyeloablative autologous HSCT warrants further investigation.

Objective To define the clinicopathologic features of amphiphysin–immunoglobulin G (IgG)–mediated neuropathy. Methods Patients examined at our institution from January 1, 1995, to September 30, 2018, with amphiphysin-IgG by indirect immunofluorescence and Western blot, were reviewed. Their phenotypes were compared to cases of coexisting collapsin response-mediator protein-5 (CRMP5)–IgG or anti-neuronal nuclear antibody type 1 (ANNA1-IgG) and CRMP5-IgG autoimmunity. Improvement in modified Rankin Scale (mRS) (≥1) on follow-up was considered a favorable outcome. Amphiphysin RNA expression was assessed in healthy nerves. Results Fifty-three amphiphysin-IgG-positive cases were identified. Of 33 (60%) patients with neuropathy, 21 had amphiphysin-IgG alone, and 12 had coexisting autoantibodies (ANNA1-IgG, n = 8; CRMP5-IgG, n = 2; ANNA1-IgG and CRMP5-IgG, n = 2). The neuropathies in isolated amphiphysin-IgG autoimmunity included polyradiculoneuropathy (62%), diffuse sensory neuronopathy (35%), and facial neuropathy with gastroparesis (3%). Among these, pain (80%), breast cancer (63%), and CNS (57%) involvements commonly coexisted, and neuropathy frequently prompted breast cancer diagnosis (76%). Stiff-person spectrum disorder was the most common CNS accompaniment (45%). Nerve biopsies showed axonal loss (n = 6/6), subperineurial edema (n = 4/6), and CD4 predominant inflammation (n = 2/6). Median mRS score at last follow-up was 3.5; 58% of patients were immunotherapy-responsive. Patients with amphiphysin-IgG alone had more favorable immunotherapy response than patients with CRMP5-IgG polyneuropathy (n = 45) (44% vs 16%, p = 0.028, odds ratio 4.2, 95% confidence interval 1.1 to 15.5). Only 1/9 (11%) patients with amphiphysin-IgG with coexisting CRMP5-IgG or ANNA1-IgG had immunotherapy response. RNA amphiphysin expression occurred at low levels in nerve. Conclusion Amphiphysin-IgG autoimmune neuropathy has a recognizable phenotype, is frequently immune responsive, and can prompt early diagnosis of breast cancer.

Objective To investigate whether aquaporin-4–immunoglobulin G (AQP4-IgG) titers and measures of complement-mediated cell killing are clinically useful to predict the occurrence of relapse, relapse severity, and/or disability in neuromyelitis optica spectrum disorder (NMOSD). Methods We studied 336 serial serum specimens from 82 AQP4-lgG–seropositive patients. NMOSD activity at blood draw was defined as preattack (24 [7.1%], drawn within 30 days preceding an attack), attack (108 [32.1%], drawn on attack onset or within 30 days after), or remission (199 [59.2%], drawn >90 days after attack onset and >30 days preceding a relapse). For each specimen, we documented the attack type and severity and immunotherapy status. Complement-mediated cell killing was quantitated by flow cytometry using an M23-AQP4 cell-based assay. Results The estimated logarithmic means of AQP4-IgG titers in preattack, attack, and remission samples were 3.302, 3.657, and 3.458, respectively, p = 0.21. Analyses of 81 attack/remission pairs in 42 patients showed no significant titer differences (3.736 vs 3.472, p = 0.15). Analyses of 13 preattack/attack pairs in 9 patients showed no significant titer differences (3.994 vs 3.889, p = 0.67). Of 5 patients who converted to seronegative status, 2 continued to have attacks. Titers for major and minor attacks (n = 70) were not significantly different (3.905 vs 3.676, p = 0.47). Similarly, measures (titers) of complement-mediated cell killing were not significantly associated with disease course, attack severity, or disability at 5 years. Conclusions and relevance AQP4-IgG titer and complement-mediated cell killing lack significant prognostic or predictive utility in NMOSD. Although titers may drop in the setting of immunotherapy, seroconversion to negative status does not preclude ongoing clinical attacks. Classification of evidence This study provides Class II evidence that in patients with NMOSD, AQP4-IgG titers and measures of complement-mediated cell killing activity do not predict relapses, relapse severity, or disability.