Faculty Bibliography

BACKGROUND:Tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin-6 receptor, is approved for treatment of rheumatoid arthritis and several other immune-mediated disorders. Off-label use of the intravenous formulation of tocilizumab for Neuromyelitis Optica Spectrum Disorder (NMOSD) decreased relapse rates in two small case series. However, treatment protocol that requires frequent intravenous infusions may adversely affect adherence to therapy, especially in the more disabled patients, thereby reducing effectiveness. A subcutaneous formulation of tocilizumab was shown to be noninferior to the IV formulation for approved rheumatologic diseases. The effectiveness of subcutaneous TCZ for NMOSD is unknown. METHODS:We retrospectively reviewed clinical, radiological and serological data on all NMOSD patients who received subcutaneous TCZ in two tertiary referral centers between 2014-2019. RESULTS:Twelve NMOSD patients who received at least 6 months of subcutaneous TCZ were identified. Eleven were female; mean age was 46.9 ± 14.5 years and mean disease duration was 6.6 ± 4.6 years. Seven patients were seropositive for AQP-4 antibodies, two - for MOG-IgG antibodies, and three were doubly seronegative. During subcutaneous TCZ treatment, eight patients (66.6%) were relapse-free, one patient (8.3%) experienced 1 relapse, two patients (16.6%) - 2 relapses, and one patient (8.3%) - 3 relapses. The median relapse rate within 1 year after starting subcutaneous TCZ - 0 (interquartile range =1.75-0) - was significantly lower than in the year prior to treatment initiation (2, interquartile range = 4.0-0.25; p = 0.04). Overall, the annual relapse rate (ARR) decreased from a median of 2 (interquartile range = 5.75-1.29) prior to subcutaneous TCZ to 0 (interquartile range= = 1.0-0) on treatment (p = 0.0015). One TCZ-treated patient died following a severe myelitis attack. CONCLUSIONS:Effectiveness of subcutaneous TCZ in NMOSD appears to be similar to that reported for the IV formulation and has an advantage of at-home administration. Prospective, comparative studies of subcutaneous TCZ for NMOSD are warranted.

BACKGROUND:Aquaporin-4-IgG positive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) is an uncommon central nervous system autoimmune disorder. Disease outcomes in AQP4-IgG+NMOSD are typically measured by relapse rate and disability. Using the MSBase, a multi-centre international registry, we aimed to examine the impact immunosuppressive therapies and patient characteristics as predictors of disease outcome measures in AQP4-IgG+NMOSD. METHOD/METHODS:This MSBase cohort study of AQP4-IgG+NMOSD patients examined modifiers of relapse in a multivariable proportional hazards model and expanded disability status score (EDSS) using a mixed effects model. RESULTS:206 AQP4-IgG+ patients were included (median follow-up 3.7 years). Age (hazard ratio [HR] = 0.82 per decade, p = 0.001), brainstem onset (HR = 0.45, p = 0.009), azathioprine (HR = 0.46, p<0.001) and mycophenolate mofetil (HR = 0.09, p = 0.012) were associated with a reduced risk of relapse. A greater EDSS was associated with age (β = 0.45 (per decade), p<0.001) and disease duration (β = 0.07 per year, p<0.001). A slower increase in EDSS was associated with azathioprine (β = -0.48, p<0.001), mycophenolate mofetil (β = -0.69, p = 0.04) and rituximab (β = -0.35, p = 0.024). INTERPRETATION/CONCLUSIONS:This study has demonstrated that azathioprine and mycophenolate mofetil reduce the risk of relapses and disability progression is modified by azathioprine, mycophenolate mofetil and rituximab. Age and disease duration were the only patient characteristics that modified the risk of relapse and disability in our cohort.

OBJECTIVE:To determine the underlying etiology in a patient with progressive dementia with extrapyramidal signs and chronic inflammation referred to the National Institutes of Health Undiagnosed Diseases Program. METHODS:Extensive investigations included metabolic profile, autoantibody panel, infectious etiologies, genetic screening, whole exome sequencing and the phage-display assay, VirScan, for viral immune responses. An etiological diagnosis was established post-mortem. RESULTS:Using VirScan, enrichment of dengue viral antibodies were detected in cerebrospinal fluid as compared to serum. No virus was detected in serum or cerebrospinal fluid, but post-mortem analysis confirmed dengue virus in the brain by immunohistochemistry, in situ hybridization, quantitative polymerase chain reaction and sequencing. Dengue virus was also detectable by polymerase chain reaction and sequencing from brain biopsy tissue collected 33 months ante-mortem, confirming a chronic infection despite a robust immune response directed against the virus. Immunoprofiling and whole exome sequencing of the patient did not reveal any immunodeficiency and sequencing of the virus demonstrated wild-type dengue virus in the central nervous system. INTERPRETATION/CONCLUSIONS:Dengue virus is the most common arbovirus worldwide and represents a significant public health concern. Infections with dengue virus are usually self-limiting and chronic dengue infections have not been previously reported. Our findings suggest that dengue virus infections may persist in the central nervous system and should be considered in patients with progressive dementia with extrapyramidal features in endemic regions or with relevant travel history. Further, this work highlights the utility of comprehensive antibody profiling assays to aid in the diagnosis of encephalitis of unknown etiologies. This article is protected by copyright. All rights reserved.