Shifting patterns of multiple sclerosis treatment in a highly prevalent United States population.

OBJECTIVE: Our objectives were to (1) obtain the prevalence and demography of people with multiple sclerosis (MS) in a representative Colorado population, and (2) to assess the utilization of disease-modifying therapy within this prevalent cohort. METHODS: This is a retrospective, observational study of patients that had contact with the University of Colorado Health System from 2012 to 2020. We queried Health Data Compass, a data warehouse, for patient data and applied the MS Prevalence Workgroup Algorithm to generate a prevalent cohort. We calculated prevalence as of 31 December 2020, and stratified by age, sex, race, and ethnicity. Payer information and treatment exposure were obtained from linked claims from the Colorado All Payers Claim Database. Disease-modifying therapies were classified as highly effective and moderately effective based on the clinical trial, TREAT-MS (NCT03500328). RESULTS: From a population of 1,382,821 individuals, 8557 people with MS were captured. Age-adjusted prevalence of MS as of 31 December 2020 was 572.3 per 100,000 with a mean age of 47.36. Prevalence varied between demographic subgroups, with the lowest prevalence in Hispanic men (215.6) and highest in White (824.1) and Black women (820.1). Overall disease-modifying therapy exposure was 62.4%, with increased highly effective therapy use and a corresponding decrease in moderately effective therapy use on a yearly basis. INTERPRETATION: MS is highly prevalent in a representative Colorado cohort. Overall treatment and proportion of highly effective therapy exposure increased significantly during a critical period of MS therapeutic advances, indicating a shift in disease management driven sharply by the availability of on-label anti-CD20 therapy.

Rescue of progranulin deficiency associated with frontotemporal lobar degeneration by alkalizing reagents and inhibition of vacuolar ATPase.

Numerous loss-of-function mutations in the progranulin (GRN) gene cause frontotemporal lobar degeneration with ubiquitin and TAR-DNA binding protein 43-positive inclusions by reduced production and secretion of GRN. Consistent with the observation that GRN has neurotrophic properties, pharmacological stimulation of GRN production is a promising approach to rescue GRN haploinsufficiency and prevent disease progression. We therefore searched for compounds capable of selectively increasing GRN levels. Here, we demonstrate that four independent and highly selective inhibitors of vacuolar ATPase (bafilomycin A1, concanamycin A, archazolid B, and apicularen A) significantly elevate intracellular and secreted GRN. Furthermore, clinically used alkalizing drugs, including chloroquine, bepridil, and amiodarone, similarly stimulate GRN production. Elevation of GRN levels occurs via a translational mechanism independent of lysosomal degradation, autophagy, or endocytosis. Importantly, alkalizing reagents rescue GRN deficiency in organotypic cortical slice cultures from a mouse model for GRN deficiency and in primary cells derived from human patients with GRN loss-of-function mutations. Thus, alkalizing reagents, specifically those already used in humans for other applications, and vacuolar ATPase inhibitors may be therapeutically used to prevent GRN-dependent neurodegeneration.

Chronic tibial nonunion in a Rothmund-Thomson syndrome patient.

Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder caused by biallelic mutations in RECQL4, a helicase involved with chromosomal instability and DNA repair. Patients typically present with a poikilodermatous facial rash, photosensitivity, congenital bony abnormalities, short stature, and have a predilection for osteosarcoma and cutaneous malignancies. We present a 34-year-old male RTS patient, previously diagnosed with osteosarcoma of the right forearm which was successfully treated with resection and chemotherapy, who has had multiple tibial fractures and has suffered from chronic nonunion of the proximal tibias bilaterally for greater than 9 years. The patient subsequently developed generalized lower extremity osteopenia with normal calcium homeostasis and calcitriol levels. As the RTS population continues to reach greater ages we must be mindful of other health concerns that may develop. Bone health is one considerable concern with a large portion of patients having congenital bony abnormalities and many receiving chemotherapy for osteosarcoma. We conclude that screening for bone health and supplementation with calcium and vitamin D may be warranted in RTS patients with a history of fractures and osteosarcoma treatment.

Prevalence of multiple sclerosis and treatment utilization in a large, highly diverse population.

BACKGROUND: Despite advances in algorithms for identifying people with MS (PwMS) in large data sets, limited data exists on regional prevalence, or prevalence and care in minority populations. OBJECTIVES: To report the 7-year (01/01/2012-12/31/2018) prevalence and demographics of MS and disease-modifying therapy (DMT) utilization in a large, diverse population. METHODS: This retrospective analysis used the OneFlorida Data Trust, which captures health data from >15 million Floridians across 10 constituent organizations. A validated algorithm identified subjects with MS. DMTs were identified using RxNorm concept unique identifiers and National Drug Codes. Results were stratified across age, sex, race-ethnicity, and location. RESULTS: Of 6,638,649 adults in the database, the algorithm identified 9681 PwMS. Overall prevalence per 100,000 was 145.83. MS prevalence was considerable in women of all races and ethnicities ranging from 138.86 to 253.76 per 100,000. 52.6% of PwMS had one or more DMT prescription. DMT prescription was more likely in Hispanic PwMS. CONCLUSION: Prevalence analysis of the OneFlorida Data Trust revealed a substantial burden of disease in women of all races and ethnicities. Variation in treatment utilization among demographic subgroups underscores the need for additional studies to assess health care disparities in MS at the population level.

Therapy-related myelodysplasia in a patient with Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder of which approximately 300 cases have been reported in the literature. Patients with RTS often present early in life with skeletal and dental abnormalities, short stature, juvenile cataracts, and a characteristic poikilodermal rash. They are at increased risk for the development of osteosarcoma that usually presents by the second decade of life. The genetic defects underlying RTS are truncating mutations in RECQL4, a gene involved with chromosomal stability. Several cases of primary hematological malignancies have been reported in RTS, but it is unclear whether patients with RTS are at higher risk to develop either primary or secondary hematological malignancies. We report a patient with RTS who presented to our clinic at the age of 7, subsequently developed multifocal and recurrent osteosarcoma that was followed by the development of a myelodysplastic syndrome with subsequent progression to acute myeloid leukemia.

Five men with arresting and relapsing cerebral adrenoleukodystrophy.

BACKGROUND: X-linked adrenoleukodystrophy (ALD) is the most common genetic peroxisomal disorder with an estimated prevalence of 1:15,000. Approximately two-thirds of males with ALD manifest the inflammatory demyelinating cerebral phenotype (cALD) at some disease stage, in which focal, inflammatory lesions progress over months to years. Hematopoietic stem-cell transplantation can permanently halt cALD progression, but it is only effective if initiated early. Although most cALD lesions progress relentlessly, a subset may spontaneously arrest; subsequent reactivation of these arrested lesions has not been previously detailed. OBJECTIVE: We describe a novel arresting-relapsing variant of cALD. METHODS: Salient clinical and radiographic studies were reviewed and summarized for cALD patients with episodic deteriorations. RESULTS: We report a series of five unrelated men with spontaneously arrested cALD lesions that subsequently manifested signs of clinical and radiologic lesion progression during longitudinal follow-up. In three of five patients, functional status was too poor to attempt transplant by the time the recurrence was identified. One patient experienced reactivation followed by another period of spontaneous arrest. CONCLUSIONS: These cases emphasize the need for continued clinical and radiologic vigilance for adult men with ALD to screen for evidence of new or reactivated cALD lesions to facilitate prompt treatment evaluation.

A case of GFAP-astroglial autoimmunity presenting with reversible parkinsonism.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a newly recognized autoimmune central nervous system (CNS) inflammatory disorder, presenting with an array of neurological symptoms in association with autoantibodies against GFAP, a hallmark protein expressed on astrocytes. Limited knowledge is available on the disease pathogenesis and clinical outcome. Here, we report a case of autoimmune GFAP astrocytopathy presenting with encephalomyelitis and parkinsonism. Our patient was a 66-year old male who experienced progressive somnolence, apathy, anxiety, right arm tremor, urinary retention, progressive weakness, and falls over the course of three months, followed by acute delusional psychosis. His neurologic exam on hospital admission was notable for cognitive impairment, myoclonus, rigidity, right hand action tremor, bradykinesia, shuffling gait, and dysmetria. Cerebrospinal fluid examination showed elevated protein, lymphocytic pleocytosis, and one unique oligoclonal band. Magnetic resonance imaging (MRI) revealed non-specific T2/FLAIR hyperintensities in the brain and longitudinally extensive transverse myelitis in the cervical spine. FDG-PET showed a pattern of brain uptake suspicious for limbic encephalitis. Serum and CSF paraneoplastic panel showed presence of GFAP immunoglobulin G (IgG). Treatment with corticosteroids resulted in clinical and radiographic improvement. However, the patient was treated with anti-CD20 immunotherapy due to steroid-dependence. This case exemplifies the recently described neurologic syndrome of autoimmune GFAP astrocytopathy presenting with encephalomyelitis and parkinsonism, reversed by B lymphocyte depletion.

Proteolytic processing of TAR DNA binding protein-43 by caspases produces C-terminal fragments with disease defining properties independent of progranulin.

Neuronal and glial deposition of misfolded, proteolytically processed, polyubiquitinated and abnormally phosphorylated C-terminal fragments (CTFs) of the TAR DNA binding protein-43 (TDP-43) is a pathological hallmark of frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U) and certain cases of amyotrophic lateral sclerosis. We demonstrate that TDP-43 can be proteolytically processed by caspases upon induction of apoptosis to a major 35 kDa and a minor 25 kDa CTF. These fragments are initially soluble, but over time they accumulate as insoluble and pathologically phosphorylated derivatives. However, proteolytic processing appears not to be absolutely required for the deposition of insoluble TDP-43 species, since a caspase resistant mutant of TDP-43 is also converted into insoluble species. Phosphorylation at S409/410 apparently occurs late during the conversion of soluble to insoluble TDP-43, suggesting that phosphorylation is not a prerequisite for aggregation. Loss of function of the progranulin (PGRN) gene causes FTLD-U with TDP-43 positive inclusions and has been suggested to lead to caspase activation and subsequent TDP-43 processing. However, siRNA-mediated knockdown of PGRN in cell culture as well as a PGRN gene knockout in mice failed to cause the formation of the disease characterizing CTFs of TDP-43. Our findings therefore suggest that caspase-mediated processing generates CTFs of similar biochemical properties as those occurring in nuclear and cytoplasmic deposits of FTLD-U patients independent of PGRN levels.

A prospective, randomized crossover study comparing direct inspection by light microscopy versus projected images for teaching of hematopathology to medical students.

Instruction in hematopathology at Mayo Medical School has evolved from instructor-guided direct inspection under the light microscope (laboratory method), to photomicrographs of glass slides with classroom projection (projection method). These methods have not been compared directly to date. Forty-one second-year medical students participated in this pilot study, a prospective, randomized, crossover study measuring educational performance during a hematology pathophysiology course. The students were randomized to one of two groups. All students received the same didactic lectures in the classroom and subsequent case-based review of peripheral blood smears using either laboratory or projection methods, on day one with a crossover to the other method on day two. Pre- and post-test examinations centered on morphology recognition measured educational performance on each day, followed by a questionnaire identifying the student's favored method. There was no significant difference in the pre-test and post-test scores between the two teaching methods (rank-sum P = 0.43). Students overwhelmingly preferred the projection method and perceived it as superior (76%), although post-test scores were not significantly different. Student's recommended method was split with 50% favoring the projection method, 43% favoring a combined approach, and 23% noting logistical challenges to the laboratory. In this study, the laboratory and projection method were equivalent in terms of educational performance for hematopathology among medicals students. A classroom-based approach such as the projection method is favored, given the large class sizes in undergraduate medical education, as well as the ergonomic challenges and additional resources required for large group instruction in a laboratory setting.

Utility of progranulin and serum leukocyte protease inhibitor as diagnostic and prognostic biomarkers in ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer-related death in females and leading gynecologic cause of cancer-related death. Despite the identification of a number of serum biomarkers, methods to identify early-stage disease and predict prognosis remain scarce. We have evaluated two biologically connected serum biomarkers, serum leukocyte protease inhibitor (SLPI) and progranulin (PGRN). METHODS: Two-hundred frozen plasma samples were acquired from the Mayo Clinic Biospecimen Repository for Ovarian Cancer Research. Samples were obtained from 50 patients with benign conditions, 50 with American Joint Committee on Cancer (AJCC) stage I and II EOC, and 100 with AJCC stage III and IV EOC. Samples were obtained before surgical resection of a mass and were analyzed for absolute levels of SLPI and PGRN using ELISA assays. Receiver-operator characteristic curves were generated for SLPI and PGRN. Median follow-up was 48 months. RESULTS: Absolute levels of SLPI were significantly elevated in patients with EOC compared with benign disease and predicted the presence of EOC (AUC of 0.812; P = 0.04); SLPI remained elevated in the subset of patients with normal CA-125. PGRN levels were not significantly increased in patients with early-stage or late-stage EOC as a whole, but an increase in PGRN levels was associated with decreased overall survival in advanced EOC. CONCLUSIONS: SLPI levels are elevated in EOC, and SLPI shows promise as a diagnostic biomarker for patients with both elevated and normal CA-125 levels. An increase in PGRN is associated with decreased overall survival. IMPACT: SLPI is elevated in EOC and warrants investigation in a screening study in women at risk for EOC.