Prevalence, patient characteristics and treatment patterns among SLE-PAH patients in real-world clinical practice: A retrospective analysis of Medical Data Vision Database in Japan.

OBJECTIVE: Real-world evidence regarding prevalence, patient characteristics and treatment patterns for pulmonary arterial hypertension (PAH) related to systemic lupus erythematosus (SLE) in Japan is limited. METHODS: We conducted a retrospective study analysing Japan's Medical Data Vision (MDV) database from April-2008 to September-2020. Prevalence, incidence, patient characteristics, treatment patterns and use of vasodilators by treatment line were evaluated. RESULTS: Prevalence of PAH was 0.392% in SLE patients (n=114/29,077). Cumulative incidence was 0.53% (3-years (y)) and 0.77% (5y). Of 114 SLE-PAH patients, 49% developed PAH <1 year from SLE diagnosis. SLE-PAH patients were more female (88% vs. 72%), had lower mean age at SLE diagnosis (53y vs. 56y) and more severe SLE (61% vs 25%), versus non-PAH SLE patients. Glucocorticoids (58%) and vasodilators (27%) were preferred first-line monotherapy for SLE-PAH. Glucocorticoids+immunosuppressants (19%) was predominant first-line combination therapy. Endothelin receptor antagonists (40% and 44%) and nitric oxide analogues (31% and 40%) were dominant first- and second-line vasodilators. CONCLUSION: SLE-PAH patients were more females, younger at diagnosis, had more severe SLE than non-PAH SLE patients. Most were diagnosed <1 year of SLE diagnosis. In Japan's real-world practice, initial treatment goal is SLE management, while vasodilators are preferred in advanced disease, as per MDV database.

A yeast functional screen predicts new candidate ALS disease genes.

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.