No abstract

Based on a small number of cases, interferon beta (IFN-β) has been added to the list of drugs that might induce pulmonary arterial hypertension (PAH) in the current European guidelines for the diagnosis and treatment of pulmonary hypertension. Here, we propose that multiple sclerosis patients who are genetically predisposed to PAH may be at higher risk to develop disease when treated with IFN-β. We included two patients with multiple sclerosis who developed a manifest PAH after five amd eight years on IFN-β 1a therapy, respectively (without confirmed right heart catheterization). In both patients, PAH markedly improved after discontinuation of IFN-β 1a and initiation of targeted PAH therapy. For genetic analysis, we used a PAH-gene panel based on next-generation sequencing of 16 PAH and 38 candidate genes. In one of the two patients, we could identify a nonsense variant in the PAH gene ATP13A3. The second patient showed a missense variant of the CYP1B1 gene, which might be linked to PAH predisposition. The results of this study support the hypothesis that multiple sclerosis patients who receive IFN-β 1a therapy might be at higher risk for the development of manifest PAH, if they carry a pathogenic variant or sequence variant genetically predisposing to the disease. However, further studies are necessary to systematically investigate the presence of predisposing PAH gene variants in these patients.

Riociguat is one of several approved therapies available for patients with pulmonary arterial hypertension (PAH). Treatment should be initiated and monitored at an expert center by a physician experienced in treating PAH, and the dose adjusted in the absence of signs and symptoms of hypotension. In certain populations, including patients with hepatic or renal impairment, the elderly, and smokers, riociguat exposure may differ, and dose adjustments should therefore be made with caution according to the established scheme. Common adverse events are often easily managed, particularly if they are discussed before starting therapy. Combination therapy with riociguat and other PAH-targeted agents is feasible and generally well tolerated, although the coadministration of phosphodiesterase type 5 inhibitors (PDE5i) and riociguat is contraindicated. An open-label, randomized study is currently ongoing to assess whether patients who do not achieve treatment goals while receiving PDE5i may benefit from switching to riociguat. In this review, we provide a clinical view on the practical management of patients with PAH receiving riociguat, with a focus on the opinions and personal experience of the authors.The reviews of this paper are available via the supplemental material section.

Background and aims Coronavirus disease 19 (Covid-19) trajectories show high interindividual variability, ranging from asymptomatic manifestations to fatal outcomes, the latter of which may be fueled by immunometabolic maladaptation of the host. Reliable identification of patients, who are at risk of severe disease remains challenging. We hypothesized that serum concentrations of Dickkopf1 (DKK1) indicate disease outcomes in SARS-CoV-2 infected individuals. Methods We recruited hospitalized patients with PCR-confirmed SARS-CoV-2 infection and included 80 individuals, for whom blood samples from two independent time points were available. DKK1 serum concentrations were measured by ELISA in paired samples. Clinical data was extracted from patient charts and correlated with DKK1 levels. Publicly available datasets were screened for changes in cellular DKK1 expression upon SARS-CoV-2 infection. Plasma metabolites were profiled by NMR spectroscopy in an unbiased fashion and correlated with DKK1 data. Kaplan Meier and Cox regression analysis were used to investigate the prognostic value of DKK1 levels in the context of Covid-19. Results We report that serum levels of DKK1 predict disease outcomes in patients with Covid-19. Circulating DKK1 concentrations are characterized by high interindividual variability and change as a function of time during SARS-CoV-2 infection, which is linked to platelet counts. We further find that the metabolic signature associated with SARS-CoV-2 infection resembles fasting metabolism and is mirrored by circulating DKK1 abundance. Patients with low DKK1 levels are twice as likely to die from Covid-19 than those with high levels and DKK1 predicts mortality independent of markers of inflammation, renal function and platelet numbers Conclusion Our study suggests a potential clinical use of circulating DKK1 as a predictor of disease outcomes in patients with Covid-19. These results require validation in additional cohorts.