Browsing by Author "Gibbs, J. Simon R."

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    Exercise Induced Changes of Vital Signs in Adults with Sickle Cell Disease
    (Wiley, 2021) Johnson, Solomon; Gordeuk, Victor R.; Machado, Roberto; Gibbs, J. Simon R.; Hildesheim, Mariana; Little, Jane A.; Kato, Gregory J.; Gladwin, Mark T.; Nouraie, Mehdi; Medicine, School of Medicine
    The six-minute walk test (6MWT) has been used in patients with sickle cell disease (SCD), in conjunction with tricuspid regurgitant velocity (TRV) and plasma N-terminal pro-brain natriuretic peptide (NT-pro BNP), to assess risk of having pulmonary hypertension. Exercise-induced vital sign changes (VSCs) are predictors of clinical outcomes in other diseases. In this study, we assess the predictors and prognostic value of 6MWT VSC in adult SCD patients. Data from a multinational study of SCD patients (Treatment of Pulmonary Hypertension with Sildenafil: walk-PHaSST) were used to calculate the 6MWT VSC. Predictors of VSC were identified by a multivariable analysis, and a survival analysis was conducted by the Cox proportional hazard method. An increase in heart rate was observed in 90% of the 630 SCD adults, 77% of patients had an increase in systolic blood pressure (SBP), and 50% of patients had a decrease in oxygen saturation. TRV (odds ratio [OR] = 1.82, p = .020), absolute reticulocyte count (OR = 1.03, p < .001), and hemoglobin (OR = 0.99, p = .035) predicted oxygen desaturation ≥ 3% during the 6MWT. In the adjusted analysis, SBP increase during the 6MWT was associated with improved survival (hazards ratio = 0.3, 95% confidence interval: 0.1-0.8). Increases in heart rate and blood pressure, as well as oxygen desaturation, are common in adults with SCD during the 6MWT. VSC is associated with markers of anemia and TRV and can be used for risk stratification. Any increase in SBP during the 6MWT was associated with improved survival and may be indicative of a patient's ability to increase stroke volume.
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    Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension
    (European Respiratory Society, 2022-03-10) Toshner, Mark; Church, Colin; Harbaum, Lars; Rhodes, Christopher; Villar Moreschi, Sofia S.; Liley, James; Jones, Rowena; Arora, Amit; Batai, Ken; Desai, Ankit A.; Coghlan, John G.; Gibbs, J. Simon R.; Gor, Dee; Gräf, Stefan; Harlow, Louise; Hernandez-Sanchez, Jules; Howard, Luke S.; Humbert, Marc; Karnes, Jason; Kiely, David G.; Kittles, Rick; Knightbridge, Emily; Lam, Brian; Lutz, Katie A.; Nichols, William C.; Pauciulo, Michael W.; Pepke-Zaba, Joanna; Suntharalingam, Jay; Soubrier, Florent; Trembath, Richard C.; Schwantes-An, Tae-Hwi L.; Wort, S. John; Wilkins, Martin R.; Gaine, Sean; Morrell, Nicholas W.; Corris, Paul A.; Uniphy Clinical Trials Network; Medicine, School of Medicine
    Background: Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling. Methods: We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg-1) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11 744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels. Results: We recruited 29 patients (male/female 10/19; mean±sd age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88). Conclusion: Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.