Evaluation of disease-specific health-related quality of life in patients with pulmonary arterial hypertension

SummaryBackgroundPulmonary arterial hypertension (PAH) remains a debilitating and life-threatening disease despite improvements in hemodynamics, exercise capacity and survival with recent therapeutic advances. Health-related quality of life (HRQOL) has, therefore, been proposed as an important outcome for evaluating care. Relatively little, however, is known regarding HRQOL or its determinants in PAH. The Minnesota Living with Heart Failure questionnaire was recently adapted and validated for HRQOL measurement in PAH. We applied this pulmonary hypertension-specific version (MLHF-PH) to a larger population of PAH patients.MethodsNinety-three consecutive outpatients with PAH completed the MLHF-PH. Scores were assessed for correlations with demographics, symptoms, hemodynamics and treatments.ResultsPatients with PAH had significantly impaired HRQOL as assessed by the disease-specific MLHF-PH. Each physical and emotional component, as well as total scores on the MLHF-PH indicated severely depressed HRQOL. As compared to other diagnoses, PAH associated with scleroderma had the worst HRQOL. Patients with WHO functional Class II symptoms reported better HRQOL than Class III patients. Fatigue, weakness and abdominal discomfort were each associated with more severely depressed HRQOL, as was current epoprostenol use. With the sole exception of the right atrial pressure, hemodynamic measurements did not correlate with HRQOL scores. Simultaneous evaluation of HRQOL with a non-disease-specific questionnaire (SF-36) revealed a similarly impaired status, although identified fewer associations with patient-specific factors.ConclusionSeverely impaired HRQOL is present in this population of patients with PAH evaluated with a disease-specific questionnaire. The availability of a pulmonary hypertension-specific HRQOL questionnaire may enable further targeted investigations of factors that might improve outcomes

Race and sex differences in response to endothelin receptor antagonists for pulmonary arterial hypertension

Background Recently studied therapies for pulmonary arterial hypertension (PAH) have improved outcomes among populations of patients, but little is known about which patients are most likely to respond to specific treatments. Differences in endothelin-1 biology between sexes and between whites and blacks may lead to differences in patients' responses to treatment with endothelin receptor antagonists (ERAs). Methods We conducted pooled analyses of deidentified, patient-level data from six randomized placebo-controlled trials of ERAs submitted to the US Food and Drug Administration to elucidate heterogeneity in treatment response. We estimated the interaction between treatment assignment (ERA vs placebo) and sex and between treatment and white or black race in terms of the change in 6-min walk distance from baseline to 12 weeks. Results Trials included 1,130 participants with a mean age of 49 years; 21% were men, 74% were white, and 6% were black. The placebo-adjusted response to ERAs was 29.7 m (95% CI, 3.7-55.7 m) greater in women than in men (P = .03). The placebo-adjusted response was 42.2 m for whites and −1.4 m for blacks, a difference of 43.6 m (95% CI, −3.5-90.7 m) (P = .07). Similar results were found in sensitivity analyses and in secondary analyses using the outcome of absolute distance walked. Conclusions Women with PAH obtain greater responses to ERAs than do men, and whites may experience a greater treatment benefit than do blacks. This heterogeneity in treatment-response may reflect pathophysiologic differences between sexes and races or distinct disease phenotypes

Health-related quality of life in patients with pulmonary arterial hypertension

BACKGROUND: Improved outcomes with expanding treatment options for patients with pulmonary arterial hypertension present the opportunity to consider additional end-points in approaching therapy, including factors that influence health-related quality of life. However, comparatively little is known about health-related quality of life and its determinants in patients with pulmonary arterial hypertension. METHODS: Health-related quality of life was evaluated in a cross sectional study of 155 outpatients with pulmonary arterial hypertension using generic and respiratory-disease specific measurement tools. Most patients had either World Health Organization functional Class II or III symptoms. Demographic, hemodynamic and treatment variables were assessed for association with health-related quality of life scores. RESULTS: Patients with pulmonary arterial hypertension suffered severe impairments in both physical and emotional domains of health-related quality of life. Patients with idiopathic ("primary") pulmonary arterial hypertension had the best, and those with systemic sclerosis the worst health-related quality of life. Greater six-minute walk distance correlated with better health-related quality of life scores, as did functional Class II versus Class III symptoms. Hemodynamic measurements, however, did not correlate with health-related quality of life scores. No differences in health-related quality of life were found between patients who were being treated with calcium channel antagonists, bosentan or continuously infused epoprostenol at the time of quality of life assessment. CONCLUSION: Health-related quality of life is severely impaired in patients with pulmonary arterial hypertension and is associated with measures of functional status. Specific associations with impaired health-related quality of life suggest potential areas for targeted intervention

Editorial

Data Sharing Statements for Clinical Trials: A Requirement of the International Committee of Medical Journal Editor

Clinical risk factors for portopulmonary hypertension

Portopulmonary hypertension affects up to 6% of patients with advanced liver disease, but the predictors and biologic mechanism for the development of this complication are unknown. We sought to determine the clinical risk factors for portopulmonary hypertension in patients with advanced liver disease. We performed a multicenter case-control study nested within a prospective cohort of patients with portal hypertension recruited from tertiary care centers. Cases had a mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dynes · second · cm−5, and pulmonary capillary wedge pressure ≤ 15 mm Hg. Controls had a right ventricular systolic pressure < 40 mm Hg (if estimable) and normal right-sided cardiac morphology by transthoracic echocardiography. The study sample included 34 cases and 141 controls. Female sex was associated with a higher risk of portopulmonary hypertension than male sex (adjusted odds ratio =2.90, 95% confidence interval 1.20-7.01, P = 0.018). Autoimmune hepatitis was associated with an increased risk (adjusted odds ratio = 4.02, 95% confidence interval 1.14-14.23, P = 0.031), and hepatitis C infection was associated with a decreased risk (adjusted odds ratio =0.24, 95% confidence interval 0.09-0.65, P =0.005) of portopulmonary hypertension. The severity of liver disease was not related to the risk of portopulmonary hypertension

Risk of Serious Infections in Patients with Psoriasis on Biologic Therapies: A Systematic Review and Meta-Analysis

A comprehensive evaluation of the risk of serious infections in biologic therapies for psoriasis is lacking. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) and prospective cohort studies reporting serious infections in people taking any licensed biologic therapy for psoriasis compared with those taking placebo, nonbiologic therapy, or other biologic therapies. The quality of the studies was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. No significant heterogeneity was detected in data from 32 RCTs (n = 13,359 participants) and one cohort study (n = 4,993 participants). In adults, low- to very-low-quality RCT data showed no significant difference between any biologic therapy and placebo at weeks 12–16 (overall pooled Peto odds ratio = 0.71, 95% confidence interval = 0.36–1.41) and weeks 20–30 (odds ratio = 2.27, 95% confidence interval = 0.45–11.49). No significant differences were found in any of the other comparisons in underpowered RCT data. Prospective cohort study data of low quality suggests that only adalimumab (adjusted hazard ratio [adjHR] = 2.52, 95% confidence interval = 1.47–4.32) was associated with a significantly higher risk of serious infection compared with retinoid and/or phototherapy in adults. No association between biologic therapies and serious infections in patients with psoriasis who were eligible for RCTs was detected. Further observational studies are needed to inform the uncertainty around this risk in the real world

Tumor-endothelial cell adhesion and tumor metastasis

The interaction of blood-borne tumor cells with the vascular endothelium is a key component of hematogenous metastasis. Increasing evidence suggests that tumor cell adhesion to the endothelial lining depends on specific cell surface adhesion molecules. Inducible Cell Adhesion Molecule 110 (INCAM-110, also termed VCAM-1), a glycoprotein expressed on endothelial cells activated by the inflammatory/immune cytokines IL-1 or TNF, is a receptor for lymphocytes and monocytes, but can also be recognized by human melanoma cells. By comparison, colon carcinoma cells can bind another cytokine-inducible endothelial cell molecule. E-selectin, normally a receptor for neutrophils. Thus, during metastatic spread, blood-borne tumor cells might utilize adhesion molecules normally supporting endothelial-leukocyte interactions. Using in vitro assays, cytokine-inducible INCAM-110-dependent binding was demonstrated with several types of human tumor cells. The adhesion of human melanoma, osteosarcoma and kidney carcinoma cells was increased 1.9- to 8.2-fold by cytokine-activation of endothelial monolayers and inhibited by anti-INCAM-110 monoclonal antibody. Each of these tumor cells expressed members of the \beta\sb1 integrin family of adhesion molecules, and antibodies to the \alpha\sb4 and \beta\sb1 integrin subunits inhibited tumor-endothelial adhesion (48 to 87% inhibition). Furthermore, using a recombinant form of INCAM-110/ VCAM-1, tumor cell surface \alpha\sb4 integrin was shown to support binding to the N-terminal domains of this endothelial adhesion molecule. The significance of this inducible mechanism of tumor adhesion in hematogenous metastasis was studied with a mouse model of melanoma spread. Murine B16-F10 melanoma cells, like their human counterparts, expressed the \alpha\sb4 integrin, which supported cytokine-inducible adhesion to human endothelium, as well as to human and murine INCAM-110/VCAM-1. Metastasis of the murine melanoma was also cytokine-inducible by an \alpha\sb4 integrin-dependent mechanism. Treatment of mice with IL-1$\beta$ resulted in an increase in experimental B16 metastasis (5.5 $\pm$ 1.9 fold increase in metastatic pulmonary nodules; n = 11). Pretreatment of melanoma cells with monoclonal antibodies to murine \alpha\sb4 inhibited metastasis in IL-1-primed mice by 57 $\pm$ 9% (n = 3), without an alteration in tumor growth. These findings demonstrate the involvement of the \alpha\sb4 integrin molecule in melanoma metastasis and provide a potential mechanism for the selective arrest of blood-borne tumor cells at the vessel wall

Panel A: Coronavirus Discussion

This panel discussion, Coronavirus Discussion, included the following presentations: COVID Comics – Alice Jaggers, https://www.graphicmedicine.org/covid-19-comics/ Brave New World: Including Graphic Medicine in a Traditional Medical Journal – Darren Taichman (Annals of Internal Medicine) Q&A and Open Discussion Resources mentioned in this session: COVID Comics on graphicmedicine.org: https://www.graphicmedicine.org/covid-19-comics/ The Amazing Captain Fit - web comic that teaches fitness and healthy lifestyle to kids: https://healthelinks.org/kidshealth/captain_fit_info_page.html Annals of Internal Medicine - Annals of Graphic Medicine: https://www.acpjournals.org/topic/web-exclusives/annals-graphic-medicine Annals of Graphic Medicine - 50 Shades of Gray Matter Video: https://doi.org/10.7326/G14-0006 Annals of Internal Medicine - Annals Story Slam: https://www.acpjournals.org/topic/web-exclusives/annals-story-sla