In the past few years, interest in rare diseases has grown, as demonstrated by the agendas of politicians and health authorities, but too little attention is still paid to ultra-rare diseases. ...Although no legal definition of an “ultra-rare” disease has yet been established, this subcategory was informally introduced by the National Institute for Health and Care Excellence for drugs with indications for diseases that have a prevalence <1 per 50 000 persons 1–3.
Too little attention is still paid to ultra-rare diseases. It is important to disseminate the best information on less common diseases in order to improve the clinical managment and improve care.
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Objective
Pulmonary hypertension (PH) is a frequent and life‐limiting complication of systemic sclerosis (SSc). However, data on survival rates and their evolution over time, as well as prognostic ...factors in SSc complicated by PH, are still conflicting. The aim of this study was to conduct a systematic review and meta‐analysis of cohort studies to assess pooled survival and prognostic factors for survival in patients with SSc–associated PH.
Methods
For this systematic review and meta‐analysis, we searched the Medline and EMBase databases (January 1960 to January 2012). All cohort studies in which survival and/or prognostic factors for SSc–associated PH were reported were included in the analysis. We calculated the pooled survival rates and analyzed their evolution over time and identified prognostic factors for survival.
Results
Twenty‐two studies were included, representing a total of 2,244 patients with SSc–associated PH. The pooled 1‐, 2‐, and 3‐year survival rates were 81% (95% confidence interval 95% CI 79–84%), 64% (95% CI 59–69%), and 52% (95% CI 47–58%), respectively. Meta‐regression did not reveal a significant change in survival over time, while baseline hemodynamic measures of PH severity were significantly correlated with survival. In patients with SSc complicated by pulmonary arterial hypertension (PAH), age, male sex, diffusing capacity for carbon monoxide (DLCO), pericardial effusion, and the parameters classically associated with the severity of idiopathic PAH, including the 6‐minute walk distance, mean pulmonary artery pressure, cardiac index, and right atrial pressure, were significant prognostic factors. DLCO and pericardial effusion were the only prognostic factors in patients with interstitial lung disease–related PH.
Conclusion
Our meta‐analysis revealed a poor pooled 3‐year survival rate of 52% in patients with SSc–associated PH. Baseline hemodynamic measures of PAH severity, but not the period of time during which patients were included in the studies, correlated significantly with survival in patients with SSc–associated PAH. All of the prognostic factors typically observed in idiopathic PAH, including the 6‐minute walk distance and right atrial pressure, were also prognostic factors in SSc–associated PAH.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Pulmonary arterial hypertension (PAH) is a dreaded complication of systemic sclerosis (SSc) that occurs in ∼10% of patients. Most individuals present with severe symptoms, significant functional ...impairment and severe haemodynamics at diagnosis, and survival after PAH diagnosis is poor. Therefore, early diagnosis through systematic screening of asymptomatic patients has the potential to identify PAH at an early stage. Current evidence suggests that early diagnosis and treatment of PAH in patients with SSc may lead to better clinical outcomes. Annual screening may include echocardiography, but this can miss some patients due to suboptimal visualisation or insufficient tricuspid regurgitation. Other options for screening include the DETECT algorithm or the use of a combination of pulmonary function testing (forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio) and N-terminal-pro-brain natriuretic peptide levels. Symptomatic patients, those with an elevated tricuspid regurgitation velocity on echocardiogram with or without secondary echocardiographic features of PAH, and those who screen positive on the DETECT or other pulmonary function test algorithms should undergo right heart catheterisation. Exercise echocardiography or cardiopulmonary exercise testing, nailfold capillaroscopy and molecular biomarkers are promising but, as yet, unproven potential options. Future screening studies should employ systematic catheterisation to define the true predictive values for PAH.
Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive and debilitating diseases characterized by gradual obstruction of the pulmonary ...vasculature, leading to elevated pulmonary artery pressure (PAP) and increased pulmonary vascular resistance (PVR). If untreated, they can result in death due to right-sided heart failure. Riociguat is a novel soluble guanylate cyclase (sGC) stimulator that is approved for the treatment of PAH and CTEPH. We describe in detail the role of the nitric oxide-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway in the pathogenesis of PAH and CTEPH and the mode of action of riociguat. We also review the preclinical data associated with the development of riociguat, along with the efficacy and safety data of riociguat from initial clinical trials and pivotal phase III randomized clinical trials in PAH and CTEPH.
Inflammatory processes are prominent in various types of human and experimental pulmonary hypertension (PH) and are increasingly recognized as major pathogenic components of pulmonary vascular ...remodeling. Macrophages, T and B lymphocytes, and dendritic cells are present in the vascular lesions of PH, whether in idiopathic pulmonary arterial hypertension (PAH) or PAH related to more classical forms of inflammatory syndromes such as connective tissue diseases, human immunodeficiency virus (HIV), or other viral etiologies. Similarly, the presence of circulating chemokines and cytokines, viral protein components (e.g., HIV-1 Nef ), and increased expression of growth (such as vascular endothelial growth factor and platelet-derived growth factor) and transcriptional (e.g., nuclear factor of activated T cells or NFAT) factors in these patients are thought to contribute directly to further recruitment of inflammatory cells and proliferation of smooth muscle and endothelial cells. Other processes, such as mitochondrial and ion channel dysregulation, seem to convey a state of cellular resistance to apoptosis; this has recently emerged as a necessary event in the pathogenesis of pulmonary vascular remodeling. Thus, the recognition of complex inflammatory disturbances in the vascular remodeling process offers potential specific targets for therapy and has recently led to clinical trials investigating, for example, the use of tyrosine kinase inhibitors. This paper provides an overview of specific inflammatory pathways involving cells, chemokines and cytokines, cellular dysfunctions, growth factors, and viral proteins, highlighting their potential role in pulmonary vascular remodeling and the possibility of future targeted therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Inflammation and endothelial dysfunction are considered two primary instigators of pulmonary arterial hypertension (PAH). CD74 is a receptor for the proinflammatory cytokine macrophage migration ...inhibitory factor (MIF). This ligand/receptor complex initiates survival pathways and cell proliferation, and it triggers the synthesis and secretion of major proinflammatory factors and cell adhesion molecules.
We hypothesized that the MIF/CD74 signaling pathway is overexpressed in idiopathic PAH (iPAH) and contributes to a proinflammatory endothelial cell (EC) phenotype.
Primary early passage cultures of human ECs isolated from lung tissues obtained from patients with iPAH and controls were examined for their ability to secrete proinflammatory mediators and bind inflammatory cells with or without modulation of the functional activities of the MIF/CD74 complex. In addition, we tested the efficacies of curative treatments with either the MIF antagonist ISO-1 or anti-CD74 neutralizing antibodies on the aberrant proinflammatory EC phenotype in vitro and in vivo and on the progression of monocrotaline-induced pulmonary hypertension.
In human lung tissues, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin expressions are markedly up-regulated in the endothelium of distal iPAH pulmonary arteries. Circulating MIF levels are increased in the serum of patients with PAH compared with control subjects, and T-cell lymphocytes represent a source of this overabundance. In addition, CD74 is highly expressed in the endothelium of muscularized pulmonary arterioles and in cultured pulmonary ECs from iPAH, contributing to an exaggerated recruitment of peripheral blood mononuclear cells to pulmonary iPAH ECs. Finally, we found that curative treatments with the MIF antagonist ISO-1 or anti-CD74 neutralizing antibodies partially reversed development of pulmonary hypertension in rats and substantially reduced inflammatory cell infiltration.
We report here that CD74 and MIF are markedly increased and activated in patients with iPAH, contributing to the abnormal proinflammatory phenotype of pulmonary ECs in iPAH.
The relationship between the initial treatment strategy and survival in pulmonary arterial hypertension (PAH) remains uncertain.
To evaluate the long-term survival of patients with PAH categorized ...according to the initial treatment strategy.
A retrospective analysis of incident patients with idiopathic, heritable, or anorexigen-induced PAH enrolled in the French Pulmonary Hypertension Registry (January 2006 to December 2018) was conducted. Survival was assessed according to the initial strategy: monotherapy, dual therapy, or triple-combination therapy (two oral medications and a parenteral prostacyclin).
Among 1,611 enrolled patients, 984 were initiated on monotherapy, 551 were initiated on dual therapy, and 76 were initiated on triple therapy. The triple-combination group was younger and had fewer comorbidities but had a higher mortality risk. The survival rate was higher with the use of triple therapy (91% at 5 yr) as compared with dual therapy or monotherapy (both 61% at 5 yr) (
< 0.001). Propensity score matching of age, sex, and pulmonary vascular resistance also showed significant differences between triple therapy and dual therapy (10-yr survival, 85% vs. 65%). In high-risk patients (
= 243), the survival rate was higher with triple therapy than with monotherapy or dual therapy, whereas there was no difference between monotherapy and double therapy. In intermediate-risk patients (
= 1,134), survival improved with an increasing number of therapies. In multivariable Cox regression, triple therapy was independently associated with a lower risk of death (hazard ratio, 0.29; 95% confidence interval, 0.11-0.80;
= 0.017). Among the 148 patients initiated on a parenteral prostacyclin, those on triple therapy had a higher survival rate than those on monotherapy or dual therapy.
Initial triple-combination therapy that includes parenteral prostacyclin seems to be associated with a higher survival rate in PAH, particularly in the youngest high-risk patients.
RATIONALE:Although many familial cases of pulmonary arterial hypertension exhibit an autosomal dominant mode of inheritance with the majority having mutations in essential constituents of the BMP ...(bone morphogenetic protein) signaling, the specific contribution of the long-term loss of signal transduction triggered by the BMPR2 (type 2 BMP receptor) remains poorly characterized.
OBJECTIVE:To investigate the role of BMP9, the main ligand of ALK1 (Activin receptor-like kinase 1)/BMPR2 heterocomplexes, in pulmonary hypertension.
METHOD AND RESULTS:The absence of BMP9 in Bmp9 mice and its inhibition in C57BL/6 mice using neutralizing anti-BMP9 antibodies substantially prevent against chronic hypoxia-induced pulmonary hypertension judged by right ventricular systolic pressure measurement, right ventricular hypertrophy, and pulmonary distal arterial muscularization. In agreement with these observations, we found that the BMP9/BMP10 ligand trap ALK1ECD administered in monocrotaline or Sugen/hypoxia (SuHx) rats substantially attenuate proliferation of pulmonary vascular cells, inflammatory cell infiltration, and regresses established pulmonary hypertension in rats. Our data obtained in human pulmonary endothelial cells derived from controls and pulmonary arterial hypertension patients indicate that BMP9 can affect the balance between endothelin-1, apelin, and adrenomedullin. We reproduced these in vitro observations in mice chronically exposed to hypoxia, with Bmp9 mice exhibiting lower mRNA levels of the vasoconstrictor peptide ET-1 (endothelin-1) and higher levels of the 2 potent vasodilator factors apelin and ADM (adrenomedullin) compared with Bmp9 littermates.
CONCLUSIONS:Taken together, our data indicate that the loss of BMP9, by deletion or inhibition, has beneficial effects against pulmonary hypertension onset and progression.
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