Volume 16: Issue 2

Pulmonary hypertension (PH) is an important and relatively frequent complication of connective tissue disease (CTD). It is most often seen as a complication of systemic sclerosis and mixed CTD, but is also recognized in systemic lupus erythematosus and other related conditions. Although PH is defined hemodynamically by mean pulmonary arterial pressure (mPAP) of ≥25 mm Hg at right heart catheterization, and may have a variety of mechanisms, it is World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH) that has deservedly received the most attention in CTD. The inclusion of cases of precapillary PH without other explanation or concurrent lung fibrosis in WHO Group 1 led to availability of licensed therapies and increased the need for screening and treatment. Approaches are now available that detect PAH, and optimal approaches to therapy are included in expert and evidence-based recommendations. Challenges include borderline elevation of mPAP, comorbidity, and mixed-etiology cases. Overall outcomes have improved, and new clinical trials are being performed that will hopefully build on recent progress to further improve outcomes. Other aspects of PH in CTD to consider include forms related to cardiac disease and lung fibrosis or hypoxia, as these may occur as complications of the underlying CTD. Thromboembolic disease may also occur and represents another important differential diagnosis. Finally, it has been reported that pulmonary veno-occlusive disease may occur, which raises diagnostic and treatment difficulties. Overall, there are major challenges in CTDPH, but also opportunities for effective multispecialty care and early detection and diagnosis of potentially treatable cases of PAH.

Systemic sclerosis (SSc) is characterized by autoimmunity, small-vessel vasculopathy, and fibrosis causing damage in multiple organ systems. Pulmonary arterial hypertension (PAH) is a serious and often fatal complication of SSc, occurring in patients with the limited (lcSSc) and diffuse (dcSSc) forms of the disease and affecting 8% to 15% of patients.1 2 While pulmonary hypertension associated with connective tissue disease (CTD-PAH) has similar clinical features as idiopathic PAH, 1-year survival and freedom from hospitalization are lower in CTD-PAH.3 SSc-PAH has the worst 1-year survival rate at 82% compared with other connective tissue diseases, including systemic lupus erythematosus, mixed connective tissue disease, and rheumatoid arthritis.3 4 Despite the recent progress in the development of disease-targeted therapies, patients with SSc-PAH have a poorer response to treatment and a worse prognosis than other subgroups of PAH.1 Autoimmunity and prolonged vasculopathy preceding the development of clinical manifestations of SSc-PAH may play a critical role in the poorer outcome of SSc-PAH patients.1 This article will provide an overview of the recent findings related to cellular and molecular mechanisms associated with the development of PAH, with an emphasis on SSc-PAH.

Background: Systemic sclerosis (SSc) is a heterogeneous disorder that results in multiorgan dysfunction. The most common pulmonary manifestations are pulmonary hypertension (PH) and interstitial lung disease (ILD). Systemic sclerosis may be complicated by World Health Organization (WHO) Group 1 PH (SSc-PAH), which is the most well-studied subtype. The PH associated with SSc may also be secondary to underlying left heart disease (SSc-PH-LHD) or ILD (SSc-PH-ILD), and these subgroups are classified as WHO Group 2 and Group 3 PH, respectively. These non-WHO Group 1 PH subsets are notoriously under-studied. Available data suggest that the impact of PH-specific therapy in SSc-PH-LHD and SSc-PH-ILD is limited and survival is poor despite attempted treatment.

Implication for clinicians: Most research and clinical trials surrounding PH in SSc have thus far focused on WHO Group 1 SSc-PAH. There are limited data surrounding therapeutic options for WHO Group 2 (SSc-PH-LHD) and Group 3 PH (SSc-PH-ILD) phenotypes. This review aims to summarize and consolidate the data surrounding these 2 distinct clinical phenotypes and to emphasize the available prognostic and treatment considerations.

Conclusions: Given the unique pathophysiology, prognostic implications, and poor response to treatment of WHO Group 2 and 3 SSc-PH phenotypes, there is an overwhelming need for more data to best understand optimal management strategies. The focus should be individual patient-level prognostication, how and when to initiate and manage PH-specific therapy, and appropriate triage with regard to the timing of lung (or heart-lung) transplantation.

Raynaud's phenomenon (RP) is the most common complication of scleroderma (SSc), affecting over 95% of patients with this disease.1 Raynaud's phenomenon results from structural and functional abnormalities in the digital arteries and is characterized by intimal proliferation. This proliferation leads to: 1) endothelial damage characterized by upregulation of vasoactive mediators that cause vasoconstriction, and 2) vascular narrowing that further impairs blood flow in these arteries.2 In addition, increased expression of alpha-2c adrenergic receptors in the digital arteries results in heightened responsiveness to cold-induced adrenergic signals.3 These factors predispose to vasospasm in the digital arteries,

EDITOR'S MEMO

GUEST EDITOR'S MEMO

PH Grand Rounds: A Case of Atypical Hemolytic Uremic Syndrome and Pulmonary Veno-Occlusive Disease

Presentation:

Systemic Sclerosis and Other Connective Tissue Diseases

Pulmonary Hypertension Associated With Scleroderma and Connective Tissue Disease: Potential Molecular and Cellular Targets

Non-Group 1 Pulmonary Hypertension Associated With Systemic Sclerosis: An Under-studied Patient Population

Pulmonary Hypertension Roundtable: PH and Connective Tissue Disease

Ask The Expert

PH Professional Network: Screening for Caregiver's Burden in Management of Scleroderma: Pulmonary Arterial Hypertension

Conference Abstracts

Guest Editor’s Memo

A Roundtable Discussion Addressing Patient-Centered Care and Quality of Life in Patients With Pulmonary Arterial Hypertension

Editor’s Memo

Pulmonary Hypertension Associated With Parenchymal Lung Disease