Pulmonary Arterial Hypertension in Connective Tissue Diseases
Introduction
Pulmonary arterial hypertension (PAH) is a progressive disease caused by a remodeling of precapillary arterioles that leads to a progressive increase in pulmonary vascular resistance and right ventricular failure. PAH is associated with significant morbidity and mortality, despite the advent of specific therapies that target pathobiologic pathways implicated in the disease process.1, 2, 3 PAH can only be diagnosed by right heart catheterization (RHC), and is defined as a mean pulmonary artery pressure greater than 25 mm Hg in the absence of elevation of the pulmonary capillary wedge pressure. PAH includes a heterogeneous group of clinical entities sharing similar pathologic changes that have been subcategorized as idiopathic PAH (IPAH), familial PAH, and pulmonary hypertension associated with other diseases such as connective tissue diseases (CTDs), portopulmonary hypertension, and pulmonary hypertension related to human immunodeficiency virus infection, drugs, and toxins. An updated classification of all pulmonary hypertension syndromes has been recently published from the fourth World Symposium held at Dana Point, California, in 2008.4
The exact mechanisms involved in the pathogenesis of PAH remain vastly unknown but are likely to involve significant alterations in endothelial function,5 an understanding of which has led over the past 2 decades to targeted therapy for this disease.6 Several lines of evidence also support a role for autoimmunity in the development of the pulmonary vascular changes, including the presence of circulating autoantibodies,7 proinflammatory cytokines (eg, interleukin [IL]-1 and IL-6),8 and association of PAH with autoimmune diseases and CTDs such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCTD). Despite the similarities in disease pathogenesis and hemodynamic perturbations, outcomes in patients with CTD-associated PAH differ significantly from other forms of PAH. In particular, patients with SSc-associated PAH (SSc-PAH) have a poorer response to therapy and significantly worse survival compared with IPAH patients.9, 10, 11 There are serologic and pathologic features suggestive of inflammation in both IPAH and SSc-PAH, although inflammatory pathways and autoimmunity are likely more pronounced in SSc-PAH, perhaps explaining clinical discrepancies between the 2 syndromes.9, 10 Other CTDs such as SLE, MCTD, and to a lesser extent rheumatoid arthritis (RA), dermatomyositis, and Sjögren syndrome, can also be complicated by PAH and are discussed separately in this review.
Section snippets
Scleroderma
SSc is a heterogeneous disorder characterized by dysfunction of the endothelium, dysregulation of fibroblasts resulting in excessive production of collagen, and abnormalities of the immune system.12 Progressive fibrosis of the skin and internal organs is a pathologic hallmark of the disease, resulting in major organ damage and failure and thus explaining the high morbidity and early death. Genetic and environmental factors are thought to contribute to host susceptibility13 in the context of
Scleroderma-associated PAH (SSc-PAH)
The prevalence of PAH in SSc patients, when the diagnosis is based on RHC for assessment of filling pressures, is about 8% to 14%.20, 21 Previous assessments based on echocardiographic measurements22, 23, 24, 25 have overestimated the true prevalence of SSc-PAH, and should not be relied on for establishing the diagnosis and initiating treatment. Echocardiography is limited in the diagnosis of PAH, because of the inaccuracy of the Doppler signal in assessing true right ventricular systolic
PAH associated with other CTDs
PAH can complicate any CTD, most frequently SSc as already discussed, but also SLE, MCTD, RA, or other diseases such as Sjögren syndrome and dermatomyositis.
Therapy for PAH related to CTD
Although randomized clinical trials of novel therapeutics for the treatment of PAH have included patients with PAH associated with CTD, the majority of the subjects included in trials were SSc-PAH. Given the differences in survival and potential differences in response to immunosuppressive therapy between the various forms of CTD-associated PAH, the generalizability of the results of the clinical trials may be limited to only SSc-PAH. However, the therapies discussed here are commonly used in
Summary
Pulmonary hypertension is a common complication of CTD, particularly SSc, for which it carries a very poor prognosis. Despite modern therapy for PAH, survival of patients with CTD-PAH remains unacceptably low. Possible reasons include an increased prevalence of pulmonary veno-occlusive lung disease in SSc-PAH patients,126 or more severe vascular lesions affecting not only proximal and distal pulmonary vessels but also the heart (such as inflammatory myocarditis) in CTD. Thus, a better
References (126)
- et al.
Primary pulmonary hypertension
Lancet
(1998) - et al.
Updated clinical classification of pulmonary hypertension
J Am Coll Cardiol
(2009) - et al.
Autoantibodies in patients with primary pulmonary hypertension: association with anti-Ku
Am J Med
(1992) - et al.
Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis
Chest
(2003) Systemic sclerosis: the susceptible host (genetics and environment)
Rheum Dis Clin North Am
(2003)Scleroderma epidemiology
Rheum Dis Clin North Am
(2003)- et al.
Prevalence of pulmonary hypertension in limited and diffuse scleroderma
Chest
(1996) - et al.
Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry
Chest
(2010) Systemic sclerosis. A vascular perspective
Rheum Dis Clin North Am
(1996)- et al.
Capillary alterations in scleroderma
J Am Acad Dermatol
(1980)
Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis
Semin Arthritis Rheum
Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension
Chest
Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene
Am J Hum Genet
The -2518 promoter polymorphism in the MCP-1 gene is associated with systemic sclerosis
J Invest Dermatol
-238 and +489 TNF-alpha along with TNF-RII gene polymorphisms associate with the diffuse phenotype in patients with systemic sclerosis
Immunol Lett
Age and risk of pulmonary arterial hypertension in scleroderma
Chest
Right heart function in scleroderma: insights from myocardial Doppler tissue imaging
J Am Soc Echocardiogr
Bull Acad Natl Med
Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial
Chest
Massive pulmonary edema and death after prostacyclin infusion in a patient with pulmonary veno-occlusive disease
Chest
Survival in patients with primary pulmonary hypertension. Results from a national prospective registry
Ann Intern Med
Primary pulmonary hypertension. A national prospective study
Ann Intern Med
Endothelial dysfunction in pulmonary hypertension
Circulation
Treatment of pulmonary arterial hypertension
N Engl J Med
Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension
Am J Respir Crit Care Med
Clinical differences between idiopathic and scleroderma-related pulmonary hypertension
Arthritis Rheum
Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era
Am J Respir Crit Care Med
Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis
Ann Intern Med
Scleroderma (systemic sclerosis): classification, subsets and pathogenesis
J Rheumatol
An epidemiological study of scleroderma in the West Midlands
Br J Rheumatol
Epidemiological study of patients with systemic sclerosis in Tokyo
Arch Dermatol Res
A study of the prevalence of systemic sclerosis in northeast England
Rheumatology (Oxford)
Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population
Arthritis Rheum
Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study
Arthritis Rheum
Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach
Ann Rheum Dis
Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis
Arthritis Rheum
Isolated pulmonary hypertension in systemic sclerosis with diffuse cutaneous involvement: association with serum anti-U3RNP antibody
J Rheumatol
Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival
Rheumatology (Oxford)
Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension
Am J Respir Crit Care Med
Pulmonary arterial hypertension in France: results from a national registry
Am J Respir Crit Care Med
An epidemiological study of pulmonary arterial hypertension
Eur Respir J
Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95
Arthritis Rheum
Predictors of survival in systemic sclerosis (scleroderma)
Arthritis Rheum
Serial circulating adhesion molecule levels reflect disease severity in systemic sclerosis
Br J Rheumatol
Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers
Arthritis Res
Elevated vascular endothelial growth factor in systemic sclerosis
J Rheumatol
Increased concentrations of the circulating angiogenesis inhibitor endostatin in patients with systemic sclerosis
Arthritis Rheum
Autoantibody to U3 nucleolar ribonucleoprotein (fibrillarin) in patients with systemic sclerosis
Arthritis Rheum
Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension
J Rheumatol
Antibodies to fibrin bound tissue type plasminogen activator in systemic sclerosis
J Rheumatol
Cited by (0)
Supported by: NHLBI K23 HL092287 (S.C.M.) and P50 HL084946 (P.M.H.).
The authors have nothing to disclose.