Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases.

Pulmonary arterial hypertension is a severe complication of connective tissue diseases. It is currently well established that pulmonary arterial hypertension associated with connective tissue diseases such as systemic sclerosis is frequently less responsive or even refractory to pulmonary vasodilator therapies. In that setting, pulmonary venoocclusive disease is believed to contribute to treatment failures. We therefore hypothesized that pulmonary arterial hypertension associated with connective tissue diseases may be associated with obstructive lesions of pulmonary veins. Lung samples from 8 patients with pulmonary arterial hypertension associated with connective tissue disease (4 limited systemic sclerosis, 2 systemic lupus erythematosus, 1 mixed connective tissue diseases, and 1 rheumatoid arthritis) were studied by light microscopy and analyzed by immunohistochemistry (5 postmortem samples, 3 explants after lung transplantation). Findings were compared with 29 pulmonary arterial hypertension cases from patients displaying neither connective tissue diseases nor associated conditions. We found that (a) 6 (75%) of 8 patients with pulmonary arterial hypertension associated with connective tissue diseases showed significant obstructive pulmonary vascular lesions predominating in veins/preseptal venules, as compared with 5 (17.2%) of 29 non-connective tissue diseases control pulmonary arterial hypertension; (b) lesions of small muscular arteries were consistently present in pulmonary arterial hypertension associated with connective tissue diseases, showing mostly intimal fibrosis and thrombotic lesions; and (c) 6 of 8 lung samples from patients with pulmonary arterial hypertension associated with connective tissue diseases revealed perivascular inflammatory infiltration. In conclusion, our study highlights the fact that pulmonary arterial hypertension complicating the course of connective tissue diseases may be characterized by a more frequent involvement of pulmonary veins and may thus explain why these patients are less prone to respond to specific pulmonary arterial hypertension treatment as compared with idiopathic pulmonary arterial hypertension.