Question
How does pulmonary arterial hypertension occur in autoimmune diseases? Does it occur in all autoimmune diseases or in just a select few?

Response from Joseph Shanahan, MD Associate Consulting Professor of Medicine, Duke University Medical Center, Carolina Arthritis Associates, Durham, North Carolina

Pulmonary arterial hypertension (PAH) may develop in the context of several autoimmune diseases. However, the association is clearly strongest in patients with scleroderma and mixed connective tissue disease. The prevalence of undiagnosed PAH in subjects with connective tissue disease at the secondary healthcare level of community-based rheumatologists (the UNCOVER study) suggested a point prevalence of approximately 26% in patients with mixed connective tissue disease (MCTD) and scleroderma.^[1] PAH may also develop in patients with systemic lupus erythematosus (SLE) in as many as 5% to 15% of cases, although estimates are likely exaggerated by referral bias to the specialty clinics that have published the prevalence rates. PAH is only rarely described in conditions such as rheumatoid arthritis, systemic necrotizing vasculitis, or idiopathic inflammatory myositis. In most cases of PAH that is associated with autoimmune disease, the pathophysiology appears similar to that seen in idiopathic PAH and PAH associated with other conditions such as congenital heart disease, sickle cell disease, or HIV infection. Histopathologic evaluation demonstrates nearly identical pulmonary vascular lesions in patients with idiopathic PAH (iPAH) and in those with scleroderma-associated PAH. An interesting exception to this observation pertains to the plexiform lesions that appear to be monoclonal endothelial cell proliferations in iPAH, but are polyclonal in scleroderma-associated disease. From a clinical standpoint, it is important to recognize that PAH developing in patients with scleroderma is likely to progress more rapidly than in iPAH. The cause of PAH is as much a mystery in patients with autoimmune disease as in patients with iPAH. However, the polymorphisms in bone morphogenetic protein genes that characterize some cases of iPAH and familial PAH are not observed in patients with autoimmune disease and PAH. There is growing evidence in the scleroderma population that a deficiency and/or dysfunction of endothelial progenitor cells may contribute to development of PAH. Whether this is a consequence of immune-mediated processes is uncertain. It appears that PAH may develop in patients with lupus as result of multiple mechanisms. PAH may develop in patients with SLE and antiphospholipid antibodies as a consequence of venous thromboembolic disease. In addition, PAH may develop in some patients with SLE as a result of inflammatory pulmonary vascular disease. Sanchez and colleagues^[2] published a retrospective review of 28 consecutive patients with connective tissue disease-associated PAH who received cyclophosphamide (and in most cases glucocorticoids also) for the initial treatment of newly diagnosed PAH. Although none of the patients with scleroderma had improvement of immunosuppression, 3 of 8 patients with MCTD and 5 of 12 patients with SLE responded with longer 6-minute walk distance and/or hemodynamic improvement. In our experience, some patients with lupus who have PAH who initially respond favorably to cyclophosphamide will eventually have recurrence of PAH and require traditional vasodilator therapy. It is speculated that at least some cyclophosphamide-responsive lupus PAH represents an inflammatory small vessel vasculitis that may cause reversible PAH that can be effectively managed with aggressive immunomodulation.

This activity is supported by an independent educational grant from Actelion.