CLAMART, France—Pulmonary arterial hypertension (PAH), a life-threatening complication of connective tissue disease (CTD), is likely to require a two-tiered approach to treatment, according to Xavier Jais, MD. Patients with PAH due to lupus or to MCTD are likely to benefit from combination cyclophosphamide and glucocorticosteroids, but pulmonary vasodilators (perhaps in combination with immunosuppressants) are likely needed for more severe cases, according to a retrospective study reported in Arthritis & Rheumatism.¹

“[O]ur study shows that some patients with PAH associated with SLE or MCTD might respond to immunosuppressive therapy alone. These responders were patients who have less severe PAH clinical and hemodynamic characteristics at baseline. For patients with more severe disease, combination therapy with immunosuppressants and PAH-specific therapy was more effective, although the exact role of immunosuppressive therapy in this combination is not known,” wrote Xavier Jais, MD, of Hôpital Antoine-Beclerc in Clamart, France.

Dr. Jais et al reported an analysis of 23 consecutive patients with SLE- or MCTD-associated PAH treated either with first-line immunosuppressive therapy alone (n = 16) or with first-line immunosuppressive therapy plus pulmonary vasolidators (n = 7). Half of the patients treated with immunosuppressive therapy alone responded with significantly improved New York Heart Association (NYHA) functional class, 6-minute walking distance, and mean pulmonary artery pressure. Adding pulmonary vasodilators improved responders in 6 of the 8 initial nonresponders and improved response rates in 4 of the 7 patients initially treated with immunosuppressive therapy plus pulmonary vasodilators (57.1%).

The researchers “cautiously propose” that SLE or MCTD patients with PAH who are NYHA class I/II/III with a cardiac index (CI) >3.1 L/min/m² receive first-line glucocorticoids and cyclophosphamide for 6 months. If “a clear response” does not develop by 6 months, immunosuppressive therapy should be stopped and PAH-specific therapy started. They recommend treating patients in NYHA class III with a CI ≤3.1 L/min/m² or treating those in NYHA functional class IV with a combination of immunosuppressants plus PAH-specific therapy. “However, it remains to be demonstrated whether adding immunosuppressive therapy to vasodilators at diagnosis could provide additional benefits to this subset of PAH patients,” they write.

Relapse after a last pulse of cyclophosphamide is a concern, so Dr. Jais recommended a maintenance regimen of low-dose prednisone with either azathioprine or mycophenolate mofetil (MMF).

Martin Aringer, MD, from the division of rheumatology at the Technical University of Dresden, Germany, reviewed the study for Musculoskeletal Report. Dr. Aringer found the overall approach is feasible but pointed out that, as Jais et al noted, early use of endothelin receptor blockers (eg, in NYHA II patients) is not yet accepted standard of care. “This likely will change, which will also influence such recommendations,” he said.

“It is quite clear that immunosuppression plays a role in treating SLE PAH. PAH associated with MCTD may be in between SLE (where immunosuppression may work often) and systemic sclerosis (where it probably does not). The switch from cyclophosphamide is an adaptation from the usual approach for lupus nephritis, and this inference has some logic. The study I would like to see is one with three arms: cyclophosphamide only, endothelin receptor blocker only, and the combination. Additional arms might include MMF with or without bosentan and, for NYHA II, possibly a placebo arm with a rescue protocol in case of worsening (for anything worse than NYHA II this is clearly unethical),” Dr. Aringer concluded.

Reference

1.    Jais X, Launay D, Yaici A, et al. Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension. A retrospective analysis of twenty-three cases. Arthritis Rheum. 2008;58:521-531.