A long-term follow-up study, EDITA-ON, published in Arthritis Research & Therapy has provided compelling evidence that ambrisentan therapy significantly reduces the risk of developing pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) patients with early pulmonary vascular disease (PVD). This open-label study offers new insights into the management of SSc-related pulmonary complications, reinforcing the potential benefit of early intervention.
The EDITA-ON study included 34 patients from the original EDITA trial, which demonstrated a short-term decline in pulmonary vascular resistance (PVR) in patients treated with ambrisentan over six months, although no significant change in mean pulmonary arterial pressure (mPAP) was observed during that time.
Out of the 34 patients, 19 received ambrisentan after the termination of the blinded phase, while 15 received no PAH therapy. Over a mean follow-up of 2.59 years, 29 patients underwent right heart catheterization. The study demonstrated a significant improvement in mPAP in the ambrisentan group, with a reduction of -1.53 mmHg, compared to an increase of +1.91 mmHg in the untreated group (P = 0.003). Notably, the incidence of PAH was substantially lower in patients treated with ambrisentan. Only 1 of 17 patients receiving ambrisentan developed PAH, versus 6 of 12 in the untreated cohort (P <0.0001), suggesting that ambrisentan therapy may play a critical role in preventing PAH in this high-risk population.
Ambrisentan is a selective inhibitor of the endothelin receptor type A (ET-A), with minimal activity against ET-B receptors at therapeutic doses used in humans. By blocking the ET-A receptor, ambrisentan disrupts intracellular signaling pathways that lead to vasoconstriction, promoting vasodilation. Since ET-A receptors are most concentrated in the pulmonary vasculature, ambrisentan primarily induces vasodilation in the lungs, resulting in reduced pulmonary vascular pressure. In prospective, randomized controlled trials, ambrisentan demonstrated efficacy in relieving symptoms, enhancing exercise tolerance, and delaying the progression of clinical worsening in patients with idiopathic PAH.
These findings underscore the importance of early and proactive treatment in SSc patients with mild PVD. By reducing pulmonary vascular resistance and potentially halting the progression to overt PAH, ambrisentan offers a valuable therapeutic option in a disease with limited management strategies. Close follow-up and monitoring remain essential, particularly as early pulmonary vascular changes in SSc often progress silently until irreversible damage occurs. Further trials are necessary to confirm these outcomes and to explore the broader implications of endothelin receptor antagonists like ambrisentan in managing early-stage pulmonary vascular disease in SSc patients. For rheumatologists, these results offer hope for a more effective, long-term approach to preventing PAH in patients with systemic sclerosis.
References
- Xanthouli P, Uesbeck P, Lorenz HM, Blank N, Eichstaedt CA, Harutyunova S, Egenlauf B, Coghlan JG, Denton CP, Grünig E, Benjamin N. Effect of ambrisentan in patients with systemic sclerosis and mild pulmonary arterial hypertension: long-term follow-up data from EDITA study. Arthritis Res Ther. 2024 Jul 18;26(1):136.
- Ambrisentan. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012 [cited 2024 Sep 14]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK548675/