Pulmonary arterial hypertension (PAH) and pulmonary fibrosis are major causes of morbidity and death in systemic sclerosis. Recent progresses have been achieved in the treatment of PAH with the development of therapies targeting dysfunctional endothelial cells (prostacyclin derivatives, endothelin receptor antagonists and type 5 phosphodiesterase inhibitors). These approaches have led to the approval of several agents worldwide, an outstanding result for a rare and devastating condition. However PAH remains a devastating disease in the modern management era and PAH drugs are less efficacious in the setting of systemic sclerosis. There is thus a need for novel therapies targeting new pathways.

Pulmonary vascular remodeling and growth factors including Platelet-Derived Growth Factor (PDGF) are believed to play a significant role in PAH. Pioneer authors have attempted to treat experimental and human pulmonary hypertension with nonselective inhibitors of the PDGF receptor tyrosine kinase such as imatinib, which also inhibits abl and kit (thus improving outcomes in chronic myelogenous leukemia and gastrointestinal stromal tumours). This novel approach was efficacious in animal models, and interesting results were reported in rare case reports of either compassionate off label use of the drug or treatment of PAH patients with comorbid chronic myelogenous leukemia. Enthusiasm was tapered by the publication of the phase II and phase III studies showing that imatinib is poorly tolerated in some patients and that it improves cardiac output and walk distance at the expense of increased morbidity.

Are we witnessing the twilight of kinase inhibitors in the treatment of PAH? Only time will tell. There is little doubt, however, that overall risks conferred with most, if not all, kinase inhibitors (imatinib, nilotinib, sorafenib, sunitinib, etc…) that have recently been proposed as treatments for PAH outweigh any potential benefits. Yet there is a signal of a potential hemodynamic effect from this therapeutic class that should be further evaluated. In addition, a better description of the pathobiology of pulmonary vascular remodeling in PAH ought to help with the designing of new drugs exclusively blocking PAH-specific pathways. A better understanding of the pathways involved in the efficacy and safety aspects of imatinib will be paramount in order to design more targeted and better tolerated agents in the field of personalized PAH medicine. Until then, healthcare professionals should be discouraged to offer compassionate imatinib therapy to PAH patients.

Disclosure of Interest M. Humbert Consultant for: Actelion, Aires, Bayer, BMS, GSK, Novartis, and Pfizer