Efficacy of the endothelin receptor blocker bosentan for refractory sickle cell leg ulcers

Abstract

In February 2007, a 46-year-old woman with sickle cell anaemia (SCA) was hospitalized for dyspnea of progressive onset. She had suffered from bilateral leg ulcers since 1979, which had been complicated with episodes of wound infections and ankle stiffness. They were very disabling, leading to frequent loss of work, intense pain and depression. The following treatments were either unsuccessful or resulted in partial improvement: classical tulles, hydrocellular dressings, hydrogels, skin grafts, topical dripping of granulocyte-macrophage colony-stimulating factor and regular transfusions. True remission exceeding more than a few weeks had never occurred during the last 18 years. A glomerulopathy was diagnosed in 2004, and treatment with ramipril was begun. At admission, the cutaneous ulcers were covered with adherent fibrinous layer and were located on the internal aspect of the right leg, and on the external ankle of the right foot, with an involved area of 29 cm2. They were painful with a score of 7 on a 1–10 visual analogue scale. Peripheral pulses were palpated and the right femoral head showed osteonecrosis. Pulmonary hypertension, characterized by an increased resting tricuspid regurgitation jet velocity of 3·5 m/s, was confirmed by right heart catheterization that disclosed a mean pulmonary artery pressure of 37 mmHg and pulmonary vascular resistance of 216 dyn.s/cm5. The pre-transfusion haemoglobin level was 85 g/l (unchanged), the lactate dehydrogenase level was 536 U/l (normal <250), and serum creatinine was 99 μmol/l. The proteinuria was 1·8 g/d. Because of pulmonary hypertension, bosentan was started at 125 mg/d for 1 month, followed by 250 mg/d. Similar programmed transfusions were continued. Progressive improvement of the ulcers was thereafter observed, with total healing at 3 weeks. No recurrence occurred in the following 10-month period. We report here a patient with refractory sickle cell leg ulcers that resolved totally and durably under bosentan therapy given for treatment of pulmonary hypertension. Of note, the course of her ulcers was the worst of our recently published series, with resistance to all classical modalities (Halabi-Tawil et al, 2008). There was no concomitant change of therapy including other oral drugs, types of dressings and frequency of transfusions. Moreover, the complete remission of ulcers under bosentan therapy lasted up to 10 months. All these points strongly suggest that in this patient, bosentan therapy was responsible for ulcer healing. Leg ulcers are one of the most common and disabling complications of SCA, whose treatment is very discouraging, especially in the prolonged ‘malignant’ form (Halabi-Tawil et al, 2008). Recently, sickle cell ulcers have been recognized to be associated with other complications, such as priapism and pulmonary hypertension, constituting a subphenotype of SCA, in which intravascular haemolysis and endothelial lesions play a key role (Kato et al, 2006). Indeed, in SCA, high levels of endothelin-1 (Hebbel & Vercelloti, 1997; Tharaux et al, 2005) and impaired bioavailability of nitric oxide (Reiter et al, 2002) exist, and lead to vasoconstriction and vasculopathy. Therefore, it is logical to hypothesize that an endothelin receptor blocker would be beneficial, by inactivating one of these two factors. Of note, the efficacy of bosentan for the prevention and, to a lesser extent, treatment of ulcers in systemic sclerosis patients has been reported (Garcia de la Peña-Lefebvre et al, 2008). A recent study evaluated that 37% of SCA patients suffering from pulmonary hypertension have also leg ulcers (De Castro et al, 2008). So, it would be interesting to monitor the evolution of ulcers in patients treated with bosentan for pulmonary hypertension, before starting a prospective trial testing this drug in the most prolonged and resistant forms of leg ulcers in SCA. This case could lead to novel endothelial directed therapy for leg ulcers, which remain one of the most difficult therapeutic problems of SCA. No financial or other potential conflicts of interest exist.