Sildenafil for treatment of pulmonary hypertension in association with systemic lupus erythematosus and anti-phospholipid syndrome

Abstracts

Severe pulmonary hypertension is a debilitating disease with short life expectancy that often affects young people. Pleuropulmonary complications of systemic lupus erythematosus occur in 50-70% of patients. Severe symptomatic pulmonary hypertension in systemic lupus erythematosus is rare and carries a bad prognosis because a fatal outcome can occur within months. The authors describe, for the first time, a patient with systemic lupus erythematosus with severe pulmonary hypertension and secondary antiphospholipid syndrome who responded favorably to oral sildenafil, after unsuccessful use of prednisone, intravenous cyclophosphamide, warfarin and diltiazem.

Vasodilator agents; Lupus erythematosuos systemic; Antiphospholipid antibodies; Phosphodiesterase inhibitors

Hipertensão pulmonar grave é uma doença debilitante, com expectativa de vida reduzida, que acomete adultos jovens. Complicações pleuropulmonares no lúpus eritematoso sistêmico ocorrem em 50% a 70% dos pacientes. A hipertensão pulmonar grave no lúpus eritematoso sistêmico é rara e tem prognóstico reservado. Descreve-se, pela primeira vez, um paciente com hipertensão pulmonar grave associada a lúpus eritematoso sistêmico e síndrome antifosfolipídio secundário que apresentou boa resposta ao uso do sildenafil oral, após falha do tratamento convencional com corticosteróides, ciclofosfamida, warfarin e diltiazem.

Vasodilatadores; Lúpus eritematoso sistêmico; Anticorpos antifosfolipídios; Inibidores da fosfodiesterase

CASE REPORT

Sildenafil for treatment of patients with pulmonary hypertension combined with systemic lupus erythematosus and antiphospholipid syndrome^*

Eduardo José do Rosário e Souza^I; Junia Rios Garib^II (te sbpt); Nasim Michel Garib^III; Paulo Madureira de Pádua^IV

^IMaster in General Medicine and Coordinator of the Department of Specialized Rheumatology at the Hospital da Santa Casa in Belo Horizonte

^IIAssistant Physician of the IV General Clinic at the Hospital da Santa Casa in Belo Horizonte and Assistant Professor of Pulmonology at the Minas Gerais School of Medicine

^IIICoordinator of the IV General Clinic at the Hospital da Santa Casa from Belo Horizonte and Professor of Pulmonology at the Minas Gerais School of Medicine

^IVCoordinator of the Rheumatology Department at the Hospital da Santa Casa in Belo Horizonte and Professor of Rheumatology at the Federal University of Minas Gerais

^{Correspondence}

ABSTRACT

Severe pulmonary hypertension (PH) is a disabling disease that appears in early adulthood and reduces life expectancy. Pleural and respiratory complications related to systemic lupus erythematosus (SLE) are present in about 50-70% patients. Severe PH in SLE is a rare condition and has a poor prognosis. Here we describe, for the first time, a patient with SLE, secondary antiphospholipid syndrome and severe PH who, after the failure of conventional treatment with corticosteroids, intravenous cyclophosphamide, warfarin and diltiazem, presented a good response to treatment to oral sildenafil.

Key words: Vasodilator. Lupus. Antiphospholipid antibody. Phosphodiesterase inhibitor.

Abbreviations used in this article

cGMP – Cyclic guanosine monophosphate

PH – Pulmonary hypertension

SLE – Systemic lupus erythematosus

NO – Nitric oxide

PDE-5 – Phosphodiesterase-5

APAS – Antiphospholipid antibody syndrome

Introduction

Pulmonary hypertension (PH) is the term used for a group of disorders presenting elevated pulmonary artery pressure, which is determined by pulmonary vascular resistance, cardiac output and pressure within the left atrium. The disease may be primary or secondary to another condition.⁽¹⁾ A diffuse disease of the connective tissue may occasionally lead to the development of PH. Secondary PH, like primary PH, may significantly affect quality of life and shorten the life span of patients with diffuse connective tissue disease.⁽²⁾

The combination of severe PH and phospholipid antibodies was described for the first time in 1983, when 5 out of 6 patients with systemic lupus erythematosus (SLE) and PH tested positive for lupus anticoagulant. Severe, symptomatic PH is rare in SLE and, when present, a poor prognosis is expected, mainly due to fatal outcomes that may occur within some months (circulatory collapse in most patients).⁽³⁾

There are not many treatment options available for severe PH. Recent reports and preliminary studies showed that sildenafil, a specific phosphodiesterase-5 (PDE-5) inhibitor widely used in the treatment of erectile dysfunction, may reduce pulmonary vascular resistance in humans with primary PH, healthy volunteers with hypoxemic pulmonary vasoconstriction, and animals with experimentally-induced severe PH.⁽⁴⁾

Here, we describe a patient with PH combined with SLE and antiphospholipid antibody syndrome (APAS), a complex condition that was resistant to conventional treatment. However, the patient responded well to the use of sildenafil.

Case report

This is the case of a 33-year-old female patient who, upon admission to the Rheumatology and Pulmonology Departments at the Hospital da Santa Casa in Belo Horizonte, presented malar erythema, pleural effusion, arthritis in hands and knees, proteinuria and a positive antinuclear factor during pregnancy. She was diagnosed with SLE. She had no history of smoking or alcohol abuse. At the time of diagnosis, she reported feeling tightness in the anterior thoracic region and pronounced dyspnea. Upon physical examination, she had a split and accentuated second cardiac sound and normal systemic blood pressure. Relevant testing showed positive lupus anticoagulant antibody. A chest x-ray revealed a prominent pulmonary artery arch. Spirometry showed a mildly restrictive ventilatory disorder. The high-resolution computed tomography scan was normal, although the electrocardiogram showed right chamber overload and the transthoracic Doppler echocardiogram showed increased cardiac right chambers in combination with right ventricle dysfunction and a pulmonary artery systolic blood pressure (PAP) of 74 mmHg. In the pulmonary scintigraphy, ventilation/perfusion ratio and arterial blood gases were normal. Venous duplex scan of the lower limbs showed proximal (non-symptomatic) thromboses, and the helical computerized tomography was normal. Based on these findings, the diagnosis of PH in combination with SLE and antiphospholipid syndrome was established. The patient was submitted to the following treatment regimen: prednisolone at 1 mg/kg/day (with stepwise reduction), chloroquine diphosphate at 4 mg/kg/day, diltiazem at 240 mg/day, oral warfarin for anticoagulation, and cyclophosphamide in monthly courses. The use of diltiazem was empirical, since the patient refused to be submitted to the vasodilation test with invasive monitoring of the pulmonary artery blood pressure. After 6 months of treatment, the Doppler echocardiogram revealed an estimated systolic blood pressure of 80 mmHg at the pulmonary artery. The use of the prostacyclin derivative iloprost was not possible due to the high cost of the drug. Subsequently, 2 additional 6-month regimens with methylprednisolone and cyclophosphamide pulses were carried out. Nevertheless, the systolic blood pressure in the pulmonary artery, as measured by Doppler echocardiogram, reached its highest level (102 mmHg). This characterized a lack of response to conventional treatment and, after obtaining approval from the Ethics Committee of the Hospital da Santa Casa in Belo Horizonte and signed informed consent from the patient, the decision was made to use oral sildenafil. The initial dose was 25 mg/day bid and was doubled every month until reaching a dose of 100 mg/day. No side effects were reported. Before each dosage increase, the systolic blood pressure was assessed with a Doppler echocardiogram. There was a 34% reduction in the estimated pulmonary artery pressure (PAP) after 6 months of treatment with sildenafil (Figure 1).

Discussion

Severe PH is a disabling disease, which commonly affects young individuals and reduces life expectancy.⁽⁵⁾ The combination of severe PH and SLE is rare, but the mild and subclinical form of the disease is not uncommon. The pathogenesis of severe PH in SLE is not well understood, but there are probably several etiological factors involved, including chronic recurrent thromboembolic phenomena, in situ pulmonary thrombosis due to antiphospholipid antibodies, endothelial dysfunction and abnormal vascular response. The prognosis of patients with severe PH depends on the intensity of the disease. The 5-year mortality rates vary from 14% to 50% and, in most patients, sudden death occurs, usually due to circulatory collapse. Medical treatment is empirical and responses are unsatisfactory. The use of corticosteroids and immunosuppressants is usually ineffective in patients with primary PH, but patients with PH combined to SLE have responded favorably to this kind of therapy.⁽³⁾

Based on encouraging data found in the literature, we began administering sildenafil orally, in 25-mg daily doses, which were gradually increased to 100-mg daily doses. The systolic pressure in the pulmonary artery was estimated by Doppler echocardiogram, which showed a progressive and sustained decrease, peaking at 34% (Figure 1), over the 6 month period of treatment. No side effects were reported. The patient continued taking daily doses of prednisolone (5 mg), chloroquine diphosphate (160 mg) and warfarin (5 mg).

The role of vasodilator agents is limited in PH, partially due to their lack of selectivity and potency in relation to the pulmonary circulatory system. However, significant progress has been made during the last few years. Sildenafil, a potent and selective inhibitor of PDE-5, is better known for its role in the treatment of male erectile dysfunction. High concentrations of PDE-5 can be found in the corpus cavernosum, in blood vessels, in the trachea, in visceral smooth muscles and in platelets. Long-term treatment (3 months) with oral sildenafil improved the physical capacity and quality of life in patients with severe PH.⁽⁶⁾ Michekalis et al.⁽⁴⁾ showed that, in high single doses, oral sildenafil is a potent and selective pulmonary vasodilator. Sildenafil has also been used, with satisfactory results, in two cases described by Watanabe et al.,⁽²⁾ the first being a patient with primary PH and the second a patient with PH and diffuse connective tissue disease combined.

Here, we describe for the first time a case of severe PH in combination with SLE and APAS, in which the patient responded well to oral sildenafil, in accordance with some findings in the literature. We believe that sildenafil may be a treatment option for patients with PH secondary to connective tissue disorders who respond poorly to conventional treatment. Further studies evaluating the safety and efficacy of oral sildenafil for patients with primary and secondary PH are needed in order to assure its proper use in this condition.

References

Submitted: 20/03/2003. Accepted, after revision: 15/06/2003.

• 1. Dweik RA. Pulmonary hypertension and the search for the selective pulmonary vasodilator. Lancet 2002;360:886-7.
• 2. Watanabe H, Ohashi K, Takeuchi K, Yamashita K, Yokoyama T, Tran OK, et al. Sildenafil for primary and secondary pulmonary hypertension. Clin Pharmacol Ther 2002;71:398-402.
• 3. Tam L-S, Li EK. Successful treatment with immunosuppression, anticoagulation and vasodilator therapy of pulmonary hypertension in SLE associated with secondary antiphospholipid syndrome. Lupus 1998;7: 495-7.
• 4. Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension. Circulation 2002;105:2398-403.
• 5. Ghofrani HA, Wieddemann R, Rose F, Alschewski H, Schermuly RT, Weissmann N, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002; 136:515-22.
• 6. Lodato RF. Viagra for impotence of pulmonary vasodilator therapy? Am J Respir Crit Care Med 2001;163:312-3.

*

Research conducted at Hospital da Santa Casa in Belo Horizonte

Publication Dates

• Publication in this collection
  02 Mar 2004
• Date of issue
  Oct 2003

History

• Received
  20 Mar 2003
• Accepted
  15 June 2003