Successful treatment of severe Raynaud's phenomenon with bosentan in four patients with systemic sclerosis

M. Ramos-Casals, P. Brito-Zerón, N. Nardi, G. Claver, G. Risco, F.-D. Parraga, S. Fernandez, M. Julià and J. Font

Department of Autoimmune Diseases, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, School of Medicine, University of Barcelona, Barcelona, Spain

Correspondence to: M. Ramos-Casals, Servei de Malalties Autoimmunes, Hospital Clínic, C/Villarroel, 170, 08036-Barcelona, Spain. E-mail: mramos{at}clinic.ub.es

SIR, Systemic sclerosis (SSc) is an autoimmune disease that mainly affects the skin and internal organs, such as the gastrointestinal tract, lungs, kidneys and heart [1]. One of the key clinical features is Raynaud's phenomenon (RP), including important pain and digital ulceration that often results in functional disability. Therapeutic management of severe RP is usually a clinical challenge, with intravenous infusions of prostaglandin analogues usually being effective, but necessarily invasive.

Bosentan is an oral antagonist of endothelin [2], a potent endogenous vasoconstrictor implicated in the aetiopathogenesis of RP [3]. Recent studies have shown a role for bosentan in the treatment of pulmonary arterial hypertension associated with SSc [4], with encouraging preliminary results in preventing the development of skin ulcers [5, 6]. We report four patients with SSc and severe RP who responded successfully to bosentan.

The first case was a 41-yr-old woman diagnosed with SSc and a history of severe RP, pulmonary alveolitis and pulmonary hypertension. Since 1999, the patient had been hospitalized repeatedly during the cold season due to multiple digital ulcers and necrotic lesions in both hands, which were treated with intravenous prostaglandins and low-molecular weight heparin, yielding a small improvement. Bosentan was started at 62.5 mg twice daily (increased after 4 weeks to 125 mg twice daily), leading to a rapid improvement in the ischaemic lesions and healing of the digital ulcers. After 1 yr of follow-up, the patient had not presented new episodes of severe RP and had not required further hospitalization.

The second case was a 56-yr-old woman diagnosed with limited SSc and a history of RP treated with calcium-channel blockers. In 2000, the patient presented with dyspnoea and chest pain. The electrocardiogram showed atrial fibrillation, and an echocardiogram revealed pericardial effusion and moderate pulmonary hypertension [pulmonary artery pressure (PAP) = 46 mmHg] with tricuspid insufficiency. Treatment with low-molecular weight heparin and digoxin was initiated with clinical improvement. In January 2004, the patient was hospitalized due to severe RP, with scars on the fingertips, ulcers and cutaneous necrosis of the interdigital region of the toes. Treatment with bosentan at 62.5 mg twice daily was started, with improvement of necrotic lesions and healing of the distal ulcers. After 4 months of follow-up, no new ischaemic lesions were noted, and bosentan therapy was well tolerated.

The third case was a 22-yr-old woman diagnosed with limited SSc due to sclerodactyly, digital pitting scars, calcinosis of the elbows and RP, which responded partially to topical application of nitroglycerin gel and nifedipine. In December 2003, the patient was hospitalized with severe RP. Treatment with bosentan (62.5 mg twice daily) was started (increasing the dosage to 125 mg twice daily at the fourth week). After a follow-up of 5 months, there has been complete healing of her fingertips with no new episodes of RP.

The fourth case was a 54-yr-old woman diagnosed with limited SSc. In January 2002, the patient was hospitalized due to severe RP, with digital pitting scars of both hands, sclerodactyly and puffy, sausage-like swelling of the fingers. An echocardiogram showed mild pulmonary hypertension (PAP = 30 mmHg). Nifedipine treatment was initiated but was suspended due to hypotension. Infusions of intravenous prostaglandins were started, but were suspended after the second infusion due to local side-effects related to central catheterization. Low-molecular weight heparin and topical nitroglycerin ointment were used, with partial improvement of RP. In January 2004, the patient was hospitalized due to severe RP, with multiple fingertip ulcers and distal ischaemic features (Fig. 1a). Bosentan was started at 62.5 mg/12 h, with improvement of lesions. The dose of bosentan was increased to 125 mg/12 h and at 4 months of follow-up an out-patient appointment showed healing of the ulcers (Fig. 1b).



View larger version (63K):
[in this window]
[in a new window]
 
FIG. 1. Patient 4. Fingertip ulcers and distal ischaemic features before (a) and after (b) treatment with bosentan. This figure may be viewed in colour as supplementary data at Rheumatology Online.

 
RP is a frequent, disabling vascular complication of SSc, in which calcium-channel blockers are the main therapeutic option for uncomplicated cases [7]. A common severe manifestation of RP is the development of ischaemic digital ulcers [8], which are estimated to occur in 15–25% of patients [9]. The prostaglandin analogues have potent vasodilator and antiplatelet effects, although intravenous administration is a drawback.

The encouraging results of a preliminary study [5] prompted us to use bosentan in SSc patients with severe RP, in whom the use of intravenous prostaglandin analogues was not considered as a first-line option (due to previous adverse effects or lack of response, or difficulties in the use of invasive techniques or hospitalization of the patient). Although our study is merely observational and involved a small number of patients, the benefit/risk ratio of the use of bosentan compared with intravenous prostaglandins is clearly beneficial. Continuous infusion of prostaglandin analogues is expensive and requires hospitalization and at least 10 days of intravenous administration through a permanent central catheter. In addition, administration of intravenous prostaglandins is associated with dose-related side-effects and with both local and systemic complications related to the drug delivery system [10, 11]. The numerous advantages of bosentan (oral administration, rapid clinical response, absence of severe side-effects and savings in hospitalization costs) point to a promising role for this drug in the treatment of complicated RP in SSc patients on an out-patient basis.

We wish to thank David Buss for his editorial assistance.

The authors have declared no conflicts of interest.

References

  1. Ferri C, Valentini G, Cozzi F et al. Systemic Sclerosis Study Group of the Italian Society of Rheumatology (SIR-GSSSc). 2. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine (Baltimore) 2002;81:139–53.[CrossRef][ISI][Medline]
  2. Mayes MD. Endothelin and endothelin receptor antagonists in systemic rheumatic disease. Arthritis Rheum 2003;48:1190–9.[CrossRef][ISI][Medline]
  3. Zamora MR, O’Brien RF, Rutherford RB, Weil JV. Serum endothelin-1 concentrations and cold provocation in primary Raynaud phenomenon. Lancet 1990;336:1144–7.[CrossRef][ISI][Medline]
  4. Denton CP, Black CM. Bosentan for scleroderma associated pulmonary arterial hypertension. A subgroup analysis of two placebo controlled trials. Arthritis Rheum 2003;47(Suppl.):1140.
  5. Black CM, Korn JH, Mayes MD, Matucci-Cerinic M. Improvements in the net ulcer burden and hand functionality in patients with digital ulcers related to systemic sclerosis. Arthritis Rheum 2003;47(Suppl.):1137.[CrossRef]
  6. Humbert M, Cabane J. Successful treatment of systemic sclerosis digital ulcers and pulmonary arterial hypertension with endothelin receptor antagonist bosentan. Rheumatology 2003;42:191–3.[Free Full Text]
  7. Thompson AE, Shea B, Welch V, Fenlon D, Pope JE. Calcium-channel blockers for Raynaud phenomenon in systemic sclerosis. Arthritis Rheum 2001;44:1841–7.[CrossRef][ISI][Medline]
  8. Rodnan GP, Myerowitz RL, Justh GO. Morphologic changes in the digital arteries of patients with progressive systemic sclerosis (scleroderma) and Raynaud phenomenon. Medicine (Baltimore) 1980;59:393–408.[ISI][Medline]
  9. Della Rossa A, Valentini G, Bombardieri S et al. European multicentre study to define disease activity criteria for systemic sclerosis: I. Clinical and epidemiological features of 290 patients from 19 centres. Ann Rheum Dis 2001;60:585–91.[Abstract/Free Full Text]
  10. Barst RJ, Rubin LJ, Long WA et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;334:296–302.[Abstract/Free Full Text]
  11. Newman JH. Treatment of primary pulmonary hypertension—the next generation. N Engl J Med 2002;346:933–5.[Free Full Text]
Accepted 29 June 2004





This Article
Full Text (PDF)
Supplementary data
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (4)
Disclaimer
Request Permissions
Google Scholar
Articles by Ramos-Casals, M.
Articles by Font, J.
PubMed
PubMed Citation
Articles by Ramos-Casals, M.
Articles by Font, J.