Vasoactive therapies in systemic sclerosis
Department of Medicine (Rheumatology and Clinical Immunology), Charité University Hospital, Humboldt-University of Berlin and 1Department of Dermatology and Venerology, University Hospital Münster, Germany.
Correspondence to: Gabriela Riemekasten, MD. Department of Rheumatology and Clinical Immunology, Charité University Hospital, Schumannstr. 20/21, D-10117 Berlin, Germany. E-mail: gabriela.riemekasten{at}charite.de
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In systemic sclerosis (SSc), vasculopathy is a central mechanism and is a major initial event in the process of sclerosis and causing different complications such as Raynaud's phenomenon, ulcer(s) or pulmonary hypertension, the latter being life threatening. Therefore, vasoactive therapies are important when taking care of patients with SSc. However, as treatment has been difficult, numerous therapeutic modalities have been suggested. Until now, the interpretation of most studies is limited due to the heterogeneity of patient groups, the low number of patients, the short duration of the treatments and, possibly, further pathogenic mechanisms such as autoimmunity.
Several drugs are now available with effects on vasculopathy and, furthermore, on specific pathogenic mechanisms in SSc. Prostacyclins, endothelin receptor antagonists and phosphodiesterase-5 inhibitors have potential effects on fibrosis, inflammation and endothelial cells, suggesting a disease-modifying capacity in systemic sclerosis.
This review summarizes evidence-based therapy recommendations.
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Vasculopathy is one of the prominent and earliest clinical features in patients with systemic sclerosis (SSc) and may reflect a central pathogenic mechanism. Altered regulation of vascular tone results in different clinical signs such as:
- digital ischaemic ulcerations,
- pulmonary vascular disease (pulmonary arterial hypertension),
- glomerular dysfunction, severe renal crisis,
- small-vessel disease of the heart,
- oesophageal dysfunction or motility dysfunction of the bowel and
- malnutrition
All of these clinical symptoms influence dramatically the quality of life and prognosis in SSc patients. In this review, we will focus on vasoactive therapies, although immunosuppressive therapies may also have some effects on SSc-associated vasculopathies.
Calcium-channel blockers (CCBs)
These are widely used; however, a published meta-analysis concluded that their effect in reducing severity and frequency of ischaemic attacks is moderate at best, and large, randomized controlled trials are still needed [1]. No disease-modifying effects have been determined. It is important to use high enough doses (such as 360 mg diltiazem or 40 mg nifedipine per day), which, however, will not always be tolerated. Some patients benefit well from this class, thus providing a rationale for the therapeutic use.
Blockade of 
1-adrenergic receptors
A Cochrane analysis of two randomised controlled studies including 40 patients with SSc-associated Raynaud's phenomenon (RP) suggests a moderate effect of 1-adrenergic modulation by 1–3 mg prazosin per day. However, side effects are frequent [2]. Other -adrenergic receptor blockers such as OPC-28326 were shown to have an effect on digital skin perfusion in SSc-associated RP.
Glyceryl trinitrate (GTN)
These patches (0.2 mg/h) were found to be effective in reducing the number and severity of Raynaud's attacks when compared with a placebo-treated group. However, occurrence frequent headaches markedly limit their use.
ACE inhibitors/angiotensin II receptor antagonists
These have dramatically improved the outcome in renal crises. Prophylactic use of angiotensin-converting enzyme (ACE) inhibitors remains controversial due to the decrease in renal blood flow. For treatment of RP, captopril has been shown to improve primary and secondary Raynaud's phenomenon in a randomized controlled study including 86 patients [3]. A small study using 50 mg losartan, an angiotensin II receptor blocker, has also shown a positive effect on RP, comparable with 40 mg nifedipine.
Serotonin antagonists
These are thought to counteract the vasoconstricting actions of serotonin in RP. One study showed an effect of the antidepressant fluoxetine on severity and frequency of RP [4]. For patients with concomitant depression, fluoxetine provides an additional therapeutic advantage.
Prostacyclins
These belong to the best established therapies of vasculopathy in SSc. Their efficacy in relief of symptoms has been demonstrated in several studies, and these agents are widely used for the treatment of RP and pulmonary hypertension. They also appear to interfere with pathogenic mechanisms [5].
Iloprost
A dose of this (0.5–2 ng/kg/min) for 3–5 days or longer decreases severity and frequency of RP, and promotes healing of digital ulcers when given 6–8 h per day. The suggested disease-modifying effect of prostacyclins on fibrosis still needs to be proven in further studies. A controlled randomized study comparing nifedipine with iloprost already indicated stabilisation of lung function and an improvement of skin scores [6]. For treatment of pulmonary hypertension, i.v. epoprostenol treatment was graded as evidence grade A by experts of the field. Continuous epoprostenol therapy improves exercise capacity and cardiopulmonary hemodynamics also in SSc patients with pulmonary hypertension [7]. A trend towards greater improvement in severity of the RP and fewer new digital ulcers were seen in the epoprostenol group. In contrast, oral prostacyclins had mostly disappointing efficacy on RP.
Bosentan
The oral dual endothelin receptor antagonist bosentan is widely used in the therapy of pulmonary hypertension, and directly interferes with pathogenic mechanisms in systemic sclerosis and pulmonary hypertension. The orally administered drug has substantially improved quality of life in patients with pulmonary hypertension [8]. In patients with PAH associated with SSc, there was a not statistical significant trend towards improvement of exercise capacity consistent with the full population analysis of two randomized placebo-controlled studies. In two randomized placebo-controlled studies, bosentan was also shown to prevent new digital ulcers suggesting an effect on fibrosis in systemic sclerosis [9; RAPIDS-2, unpublished data].
Phosphodiesterase-5 inhibitors
These increase cyclic guanosine monophosphate (cGMP) and have different effects on vascular tone when compared to prostacyclins and endothelin receptor antagonists. In pulmonary hypertension associated with connective tissue diseases, sildenafil improved exercise capacity and hemodynamics in a study including 80 SSc patients [10]. There are promising case reports and a controlled cross-over study using sildenafil for treatment of RP. Nevertheless, further studies for RP and ulcer healing are needed.
Miscellaneous
Inhibitors of the potent mitogen platelet-derived growth factor (PDGF) imatinib are currently under early investigation for the treatment of pulmonary hypertension. Estrogens also induce vasodilation. In a small randomized study, placebo-controlled study intravenous calcitonin gene-related peptides (CGRPs) improved healing of ulcers, digital blood flow and digital temperatures.
C. S. and G. R. received speakers’ honorarium for participation at Actelion Winter School 2006. The paper was supported by the German network for systemic sclerosis founded by the BMBF network of rare diseases as well as from the European Systemic Sclerosis Trial and Research program (EUSTAR).
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