Contemporary Management of Raynaud's Phenomenon and Digital Ischaemic Complications

Ariane L. Herrick

Disclosures

Curr Opin Rheumatol. 2011;23(6):555-561. 

In This Article

Recent Advances

In the past 2–3 years, the main advances in the therapeutics of Raynaud's phenomenon have been in supplementing the L-arginine/nitric oxide pathway (mainly with phosphodiesterase inhibitors), and ET-1 receptor antagonism, the latter approach currently confined to patients with SSc-related recurrent digital ulcers. In addition, there has been interest in statin therapy (considered under 'possible future approaches') and increased experience with digital sympathectomy.[17]

Supplementation of the L-arginine/Nitric Oxide Pathway (Phosphodiesterase Inhibitors and Topical Glyceryl Trinitrate)

Nitric oxide is a potent vasodilator that acts directly on vascular smooth muscle. Phosphodiesterase inhibitors enhance nitric oxide effect by inhibiting degradation of cyclic guanosine monophosphate. A small number of clinical trials examining safety and efficacy of phosphodiesterase inhibitors in Raynaud's phenomenon have given somewhat conflicting results.[18–20,21•,22•] A small early trial by Fries et al.[18] (including 16 patients with secondary Raynaud's phenomenon) suggested benefit from 4 weeks' treatment with sildenafil 50 mg twice daily, although the study was not truly blinded as most patients correctly guessed which treatment they were on. Vardenafil was reported to improve clinical symptoms and blood flow in an open-label, 2-week pilot study[19] of 40 patients (33 of whom had secondary Raynaud's). Schiopu et al.[20] found no benefit from 4 weeks' treatment with 20 mg tadalafil in a double-blind cross-over trial of 39 women with SSc. Conversely, in a double-blind cross-over trial of 6 weeks' treatment with alternate day 20 mg tadalafil as 'add-on' therapy in 24 patients with mainly SSc-related Raynaud's phenomenon, Shenoy et al. [21•] reported benefit in Raynaud's symptoms and in digital ulceration. In a study[22•] of 57 patients with SSc-related Raynaud's phenomenon, 4 weeks' treatment with modified-release sildenafil was associated with a greater mean percentage reduction in Raynaud's phenomenon attacks per week than placebo (P = 0.034). These studies have all been short-term (6 weeks or less). An open study[23•] of 19 patients with SSc-related digital ulceration, observed for up to 6 months, reported benefit in terms of digital ulceration and other clinical symptoms (including Raynaud's phenomenon and pain). The place of phosphodiesterase inhibition in the treatment of Raynaud's phenomenon is not yet established: clinical trials of longer duration would help to inform this. However, many clinicians are prescribing phosphodiesterase inhibitors increasingly in patients with severe disease, with and without digital ulceration.

The other 'new' development in terms of the nitric oxide pathway is the revisiting of topical nitrate therapy. Topical nitrate therapy is far from new.[24] It produces both local and systemic effects. GTN patches, administered for their systemic effects, have been shown to be effective[25] (including in children[26]) but cause vasodilatory side-effects. Therefore, low-dose, topical treatment to the fingers with minimal (if any) systemic side-effects would be an attractive option to prevent/treat Raynaud's attacks. Up till relatively recently, nitrate therapy applied directly to the fingers has attracted little attention, probably because available preparations have been relatively difficult to use. A novel formulation of nitroglycerin (GTN), MQX-503, was compared to placebo in a large multicentre, parallel-group, randomized controlled trial[27] (4 weeks' duration) of 219 patients with Raynaud's phenomenon. Patients applied active or placebo gel, supplied in pouches, immediately before or up to 5 min after the onset of a Raynaud's attack.[27] The mean improvement in Raynaud's Condition Score (RCS) in the MQX-503 group (14.3% reduction) was greater (P = 0.04) than that in the placebo group (1.3% reduction), but there were no significant differences between groups in changes in frequency or duration of attacks. The improvement in RCS was lower in patients with SSc-related Raynaud's phenomenon (12.3% change) than in those with primary Raynaud's phenomenon (21.3% change), although there was a placebo response in patients with primary Raynaud's phenomenon. Side-effects (including headaches and dizziness) were similar between groups.[27] Topical nitrate therapy is an attractive option, especially in patients prone to vasodilatory side-effects and deserves further study.

Endothelin-1 Receptor Antagonism

ET-1, a 21-aminoacid peptide, is a potent vasoconstrictor both in the systemic and pulmonary vascular beds in man[28] and has effects also on vascular remodelling and fibrosis. ET-1 is thought to be one of the key players in pathogenesis of SSc and is overexpressed in sclerodermatous skin.[29] ET-1 exerts its actions via two types of receptor, ETA and ETB. Vasoconstriction is thought to occur mainly via the ETA receptor, whereas the ETB receptor may in certain situations also mediate vasodilatation.[30]

Bosentan, a dual ET-1 receptor antagonist, has been licensed since 2007 for reduction in the number of new digital ulcers in patients with SSc and ongoing digital ulcer disease. The evidence base for bosentan comes primarily from two multicentre, double-blind, randomized controlled clinical trials.[31,32••] The recently published RAPIDS-2 (Randomised Placebo-controlled study on prevention of Ischemic Digital ulcers in Scleroderma) trial,[32••] which included 188 patients with at least one digital ulcer at baseline (98 treated with bosentan and 90 treated with placebo), confirmed the results of RAPIDS-1:[31] bosentan was associated with a reduction in the number of new ulcers, but not with healing of existing ulcers. The mean number of new ulcers during the 24-week treatment period was 1.9 in the bosentan group and 2.7 in the placebo group (P = 0.035).[32••] Patients with more than three digital ulcers at baseline benefited most. Selective inhibition of the ETA receptor is also being studied.[33]

Bosentan should, therefore, be considered for patients with SSc and recurrent digital ulcers. Liver function must be carefully monitored in patients on ET-1 receptor antagonists as a proportion develop elevations in transaminases. At present, there is no evidence base to support the use of ET-1 receptor antagonists for the treatment of Raynaud's phenomenon in the absence of digital ulcers. A single-centre, double-blind, parallel-group trial of 17 patients with SSc (but without digital ulcers) reported no benefit in terms of Raynaud's symptoms from 16 weeks' treatment with bosentan.[34]

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