sábado, 8 de septiembre de 2012

Diagnosis and management of Raynaud’s phenomenon

Information sourced from BMJ:
BMJ 2012;344:e289
[Link to free BMJ article PDF for full text, images, and references | BMJ extract | PubMed® abstract]
Clinical Review
Diagnosis and management of Raynaud’s phenomenon
Beth Goundry, Laura Bell, Matthew Langtree, et al

Fig 1 Raynaud’s phenomenon showing typical colour changes
Fig 2 Severe Raynaud’s phenomenon showing colour changes and digital ulceration
Box 1 Conditions associated with secondary Raynaud’s phenomenon
  • Systemic sclerosis (90% of patients with this condition have Raynaud’s phenomenon)
  • Mixed connective tissue disease (85%)
  • Systemic lupus erythematosus (40%)
  • Dermatomyositis or polymyositis (25%)
  • Rheumatoid arthritis (10%)
  • Sjögren’s syndrome
  • Vasculitis
  • Polycythaemia ruba vera
  • Leukaemia
  • Thrombocytosis
  • Cold agglutinin disease (Mycoplasma infections)
  • Paraproteinaemias
  • Protein C deficiency, protein S deficiency, antithrombin III deficiency
  • Presence of the factor V Leiden mutation
  • Hepatitis B and C (associated with cryoglobulinaemia)
Occlusive arterial disease
  • External neurovascular compression, carpal tunnel syndrome, and thoracic outlet syndrome
  • Thrombosis
  • Thromboangiitis obliterans
  • Embolisation
  • Arteriosclerosis
  • Buerger’s disease
Fig 3 Digital ulcer in severe Raynaud’s phenomenon
How is Raynaud’s phenomenon treated?
The first step in managing Raynaud’s phenomenon in primary care is lifestyle modification. Such advice can be given to patients while awaiting investigations and referral to secondary care if an underlying cause is suspected. Most people with primary Raynaud’s phenomenon respond well to lifestyle measures and need no further treatment. Patients with secondary Raynaud’s phenomenon require treatment of the underlying disorder, which entails referral to secondary care.
Non-drug based treatments
Conservative approaches to treatment aim to reduce exposure to triggers, such as cold and emotional stress.
Advise the patient to try to keep warm, perhaps by using hand and feet warmers, which are commercially available. The frequency and severity of attacks can be reduced by avoiding dramatic changes in environmental temperature and taking steps to reduce occupational cold exposure. Vasodilation can be increased during attacks by rotating the arms in a windmill pattern, placing the hands under warm water or in a warm body fold such as the axilla, and performing the swing-arm manoeuvre (raising both arms above the shoulders and forcefully swinging them across the body to generate a force that promotes blood flow distally to the fingers). Another simple tip is to avoid carrying bags by the handles, which impairs circulation to the fingers. There is little objective evidence to suggest that any nutritional supplement benefits patients with the condition. Minimising stress through general relaxation techniques may be of benefit. Biofeedback has been a popular treatment, but a recent Cochrane review found it to be no more effective than sham biofeedback. Support groups can provide helpful tips and guidance on self management. A prospective study showed that smoking cessation may help to reduce the severity but not occurrence of the condition.
Ginkgo biloba has been investigated over the past 10 years. A double blind placebo controlled trial found a 56% reduction in the frequency of attacks in established Raynaud’s phenomenon (compared with a 27% reduction in the placebo group). Another randomised multicentre flexible dose open trial found a 31% reduction compared with 50.1% for nifedipine, suggesting that Ginkgo may not be as effective as nifedipine. However, given that Ginko had no adverse effects and was well tolerated, further research may be worthwhile.
Drug treatments
Several randomised controlled trials are under way that may lead to an increase in the number of treatments for Raynaud’s phenomenon. However, to date, no guidelines have been published on the medical treatment of Raynaud’s phenomenon. We discuss drugs that are currently used off-label in the treatment of this condition and which the clinician may consider using on a case by case basis, taking care to balance evidence on efficacy versus toxicity. It is also important to review prescription drugs that aggravate symptoms.
Calcium channel blockers—Non-cardioselective dihydropyridine calcium channel blockers are most widely used in the treatment of Raynaud’s phenomenon. Nifedipine promotes relaxation of vascular smooth muscle cells and leads to vasodilatation. A meta-analysis of randomised controlled trials found that nifedipine (10-20 mg three times daily) reduced the number of attacks by 2.8-5.0 a week and reduced their severity by 33%. However, effects may be short lived, and longer acting calcium channel blockers or amlodipine and diltiazem may be needed. Unfortunately, patients commonly report troubling adverse effects such as hypotension, flushing, headache, and tachycardia, so alternative treatments have been researched.
Topical nitrates—A randomised controlled study of 33 patients found that topical glyceryltrinitrate applied to the dorsum of the finger resulted in digital vasodilatation with fewer systemic side effects than with oral nitrates. Two large recent randomised controlled trials of MQX-503, a new formulation of nitroglycerin, applied to the affected finger found that it reduces the severity of Raynaud’s phenomenon, but not the duration or frequency of attacks. Evidence on topical nitrates is limited, but the results of current trials may provide more robust evidence of efficacy.
Prostaglandins—Prostaglandins have vasodilatory and antiproliferative effects, and they inhibit platelet aggregation. Their side effects are similar to those of calcium channel blockers. The European League Against Rheumatism recommends prostaglandins when calcium channel blockers have failed. Most published studies have focused on the use of intravenous iloprost. A randomised open label single centre study and a 2009 Cochrane review found that iloprost reduces the frequency and severity of attacks. A randomised study found cyclic use to be beneficial in terms of patient adherence and quality of life. However, two randomised controlled trials found that iloprost was only slightly better than nifedipine, and because iloprost is more expensive, the European League Against Rheumatism has advised that nifedipine should remain the first line drug for patients with Raynaud’s phenomenon. A double blind multicentre placebo controlled study and randomised double blind study found that orally administered prostaglandins are less effective than intravenous ones, although higher doses may confer benefit. Research is currently ongoing into the use of treprostinil, an oral prostaglandin analogue.
Phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, and vardenafil)—Phosphodiesterase type 5 breaks down cGMP in endothelial cells. Inhibition of this enzyme increases the amount of cGMP available to promote vascular smooth muscle relaxation and blood flow. A randomised double blind placebo controlled fixed dose crossover study and two case series found a decrease in the frequency and severity of attacks in patients treated with oral sildenafil but not tadalafil compared with placebo. These inhibitors also have a favourable effect on the Raynaud’s condition score and ulcer healing. The benefits of these orally delivered and well tolerated drugs suggest that they may be an effective treatment for patients with severe and disabling Raynaud’s phenomenon, although further studies are needed.
Antioxidants—N-acetylcysteine acts as a vasodilator via modulation of the vasodilator adrenomedullin. A recent observational study found that it decreases the frequency and severity of attacks. The number of digital ulcers and ulcer healing also improved.
Inhibitors of vasoconstriction
Angiotensin receptor antagonists—A randomised controlled trial suggested that losartan reduces the frequency and severity of attacks to a greater extent than nifedipine. The European League Against Rheumatism recommends its use, but this is an informal recommendation because of the lack of sufficient evidence.
Angiotensin converting enzyme inhibitors—These drugs are no longer recommended since a randomised double blind placebo controlled trial found that they do not reduce digital ulcers or the frequency or severity of attacks.
α1 adrenoceptor blockers—Limited low level evidence from a randomised double blind placebo controlled crossover study of 24 patients suggests that prazosin may reduce the frequency but not the severity of attacks compared with placebo. However, prazosin is rarely used in the treatment of Raynaud’s phenomenon because its potential adverse effects outweigh any benefit.
Endothelin receptor antagonists (bosentan)—Endothelin is a potent vasoconstrictor of vascular smooth muscle cells. Among its other actions, bosentan exerts a consistent effect on vasculature. The Randomized Placebo-controlled Investigation of Digital Ulcers in Scleroderma (RAPIDS-1 and 2) trials have shown that the number of new digital ulcers in patients with secondary Raynaud’s phenomenon decreased significantly when treated with bosentan. The European League Against Rheumatism recommends its use when symptoms are refractory to treatment with calcium channel blockers and prostaglandins.
Serotonin reuptake inhibitors—The exact role of serotonin reuptake inhibitors in the treatment of Raynaud’s phenomenon is not yet clear. These agents block the uptake of serotonin, which is a vasoconstrictor. A pilot study of 53 patients showed that fluoxetine reduces the severity and frequency of attacks compared with nifedipine in primary Raynaud’s phenomenon. Its effect in secondary Raynaud’s phenomenon was less pronounced. A Cochrane review of a small number of studies concluded that another serotonin reuptake inhibitor, ketanserin, was not beneficial in the treatment of Raynaud’s phenomenon. This agent may have a role in patients who cannot tolerate other drugs because of hypotension, but more research is needed.
Botulinum toxin A—Botulinum toxin A blocks vasoconstriction and, although there are no blinded placebo trials to date, preliminary reports have suggested that it can improve symptoms, decrease frequency of attacks, and improve healing of digital ulcers.

No hay comentarios:

Publicar un comentario