Management of Raynaud’s Phenomenon and Digital Ischemia
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This review focuses on new findings and developments relevant to the clinician caring for patients with primary and secondary [especially systemic sclerosis (SSc)-related] Raynaud phenomenon (RP). In the last 18 months, several clinical trials and observational studies of RP and of SSc-related digital ulceration have been published, reflecting increased awareness of disease burden and increased interest by pharmaceutical companies: new insights into pathophysiology are driving new approaches to treatment. Key developments are the increased use of phosphodiesterase type V inhibitors in severe RP, and of bosentan (an endothelin-1 receptor antagonist) for prevention of recurrent SSc-related digital ulcers. Other treatments being researched include topical glyceryl trinitrate (applied locally to the digits), botulinum toxin (for severe digital ischemia/ulceration), and several other drugs including oral prostanoids. Increased availability and interest in nailfold capillaroscopy, by facilitating early diagnosis of SSc, should pave the way for studies of early intervention and vascular protection.
KeywordsRaynaud’s phenomenon Systemic sclerosis Digital ulcers Digital ischemia Critical ischemia Clinical trials Phosphodiesterase inhibitors Endothelin-1 receptor antagonists Glyceryl trinitrate Prostanoids Botulinum toxin Nailfold capillaroscopy Management
It should also be remembered that the first principle of management is to establish the diagnosis. In the context of RP (which is a clinical diagnosis based on colour change of the fingers in response to cold or to emotional stress), the challenge to rheumatologists is to diagnose any underlying SSc-spectrum disorder early, to allow early intervention before irreversible tissue damage has occurred.
SSc-related digital ulceration.
SSc-related critical digital ischemia.
Early diagnosis of a SSc-spectrum disorder in the patient with RP.
Some key unanswered questions and future areas for research are then briefly discussed.
By definition, all patients with PRP have uncomplicated RP, because the presence of irreversible tissue injury (pitting scars, ulcers or gangrene) precludes this diagnosis . A significant proportion of patients with SSc (and with other connective tissue diseases) will also have uncomplicated RP, as many do not progress to irreversible tissue injury, although their RP will probably be more severe than that in patients with PRP, evidenced by the severity of change on thermographic testing. Management depends on severity. Many patients with PRP will respond to ‘non-drug measures’ and in some the RP will resolve completely . However, a proportion will require drug treatment, as will most patients with SSc-related RP. The EULAR (European League Against Rheumatism) treatment recommendations for SSc include digital vasculopathy and outline the evidence base for treatment of both SSc-related RP and digital ulceration . A calcium channel blocker is generally the drug of first choice. However, if this not tolerated or ineffective then there are a number of other options, although the evidence base for other oral vasodilators is very weak: these options include an angiotensin II receptor antagonist, an angiotensin-converting enzyme (ACE) inhibitor, an alpha-blocker or a selective serotonin reuptake inhibitor. Although there are no controlled clinical trials of combination therapy, certain combinations (for example a calcium channel blocker together with an angiotensin II receptor antagonist) seem sensible in patients who have not had a satisfactory response to either treatment alone. Recent reviews of the evidence base for (1) oral vasodilators for PRP (other than calcium channel blockers) [8•] and (2) different treatments for secondary RP  highlight the need for more high quality randomised controlled trials.
New Findings and Developments
Supplementation of the L-Arginine/Nitric Oxide Pathway
Clinical trials of phosphodiesterase inhibitors in RP
Number of subjects
Main efficacy findings
Fries et al. 
Sildenafil 50 mg bd
16 with secondary RP (14 had SSc)
Improvement in RP symptoms (including Raynaud’s Condition Score) with active treatment
Caglayan et al. 
Vardenafil 10 mg bd
40 (33 with secondary RP
Improvement in Raynaud’s Condition Score
Schiopu et al 
Tadalafil 20 mg
39 women with SSc
No benefit in terms of RP symptoms (including Raynaud’s Condition Score) with active treatment
Shenoy et al. [10•]
Tadalafil 20 mg on alternate days
24 (23 with SSc)
Improvement in RP symptoms (including Raynaud’s Condition Score), and in digital ulceration with active treatment
Herrick et al. [11•]
Sildenafil modified release (100 mg once daily for 3 days then 200 mg)
57 with limited cutaneous SSc
Placebo-controlled parallel group
Greater mean percentage reduction in RP attacks in active treatment group
Caglayan et al. [12•]
Vardenafil 10 mg bd
53 (6 with primary RP, 47 with secondary RP, of whom 38 had SSc)
Improvement in RP symptoms (including Raynaud’s Condition Score) with active treatment
A key point is that the randomised controlled trials of phosphodiesterase inhibitors have so far been of only 6 weeks’ duration or less. Although longer-term studies are required to better evaluate the role of phosphodiesterase inhibitors in RP, many clinicians are now prescribing these on the basis of the existing short-term studies and their own anecdotal experience. Increasing use of phosphodiesterase inhibitors for SSc-related RP is evidenced by recent surveys of (1) case records from patients within the Canadian Scleroderma Research Group  and (2) SSc experts, many of whom reported that their second choice of drug therapy after a calcium channel blocker was a phosphodiesterase inhibitor .
Nitric oxide can also be supplemented directly, via topical application. Although effective when administered systemically by glyceryl trinitrate (GTN) patch, this is at the expense of vasodilatory side effects. Local application of GTN to the fingers (delivering a lower dose to the symptomatic area, without systemic adverse effects) is an attractive option in which interest has recently been reawakened. A multicentre, placebo-controlled trial of parallel group design  examined tolerability and efficacy of 4 weeks’ treatment with a novel formulation of GTN, MQX-503, applied as a gel (supplied in pouches) immediately before or within 5 min of the onset of a Raynaud’s attack. Of the 219 patients studied, 69 had primary RP and 150 secondary (of whom 131 had SSc). MQX-503 conferred benefit in terms of improvement in Raynaud’s Condition Score . However, as yet there is no commercially available preparation specifically for use in RP.
Other Recent Studies
The last 18 months have seen publication of a small number of clinical trials investigating other possible therapies for RP. Disappointingly none suggested benefit. Fasudil, a RhoA/Rho kinase inhibitor, did not improve temperature and blood flow response to a cold challenge in a single dose study of 17 patients with SSc-RP . Gingko biloba was not found to be superior to placebo in a 10-week parallel group study in 41 patients with PRP . St. John’s Wort (6 weeks’ treatment) conferred no clinical benefit over placebo in a study of 18 patients with either primary or secondary RP .
Author’s Approach Focusing on New Developments
Pending longer duration clinical trials, I currently recommend a phosphodiesterase inhibitor for patients with severe RP (these will usually be patients with SSc) unresponsive to more commonly used vasodilators. At present, I rarely recommend topical (local) nitrate therapy, because there is currently no easy to use, commercially available, preparation.
SSc-Related Digital Ulceration
As with uncomplicated RP, management depends on severity. Some digital ulcers are relatively minor and heal spontaneously. An antibiotic should be prescribed if there is any question of superadded infection. Conversely, many digital ulcers are extremely painful (requiring treatment with opiates in the short term) and difficult to heal: patients with these ulcers require hospitalisation for intravenous prostanoid therapy such as iloprost [7, 19, 20].
All patients with digital ulceration require optimisation of therapy for their RP including non-drug measures: stopping smoking is particularly important in those patients with SSc who have severe digital ischemia. Expert nursing/tissue viability input is another important aspect of management. The EULAR recommendations  include intravenous prostanoids for ulcer healing, and bosentan (discussed below) for prevention of digital ulcers in selected patients. A recent survey highlighted how management varies across continents .
Some patients with digital ulcers will require surgical debridement, especially if there is necrotic tissue present. Digital (palmar) sympathectomy, a highly specialised technique, has attracted interest recent years , although there have been no new reports in the last 18 months.
New Findings and Developments
Digital ulceration has been the most studied aspect of SSc-related vasculopathy in the last 5 years: large multinational clinical trials have helped to increase awareness of the enormous burden of digital ulceration, leading to studies of epidemiology and pathophysiology, and further clinical trials and observational treatment studies.
Endothelin-1 receptor antagonists, phosphodiesterase inhibitors, oral prostanoids and botulinum toxin have all attracted interest.
Endothelin-1 Receptor Antagonism
There is a strong theoretical rationale for blocking endothelin-1, which is both vasoconstrictive and profibrotic, in patients with SSc. Endothelin-1 acts through two receptors, ETA and ETB: vasoconstriction is mediated mainly via the ETA receptor whereas the ETB receptor may also mediate vasodilation. The endothelin-1 receptor antagonist bosentan has now been shown to prevent SSc-related digital ulcers in two randomised, double-blind controlled clinical trials [23, 24••]. Essentially RAPIDS-2 (randomised, double-blind, placebo-controlled study with bosentan on healing and prevention of ischemic digital ulcers in patients with systemic sclerosis) [24••], which included 188 patients with SSc who had at least one active digital ulcer at baseline, confirmed the findings of RAPIDS-1 . Key findings from RAPIDS-2 were that treatment with bosentan reduced the number of new digital ulcers by 30 % compared to placebo, but did not increase the healing rate of existing ulcers. The number of new ulcers over 24 weeks was 1.9 in the bosentan-treated group compared to 2.7 in the placebo-treated group (p = 0.035) [24••]. The effect was most marked in patients with the most severe digital vascular disease (four or more digital ulcers at baseline). Bosentan is a dual receptor antagonist, blocking both ETA and ETB receptors. Research into the role of different endothelin-1 receptor antagonists in the treatment of SSc-related digital ulcers is ongoing.
In addition to the RAPIDS-2 study, the last 18 months have seen publication of a number of observational studies supporting the use of bosentan in patients with SSc and digital ulceration, adding to the previous literature as reviewed by Arefiev et al. . Although these reports are anecdotal, they are of some interest and describe experience with longer than the 6 months’ bosentan therapy reported in RAPIDS-2 [26, 27]. Ischimura et al. reported some regression in ulnar artery stenosis (as assessed by magnetic resonance angiography) after 5 weeks’ bosentan treatment in a patient with SSc and multiple digital ulcers, and suggested that this improvement was due to vascular remodelling properties of bosentan . Tanigushi et al. reported improvement in 3 patients with lower limb ulceration associated with cyanosis, treated with bosentan for pulmonary artery hypertension . Although case reports and small series always have to be interpreted with caution, these reports provide further cautious support for bosentan conferring benefit in patients with SSc and recurrent/refractory ulcers. There is, however, no evidence base to support the use of bosentan in patients with SSc-related RP without digital ulceration: 16 weeks’ of bosentan conferred no benefit in RP symptoms in a parallel group study of 17 patients with SSc .
As yet, there are no reported controlled clinical trials of phosphodiesterase inhibitors specifically for digital ulceration. In the cross-over study of tadalafil by Shenoy et al. already referred to above [10•], improvement in digital ulceration was reported in terms of both healing of existing ulcers and a reduction in the number of new ulcers. Open/observational studies have reported improvements in SSc-related digital ulceration with sildenafil [31, 32]. This is an area which is being actively researched, with studies ongoing. A recent care report describing a 55-year-old male patient with refractory SSc-related digital ulcers, which responded to the addition of bosentan to sildenafil , highlights how trials of combination therapies are required for patients with severe, refractory disease.
Prostanoids have a number of mechanisms of action which could be beneficial in SSc. However, they require admission for intravenous administration. Earlier studies of oral prostanoids were disappointing, but oral prostanoids are now being revisited. Although a recent study of oral treprostinil (so far reported only in abstract form) failed to meet its primary endpoint, there were improvements in physician global assessment and patient-reported RP symptoms .
There have been a number of recent case series reporting beneficial effects of botulinum toxin in patients with digital ischemia/ulceration, including patients with SSc, and these have been reviewed . The mechanism of any effect is unclear: a recent laboratory study suggested that increased blood flow after local administration of botulinum toxin may result from arteriolar vasodilation from sympathetic blockade . Further and longer-term evaluation is required for the role (if any) of botulinum toxin to be established.
A recent observational study in 11 patients suggested that sarpogrelate hydrochloride, a selective 5-hydroxytryptamine 2A serotonin receptor antagonist, confers benefit in SSc-related digital ulceration . As with other open studies, results must be interpreted with caution and further research is required before this approach to therapy can be recommended.
Author’s Approach Focusing on New Developments
I recommend bosentan in patients with refractory SSc-related digital ulcers, for example those requiring repeated admissions for intravenous iloprost. I refer a significant proportion of patients with digital ulceration for surgical debridement; while there is no good evidence base for this approach (and there is unlikely to ever be a controlled clinical trial of surgical debridement), my own feeling is that with early debridement, very few patients go on to require more radical surgery (digital sympathectomy or amputation).
SS-Related Critical Digital Ischemia
This is much less common that digital ulceration (and can occur concomitantly), but is always a medical emergency. By the time the patient presents, it may be too late to save the digit; hence, the importance of reinforcing to patients that they must seek medical advice immediately if a finger or toe becomes permanently discoloured. The approach to treatment in the acute setting is very similar to that of severe digital ulceration (admission for intravenous prostanoid treatment and analgesics), although most clinicians would in addition give an antiplatelet agent, and consider short-term anticoagulation. The situation should be discussed with a hand or vascular surgeon because surgery may be required. Surgical options include debridement of necrotic tissue (although this may autoamputate), digital sympathectomy or amputation.
New Findings and Developments
The rarity of critical digital ischemia means that controlled clinical trials, for example of anticoagulation, are unlikely ever to be mounted. The focus of treatment must be to maximise nutrient blood flow to the affected digit, and this will include:(1) optimising vasodilator treatments in the acute situation, on the assumption that there may still be some reversibility to the impaired blood flow; (2) treating any procoagulant tendency, on the assumption that thrombi may be contributory to the critical ischemia; Although there is no good evidence base for this approach, in some patients arterial thromboses have been found in digital arteries from amputation specimens ; and (3) identifying whether there might be a vascular lesion amendable to surgical intervention, for example an ulnar artery occlusion . While proximal lesions can often be diagnosed by careful clinical examination of the peripheral pulses and arterial Dopplers, more distal lesions can be difficult to detect non-invasively. Advances in magnetic resonance angiography may in the future obviate the need for the more invasive X-ray angiography to visualise the distal circulation, including the digital arteries, in patients with SSc .
Author’s Approach Focusing on New Developments
My practice has not changed significantly over the last 2 years, other than a more aggressive use of oral vasodilator therapy once the acute episode has passed (as per ‘uncomplicated RP’). I anticipate using more phosphodiesterase inhibition over the next 5 years. In our centre, we are currently gaining experience in the use of botulinum toxin in patients with critical ischemia and/or refractory digital ulceration, although I would prefer to be doing this in the context of a clinical trial.
Early Diagnosis of a SSc-Spectrum Disorder in the Patient with RP
Optimal management of RP includes using this ‘opportunity’ to diagnose SSc early. Most clinicians agree that early diagnosis of SSc is worthwhile: even if we cannot at present modify the underlying disease process, we can screen the patient for internal organ involvement for which effective treatments are available (for example pulmonary arterial hypertension) and/or recruit patients into clinical trials of potential disease-modifying (and other) therapies.
It is now well established that abnormal nailfold capillaries and the presence of SSc-specific autoantibodies are independent risk factors for SSc. In a study of 586 patients with RP followed for 3,197 patient years , SSc developed in 25.8 % of patients with an abnormal capillary pattern, in 35.4 % of those with a specific autoantibody, and in 79.5 % of those with both abnormal nailfold capillaries and a specific autoantibody. Those patients with both predictors were 60 times more likely to develop SSc than those with neither .
New Findings and Developments
The importance of diagnosing SSc early is now recognised internationally: proposed criteria for early diagnosis include RP, abnormal capillaroscopy, and SSc-specific autoantibodies . A key point to highlight is the increasing awareness of the role of nailfold capillaroscopy in patients with both primary and secondary RP . While the usefulness of nailfold capillaroscopy in predicting an underlying SSc-spectrum disorder has long been recognised, its role in predicting digital ulceration is an area of active research [44, 45•].
Key Questions Yet to be Answered for the Practicing Clinician
Ideally, we need treatments which will effectively prevent RP attacks, without systemic side effects, and also drugs which will (for the patient with SSc) prevent and reverse structural vascular change. The next 5−10 years should see controlled trials addressing these issues, facilitated by increased international networking of clinicians with an interest in RP, and by work in progress developing robust outcome measures of digital blood flow for application in clinical trials.
Pending these developments, practising clinicians often ask the following:
Does Statin Therapy Confer Benefit in Patients with RP and/or SSc?
There are many reasons why statins should confer benefit in SSc-related digital vasculopathy, and a study of 84 patients with SSc suggested that 4 months’ atorvastatin 40 mg/day improved both clinical and laboratory parameters . Further studies of statin therapy in patients with SSc-related RP are urgently required: at present, there is insufficient evidence base for these to be recommended as standard therapy for either PRP or SSc-related RP.
Should Aspirin or Another Antiplatelet Agent be Prescribed for Patients with RP?
As with statin therapy, there is a strong therapeutic rationale for the use of antiplatelet therapy for patients with SSc-related RP (less so in patients with PRP). However, there is no good evidence base for this approach. Given that clinical trials of antiplatelet agents are unlikely to be mounted in the near future, the pragmatic approach adopted by many clinicians is to prescribe these for patients with complicated RP, remembering that patients with SSc often have gastrointestinal involvement and are at increased risk of side effects from aspirin.
What About Antioxidants?
Again, despite there being considerable evidence to support oxidant stress as a contributor to the SSc disease process , currently there is not the evidence base to support antioxidant therapy as standard therapy.
The main recent developments in the management of RP with direct relevance to the practising clinician in the community are the increasing use of (1) phosphodiesterase inhibitors for patients refractory to more commonly used vasodilators and (2) endothelin-1 receptor antagonists for patients with recurrent SSc-related digital ulcers. In addition, clinicians should be aware of the recent (and long overdue) recognition of the enormous pain, morbidity and functional disability associated with SSc-related digital ulcers, necessitating a proactive approach to management including skilled nursing/wound care and collaboration with surgical colleagues, because surgical debridement and/or digital sympathectomy may help to preserve a digit. Finally, when confronted with a patient with RP, every clinician should ask him/herself: could this patient have SSc? Early identification of SSc, including with nailfold capillaroscopy and checking of SSc-specific autoantibodies, alerts the clinician to the possibility of the patient’s RP progressing to complications. Looking into the future, high quality clinical trials should deliver answers to the questions as to whether patients with RP should be prescribed statins, antiplatelet agents, or one of a number of exciting therapies which may offer vascular protection.
Dr. Herrick has served as a consultant for Actelion Pharmaceuticals and Pfizer; has received royalties from UpToDate; has received payment for development of educational presentations (including service on speakers’ bureaus) from Actelion Pharmaceuticals; has had travel/accommodations expenses covered/reimbursed by Actelion Pharmaceuticals; and has been an investigator in studies sponsored by Actelion Pharmaceuticals, Pfizer, MediQuest, United Therapeutics Corp., and Orion Pharma.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance
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