bedside examination including a palpation of all pulses, bilateral arm blood pressures, and use of an Allen’s test at the wrist to assess for ulnar, radial artery, or palmar arch occlusion. Squeezing and releasing the distal digit provides a view of nutritional blood flow in that a rapid return of a blush to the skin should be observed, even if the surface skin is cold to touch or cyanotic in color. A lack of return or persistent pallor is an indication of poor nutritional blood flow and associated structural vascular disease rather than vasospasm alone. Lace-like mottling of the skin of the limbs due to vasoconstriction of thermoregulatory vessels is common in primary RP and is quickly reversible with rewarming. Fixed or impressive irreversible mottling (livedo racemosa) would be suggestive of antiphospholipid syndrome, while petechiae and/or purpura is suggestive of an inflammatory or occlusive process. Underlying associated macrovascular disease may occur due to vasculitis, proximal atherosclerosis, embolic disease, thrombotic or extrinsic vascular obstruction. Splinter hemorrhages under the nail are not seen secondary to RP alone and suggest an inflammatory or embolic process; while digital ulcers or deep areas of gangrene point toward digital artery and/or associated macrovascular disease.

Noninvasive assessment of the peripheral circulation will supplement the physical examination and may provide clues as to the cause and size of the vessels involved. Doppler ultrasound is a useful noninvasive test that can quickly give evidence for larger vessel disease [56]. Arteriography is recommended in specific cases with digital ischemia when the underlying cause is in question or the option of surgery is considered. Magnetic resonance angiography (MRA) is a fast, noninvasive method that can visualize vessel in the hand and digits. MRA studies in patients with scleroderma found substantial arterial and venous damage in the hands and could correlate these changes with clinical severity [57].

15.2Management of Raynaud’s Phenomenon

RP associated with primary SS is generally mild without vascular complications and therefore, like primary RP, conservative management is appropriate. The use of nondrug modalities are often very effective and may be all that is needed. An interaction between both cold sensitivity and emotional stress exists such that the intensity of the RP events becomes more severe if both cold exposure and the patient’s emotional state are not addressed. Treatment begins with education. Patients need to have a clear understanding of the causes, consequences, and factors triggering the RP attacks. Education reduces fear and tension about the disease process and offers strategies for the patient in avoiding triggering factors. Patients need to know that the events are an exaggeration of a normal response to cold and emotional stress and, in uncomplicated cases, these events are not harmful even if they are uncomfortable. Treatment of anxiety/depression with medication may help the RP [58]. Cold exposures, especially shifting temperatures (e.g., going to the frozen food section of the grocery store) and situations such as sitting in a cold breeze without body movement, are best avoided. Keeping the whole body warm by wearing layered

clothing and good head coverage will reduce the severity of attacks. Chemical warmers placed in gloves, stockings, or pockets can provide local heat in an ambulatory setting. Biofeedback and other forms of cognitive training are reported helpful, but a controlled trial of biofeedback compared with a sham procedure found no measurable benefit [59]. Treatment of both primary and secondary RP should always start with a foundation of nondrug methods.

15.2.1Vasodilator Therapy

Whenever deciding on which type of vasodilator therapy to use for RP, one must look critically at the evidence for their benefit. RP varies greatly with weather conditions, activity, and stress; thus, drug interventions may appear helpful when in fact these other issues are influencing the outcome. The placebo effect in RP is robust, as documented in clinical trials where a 20–40% reduction in the severity of RP is reported [60]. Many agents are used with enthusiasm to treat RP but few have been formally studied to provide solid guidelines for their use.

15.2.2Calcium Channel Blockers

Calcium channel blockers are the best studied and are still the most widely used agents for the treatment of RP. They continue to be both reasonable and safe as firstline drug therapy [61, 62]. It is recommended that a calcium channel blocker be used alone as initial therapy, titrating the medication to the maximal tolerated dose and then assessing its impact on the severity and frequency of RP by clinical followup. This titration should be done before changing therapy or adding other agents to the calcium channel blocker. The dihydropyridine calcium channel blockers (e.g., nifedipine, amlodipine) are more potent peripheral vasodilators than other calcium channel blockers (e.g., verapamil) but studies show that diltiazem, a benzothiazepine, is also effective [63]. Adverse effects such as hypotension, dizziness, flushing, dependent edema, and headaches are fairly common with these agents but usually mild. In cases of severe RP, the addition of a second vasodilator to a calcium channel is commonly done, but this approach is not evidence based.

15.2.3Adrenergic Blockers

Studies of the cutaneous blood vessels demonstrate that while some alpha-1 adrenoreceptors are present on vessel, the alpha-2 adrenoreceptors are dominant and play a significant role in cutaneous thermoregulation [64]. Prazosin, an alpha-1 inhibitor is modestly effective in treating RP secondary to scleroderma, but side effects often limit tolerability [65]. Although a good alpha-2 inhibitor is not yet available, a study

analog, decreases the frequency and severity of RP attacks and improves healing of digital ulcers [78, 79]. Low dose (0.5 ng/kg to 2 ng/kg body weight per minute) iloprost or epoprostenol is now used for severe RP and critical digital ischemia, primarily in patients with scleroderma by short term (several days) or intermittent intravenous infusion via peripheral vein [80]. Intravenous treprostinil may also be effective [81]. Studies of oral prostacyclins (beraprost, iloprost, and cisaprost) have variable and generally disappointing results, but a new formulation of oral treprostinil is now under study. Other prostaglandins (PGE1) have also shown benefit when delivered intravenously and are an alternative to prostacyclins [82].

15.2.7Other Agents

Angiotensin converting enzyme (ACE) inhibitors were thought to have some benefit for RP but a multicenter, randomized, double-blind, placebo-controlled study evaluating quinapril in over 200 patients with RP found no benefit in limiting the occurrence of digital ulcers or influencing the frequency or severity of the RP episodes [83]. ACE inhibitors are not recommended for the treatment of RP. A relatively small study suggested that losartan, an angiotensin receptor blocker (ARB), offered benefits that were similar to those of low-dose nifedipine [84]. ARBs may provide some minor benefits in the relief of RP, although no definite evidence exists to suggest that they are superior to traditionally used treatments such as calcium-channel blockers. Larger, randomized controlled trials of longer duration are needed [85].

A study of the selective serotonin reuptake inhibitor (SSRI) fluoxetine also found comparable benefit to low-dose nifedipine [86]. More studies are needed, but SSRIs have the potential to induce vasodilation by blocking uptake of the vasoconstrictor serotonin. The use of these agents is particularly attractive for mild RP in patients with low blood pressure.

Endothelins, released from the endothelial layer of blood vessels, act as potent vasoconstrictors. Two placebo-controlled trials of bosentan, a endothelin receptor inhibitor, demonstrated a reduction of new digital ulcers compared to placebo but no change in the frequency or severity of RP [87, 88]. This suggests that bosentan have vasoprotective properties that may help prevent ischemic ulcers but is insufficient for RP alone.

Statins demonstrate vasculoprotective effects by improving lipid profiles, decreasing free radicals, coagulation, and blood viscosity, decreasing matrix metalloproteases, and increasing platelet function [89]. A placebo-controlled trial of atorvastatin in patients with scleroderma and RP demonstrated fewer digital ulcers and a reduction in the severity of RP in the treated group [90]. This study sets the scene for further investigations into the role of statins in patients with RP associated with rheumatic diseases when there is associated peripheral vascular disease and digital ischemia.