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The author practices with Internal Medicine Associates at Crozer-Chester Medical Center, Upland, Pa. She has indicated no relationships to disclose relating to the content of this article.

Most common among women younger than 30 years, Raynaud’s disease is an idiopathic, vasospastic disorder that affects an estimated 10% of the US adult population. Many patients with the condition also suffer from migraine headaches and chronic stress.¹ This clinical review differentiates primary Raynaud’s (or Raynaud’s disease) from secondary Raynaud’s (or Raynaud’s phenomenon), highlights key clinical features that distinguish Raynaud’s disease from other peripheral vascular diseases, and presents some emerging treatment options.

Although there is no mortality associated with it, Raynaud’s disease is uncomfortable and can be embarrassing for many patients. Moreover, the possibility that the signs and symptoms represent a more serious underlying condition (such as lupus erythematosus or scleroderma) is cause for concern. Therefore, clinicians must distinguish carefully between primary and secondary Raynaud’s and be prepared to offer both reassurance and current treatment options when the condition truly proves to be primary and idiopathic.

Primary versus secondary Raynaud’s

Patients with primary Raynaud’s present with the well-known, classic signs of “red, white, and blue” fingers or toes, indicative of reactive hyperemia followed by pallor and cyanosis. This triphasic color response occurs in up to 65% of patients,² many of whom also experience pain and/or paresthesia in the affected digits. Attacks of primary Raynaud’s are set off abruptly and predictably by exposure to cold environments, including air-conditioned spaces, and by emotional stress³ (see Figure 1). Bilateral involvement usually occurs in the fingers; but the toes, nose, ears, lips, and nipples may also be affected. Primary Raynaud’s is considered benign; however, 10% to 15% of patients actually have early connective tissue disease, or secondary Raynaud’s.⁴ Table 1 lists some factors that are key to distinguishing between primary and secondary Raynaud’s.

Secondary Raynaud’s, which produces similar vasospastic signs and symptoms, results from trauma, toxicity, or an underlying vascular or connective tissue disorder (see Table 2).¹ The signs that an underlying disease is the cause include skin changes, nail pitting, ulcers on the fingertips, or an abnormal result on the Allen test. The diagnoses that should be considered include connective tissue disease, arterial occlusive disease, drug or heavy metal toxicity, hematologic abnormalities, neurologic disorders, renal failure, and neoplasm.

Secondary Raynaud’s is one of the five components of the CREST (calcinosis, Raynaud’s, esophageal dysfunction, sclerodactyly, telangiectasia) syndrome, which is associated with scleroderma. But a more common cause of secondary Raynaud’s is repeated trauma, especially among people who work with vibratory tools such as pneumatic hammers, chain saws, sanders, or grinders. It also has been seen in typists, pianists, meat cutters, and sewing machine operators.

Patients who are not experiencing an acute attack of Raynaud’s will have normal findings on physical examination. Although trauma may be detected through the patient history, a differential diagnosis of systemic illness requires a thorough serologic evaluation—including, but not limited to, urinalysis, CBC, ESR, C-reactive protein, complement, cryoglobulins, and autoantibodies (antinuclear antibodies [ANA], anti-DNA, SCL-70 [scleroderma], and anticentromere antibodies).⁵

Other mimicking conditions

In addition to scleroderma and other connective tissue diseases, three other syndromes that should be ruled out when evaluating a patient with cold hands are peripheral arterial disease (PAD), chronic idiopathic acrocyanosis (CIA), and thromboangiitis obliterans (Buerger’s disease). Signs and symptoms of each of these conditions can mimic those of Raynaud’s.

PAD, a vaso-occlusive disorder that results from atherosclerosis, is a strong possibility in diabetic patients and in patients older than 40 years who smoke. Hyperlipidemia, hypertension, and hyperhomocysteinemia are other risk factors for PAD. The prompt and accurate diagnosis of PAD is critical, as patients with PAD have almost the same relative risk for death as patients with coronary or cerebrovascular disease.⁶

CIA is an uncommon condition characterized by symmetric coolness and violet discoloration of the hands and feet. As with secondary Raynaud’s, the toes, nose, ears, lips, and nipples may be affected; the condition generally worsens with cold temperatures; and it may be secondary to a variety of underlying conditions (see Table 3). Unlike Raynaud’s, CIA persists in both warm and cool environments, even though the lesions may change in appearance during the course of the day. CIA does not produce sclerodactyly, digital ulceration, or oral telangiectasias, all of which may occur in secondary Raynaud’s.^6,7

Buerger’s disease is both an inflammatory and a thrombotic process of the peripheral vessels. The cause is unknown, but 80% of patients with Buerger’s disease are men, usually younger than 40 years, who smoke. A classic symptom is digital pain at rest caused by intermittent claudication, which can lead to tissue necrosis. By definition, Buerger’s disease affects more than one limb, in which proximal pulses are intact but distal pulses are diminished. Patients have pale, cyanotic, or erythematous digits, resembling those of patients with primary Raynaud’s. In fact, patients with Buerger’s disease often have a history of primary Raynaud’s or cold sensitivity.¹

Etiology and treatment

The vasculopathy of primary Raynaud’s continues to be the subject of much debate. Multiple dilator and constrictor pathways interact to determine blood vessel diameter. Blood vessels constrict as a result of the contraction of vascular smooth muscle, which is regulated by multiple physical and chemical stimuli. The French physician Maurice Raynaud (1834-1881) claimed that hyperactivity of the CNS was responsible for the syndrome.⁸ However, it is now widely accepted that vasospasm results from a “local fault” in the blood vessel, as proposed by Sir Thomas Lewis in 1930.⁸

Researchers at Ohio State University Medical Center recently found that a specific type of endothelial receptor protein, alpha-2C, interacts with norepinephrine to constrict blood vessels in response to cold temperatures. Why the response is amplified in patients with primary Raynaud’s is still not known. The researchers admit that primary Raynaud’s is probably the result of multiple forms of vascular stress, including as-yet-unidentified constrictor proteins and impaired dilator function.^8,9

The ability to target endothelial cold receptors may lead to highly specific interventions for primary Raynaud’s in the future. However, the key principles of treatment remain the same: reduce vasoconstriction and produce vasodilation, with a minimum of systemic side effects. Herrick profiled state-of-the-art treatments of primary Raynaud’s, highlighting recent advances.¹⁰ To date, the most conventional treatment involves vasodilator drugs, such as calcium channel blockers. Diltiazem, short-acting nifedipine, and low-dose/sustained-release nifedipine are now being used in primary Raynaud’s.¹⁰

Pharmaceutical approaches to secondary Raynaud’s include use of ACE inhibitors and angiotensin II receptor blockers, alpha-adrenergic blockers, topical glyceryl trinitrate, antioxidants (eg, probucol), and serotonin receptor antagonists (eg, ketanserin). Beta-blocking agents, which may exacerbate the symptoms of both primary and secondary Raynaud’s, should be avoided. Prostanoids, in the form of IV prostacyclin (eg, epoprostenol), have become a mainstay of treatment for patients with acute digital ischemia. Endothelin-1 receptor antagonists show promise in the treatment of severe ischemia with digital ulceration.¹⁰

Using serotonin as a psychotropic agent is another area of active clinical research. The role of stress in precipitating acute Raynaud’s has prompted some clinicians to prescribe anxiety-modulating agents, including selective serotonin reuptake inhibitors. British researchers found that fluoxetine, at a standard dose of 20 mg daily, yields promising results, particularly in female patients with primary Raynaud’s. The researchers found statistically significant reductions in attack severity (P = .0002) and attack frequency (P = .003).¹¹ Along the same lines, Scottish researchers have reported a 56% reduction in Raynaud’s attacks using a standardized Ginkgo biloba extract.¹²

One of the newest and most novel approaches to Raynaud’s disease utilizes a metabolic as opposed to a vascular route. Researchers at Texas A&M College of Medicine have used the thermogenic steroid 7-oxo-dehydroepiandrosterone to boost basal metabolic rate, improve central warming, and thus inhibit vasospasm.¹³ Because of the systemic side effects of vasodilator drugs and psychotropic and metabolic agents, alternative treatments are being investigated. A topical gel containing sodium nitrate and ascorbic acid was found to stimulate the synthesis of nitric oxide, a vasodilator, in the extremities. The increased microvascular blood flow is a strictly local response but results in digital warming.¹⁴

A second local approach is low-level laser therapy (LLLT), which is still experimental but has been applied to a multitude of medical conditions. Although LLLT did not reduce the frequency of Raynaud’s attacks, the therapy appeared to diminish their intensity.¹⁵ Biofeedback has been applied with mixed success. Unfortunately, the effectiveness of this method is limited by each patient’s anxiety level and overall coping abilities.¹⁶

Summary

The availability of new treatments for Raynaud’s disease, as with any medical condition, depends on how convincing the results of clinical research prove to be. The validity and reliability of research in Raynaud’s disease is subject to two major constraints: the seasonal and intermittent nature of the condition limits the amount of time patients can be studied continuously, and researchers have failed to agree on objective outcome measures.¹⁰ Vascular physiology is, and no doubt is destined to remain, a dynamic and technology-driven clinical realm.

Despite the wide array of promising treatments, the best and most basic management of Raynaud’s disease seems to be behavioral and at least partly pharmaceutical. The two biggest behavioral factors are nicotine use and exposure to cold environments.^1,2,16 Giving up nicotine can be a daunting challenge for long-term smokers and chewing-tobacco users. Avoiding cold environments may be easier said than done, especially for patients who work outdoors or in air-conditioned spaces. Perhaps the best treatment for Raynaud’s disease is a reliable diagnosis and the positive prognosis that comes with it. Most patients have a stable course, and nearly half will actually improve with time and steady reassurance.

REFERENCES

16. Middaugh SJ, Haythornthwaite JA, Thompson B, et al. The Raynaud’s Treatment Study: biofeedback protocols and acquisition of temperature biofeedback skills. Appl Psychophysiol Biofeedback. 2001;26(4):251-278.

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