Approach to the Patient with Raynaud Phenomenon

Sensitivity of the fingertips and toes to cold is a common symptom, reported in up to 10% of adults. In 3% to 5%, the response to cold or stress is characterized by bilateral blanching and discomfort in the fingers, followed by purplish discoloration and reactive erythema, the hallmarks of Raynaud phenomenon. For some, it is an isolated problem; for others, it may represent the first manifestation of connective tissue disease, arterial occlusion, or a hematologic problem. The primary physician needs to be able to determine the probability and risk of underlying disease, perform the initial workup, and provide symptomatic relief.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8 and 9)

Alteration in dermal blood flow is a basic mechanism of thermoregulation and is also a common response to stress-induced catecholamine release. In patients with Raynaud phenomenon, the normal vasoconstrictive responses to cold and stress are exaggerated. It may be functional (secondary to vasospasm), anatomic (secondary to arterial occlusive disease), or rheologic (secondary to alterations in blood viscosity or red cell deformability). Platelet activation appears to play a role in patients with abnormal vascular anatomy. In many instances, the pathophysiology
is multifactorial. The characteristic clinical sequence begins with a rapid onset of digital blanching (vasospastic phase), which is followed by cyanosis (venospastic phase). It ends with the restoration of flow and redness (reactive hyperemia).

Clinically, Raynaud phenomenon is classified as primary or idiopathic (Raynaud disease) if no evidence of an associated condition can be found and secondary if an associated condition is present. Some have objected to this designation because secondary causes (e.g., connective tissue disease) may not become clinically evident for years.

Primary Raynaud Phenomenon (Raynaud Disease)

Patients with truly idiopathic disease typically experience mild symptoms that are often precipitated by emotional stress or cold. Although an episode may begin in one or two fingers, it quickly spreads symmetrically to involve all of the fingers of both hands. Attacks may occur as often as several times daily and are more frequent in winter. Peripheral adrenergic tone is believed to be especially high. Women predominate, with onset often at menarche; onset after age 40 years is much less common. Some patients manifest other vasomotor problems, such as migraine, Prinzmetal angina, or livedo reticularis. Prognosis is excellent; the risk of eventually developing connective tissue disease is less than 2%, especially if signs and serologic evidence of secondary disease (see later discussion) are absent at the time of the initial clinical presentation and do not appear over the subsequent 2 years.

A pathophysiologic relative of primary disease is druginduced disease. Vasoactive drugs used to treat migraine (β-blockers, ergotamine, methysergide) have all been implicated, as has migraine itself. Whether drugs can cause the problem in the absence of an underlying vasomotor disorder is unclear.

Secondary Raynaud Phenomenon (Underlying Disease)

In comparison with primary disease, secondary Raynaud phenomenon affects men as well as women and tends to appear later (often, after age 30 years). The episodes are more severe and less likely to be precipitated by emotional stress. Loss of finger pulp and skin ulcers as a consequence of ischemia may be evident. The common pathophysiologic denominator is vasoocclusion. The pathophysiology includes deranged blood vessel anatomy, platelet activation, and defective fibrinolysis. Causes range from connective tissue disease to mechanical and atherosclerotic etiologies.

Connective Tissue Disease

Raynaud phenomenon is associated with a wide range of connective tissue diseases, including scleroderma, systemic sclerosis, systemic lupus erythematosus, mixed connective tissue disease, and Sjögren syndrome. Joint complaints and systemic symptoms may dominate the clinical picture; antinuclear antibody (ANA) positivity is common (see Chapter 146).

Raynaud phenomenon is especially prevalent in systemic sclerosis, occurring in more than 90% of cases. Structural narrowing of digital vessels develops as a consequence of intimal fibrosis. Abnormal vascular reactivity and platelet activation have been demonstrated. Symptoms may be especially severe, and the risk for digital ischemic injury is substantial. The compromise to digital blood flow is considerably less in patients with scleroderma.

At the time of initial presentation of Raynaud phenomenon, the signs of sclerodermal disease and other connective tissue disorders may be subtle. Abnormal nail-fold capillary pattern, mild sclerodactyly, early calcinosis, or telangiectasia is characteristic. The presence of antinuclear antibodies increases the risk of eventually developing frank connective tissue disease, but its positive predictive value is only 30% in persons with Raynaud phenomenon. More predictive is the presence of disease-specific autoantibodies (e.g., anticentromere and anti-topoisomerase antibodies; see later discussion). The best predictors for the development of connective tissue disorders (especially sclerodermal disease) include abnormal nail bed capillary pattern, the presence of autoantibodies, characteristic skin lesions, abnormal pulmonary function, and esophageal dysmotility. Although predictive, none of these factors has a positive predictive value of greater than 50%. The mean onset of clinically frank disease is almost 3 years from the time of initial diagnosis of Raynaud phenomenon, and fullblown disease may take 10 years to develop.

Other Vasoocclusive Diseases

A host of other vasoocclusive conditions can cause Raynaud phenomenon, including atherosclerotic disease, occupational vibratory injury (jackhammer operators, welders, sheet-metal workers), and neurovascular compression syndromes (thoracic outlet, carpal tunnel). The neurovascular syndromes may exhibit cold sensitivity. The clinical course is a function of the underlying disease, which in some instances is reversible. Hyperviscosity states compromising blood flow may occur as a consequence of hematologic conditions such as polycythemia or multiple myeloma. Besides symptoms of poor peripheral blood flow (which may be severe enough to cause acrocyanosis), the clinical picture may include headache, confusion, weakness, and hematuria; relative serum viscosity is usually greater than 4. In mixed cryoglobulinemia due to such conditions as hepatitis C or connective tissue disease, there may be cold sensitivity, as well as purpura, arthralgias, fever, proteinuria, and reductions in serum complement levels (e.g., C3 and C4). In cold agglutinin syndrome (seen idiopathically and with Mycoplasma infection and mononucleosis), the patient complains of transient cold-induced acrocyanosis of the finger tips, ears, and tip of the nose that quickly resolves with warming. Splenomegaly and autoagglutination of blood are characteristic.

DIFFERENTIAL DIAGNOSIS (9)

The causes of Raynaud phenomenon can be grouped according to the predominant pathophysiologic mechanism (Table 163-1), although, as noted, multiple mechanisms may be operative.
About 20% of patients presenting initially with idiopathic or primary Raynaud phenomenon prove after 2 to 3 years to have underlying connective tissue disease.

TABLE 163-1 Important Causes of Raynaud Phenomenon

Purely Vasospastic Disease

Primary Raynaud phenomenon (with or without migraine, Prinzmetal angina, livedo reticularis)

Drug induced, typically in persons with primary disease (methysergide, ergotamine,? β-blockers)

Vasospasm plus arterial occlusive disease

Connective tissue disease (scleroderma, systemic sclerosis, systemic lupus, mixed connective tissue disease, Sjögren syndrome)

Atherosclerotic disease

Occupational vascular trauma

Compression (thoracic outlet syndrome, carpal tunnel syndrome)

Toxin or substance exposure (chemotherapeutic agents, interferon, nicotine, narcotics, cyclosporine, cocaine, polyvinyl chloride)

Hemorrheologic Disease

Polycythemia vera

Paraproteinemia (multiple myeloma, Waldenström macroglobulinemia)

Mixed cryoglobulinemia (e.g., hepatitis C, connective tissue disease)

Cold agglutinin syndrome (idiopathic, Mycoplasma infection, mononucleosis)

WORKUP (6,9, 10, 11, 12, 13, 14 and 15)

History and Physical Examination

History and physical examination are essential in the workup of Raynaud phenomenon because the diagnosis is determined clinically and subtle manifestations of an underlying etiology may predate the appearance of overt disease. The findings are essential to determining the need for further evaluation.