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Chapter 12 Raynaud's Phenomenon

Manual of Rheumatology and Outpatient Orthopedic Disorders


Chapter 12 Raynaud's Phenomenon

Kyriakos A. Kirou and Mary Kuntz Crow

Pathogenesis
Diagnosis
Treatment
Prognosis

Raynaud's phenomenon (RP) is characterized by episodic ischemia of the digits. Typically, exposure to cold or emotional stress produces vasospasm and occlusion of the digital arteries, with well-demarcated ischemic blanching of the involved digits. This may be followed sequentially by cyanosis and rubor, although the classic triphasic color change is not common. Numbness and sometimes pain occur, especially during the reactive hyperemia phase (rubor). An attack may last from several minutes to hours (usually 10 to 30 minutes). Upper extremities are most frequently involved, but 40% of patients have symptoms in their lower extremities.

The phenomenon is named after Maurice Raynaud, who first described it in 1862. It can occur in otherwise healthy persons (primary RP) or in association with other disorders (secondary RP). In 1932, Allen and Brown defined the criteria for diagnosing primary RP: (a) appearance of symptoms with exposure to cold or emotional upset; (b) bilateral symmetric involvement of the hands; (c) presence of normal pulses ; (d) absence of, or only superficial, digital gangrene; (e) absence of an underlying disorder commonly associated with the symptom complex; (f) presence of symptoms for at least 2 years without the appearance of an underlying cause.

These guidelines for diagnosis remain valid. However, a systemic disease may develop in patients with presumed primary RP many years after the onset of symptoms. LeRoy and Medsger have proposed a stricter definition of primary RP that would exclude all patients with evidence of digital pitting, ulcerations, or gangrene; abnormal nailfold capillaries; a positive antinuclear antibody (ANA) test; or an abnormal erythrocyte sedimentation rate (ESR) at presentation. According to a recent metaanalysis of ten studies, a connective tissue disease (CTD) developed in 80 of 639 patients with primary RP (12.5%) after a mean follow-up of 2.8 years. An abnormal nailfold capillary pattern was the best predictor of transition, with a positive predictive value of 47% (Spencer-Green). In another study (Landry et al.), a CTD developed after 10 years of follow-up in 19 of 80 patients (24%) who had what appeared to be primary RP. This value increased to 55% for seropositive patients [for antinuclear antibody (ANA) or rheumatoid factor (RF)] and to 81.8% for seropositive patients with evidence of fixed arterial obstructions (on vascular laboratory evaluation).

Population-based studies estimate a prevalence of RP of 5.8% to 20.2% among women and 4.1% to 12.7% among men, with the highest rates noted in the coldest geographic regions . Primary is much more common than secondary RP, and it usually affects young women (onset in teens is characteristic of primary RP).

I. Pathogenesis. Vasospasm of the digital arteries and cutaneous arterioles is the sine qua non of RP. Neural signals, including sympathetic, parasympathetic, and sensory -motor fibers (that release substance P and calcitonin gene- related peptide), and the endothelium are the major determinants of vascular reactivity. Circulating hormones and mediators released from circulating cells are also very important. Some of the neurotransmitters and mediators act directly. Notably, epinephrine (released by sympathetic nerves) acts directly on a 2 -adrenoreceptors, abundantly present on smooth-muscle cells of small digital and cutaneous arteries, to cause vasoconstriction. Others act indirectly by activating endothelial cells to produce either vasodilators (i.e., nitric oxide) or vasoconstrictors (i.e., endothelin-1). Reduced digital blood flow can be triggered by either a whole-body exposure to cold (through a sympathetic reflex mechanism) or local digital cooling.

  1. Vasospasm alone, without an underlying arterial structural abnormality, is responsible for primary RP. Residence in cold climates may predispose to it. Patients with primary RP have an increased a 2 -adrenoreceptor sensitivity to cold. The underlying mechanism remains unknown.
  2. Secondary RP is associated with many and diverse disorders. Vasospasm is important, but a structural arterial abnormality compromising even the resting digital blood flow is likely to exist also.
    1. Connective tissue disease
      1. Systemic sclerosis (SSc) or scleroderma. There are two forms of SSc, a diffuse cutaneous form, associated with auto-antibodies to topoisomerase-1, and a limited cutaneous form, the CREST syndrome (calcinosis, RP, e sophageal dysmotility, s clerodactyly, and t elangiectasia), associated with anti-centromere antibodies. Most (90% to 95%) patients with SSc exhibit RP, which is frequently the presenting feature of the disease. RP is usually worse in limited SSc. On examination, sclerodactyly, evidence of ischemic tissue necrosis with digital pitting, digital ulcerations, and even gangrene may be present. Nailfold capillary microscopic abnormalities include enlargement of the capillary loops and the presence of intervening avascular areas. The latter predict transition to diffuse SSc. Endothelial cell damage or dysfunction is a prominent and early characteristic in the disease course, but the underlying mechanisms are unknown. Oxygen free radicals generated during reperfusion injury from repeated ischemic attacks may contribute. Histologically, intimal hypertrophy and thrombosis in small (including the digital) arteries occur. Adventitial fibrosis is common and has been implicated in digital ischemia, by virtue of external compression. Cold-induced vasospasm in the heart and other internal organs has been noted in SSc and is called systemic or visceral RP. Scleroderma-overlap CTD syndromes such as mixed connective tissue disease (MCTD), characterized by features of SSc, SLE, polymyositis, and anti-U1RNP antibodies, and tRNA synthetase-associated syndromes, characterized by antibodies to tRNA synthetases and features of myositis and fibrosing alveolitis, have a similarly high prevalence of RP.
      2. Systemic lupus erythematosus (SLE). RP occurs in 10% to 35% of cases of SLE. Nailfold capillaroscopy may show increased capillary tortuosity. It is usually benign without occurrence of tissue necrosis.
      3. Sj gren's syndrome.
      4. Rheumatoid arthritis.
      5. Systemic vasculitis. Inflammatory occlusion of the involved vessels frequently leads to severe digital ischemia and gangrene.
      6. Polymyositis.
    2. Traumatic vasospastic disease. Persons who are exposed to repetitive trauma to the digits are at increased risk for the development of RP. It has been postulated that chronic stimulation of the pacinian corpuscles in the hands may result in digital artery vasospasm through a reflex that involves the sympathetic system. It most commonly occurs in workers who use vibratory tools such as pneumatic hammers and chain saws. The term vibration -induced white finger is used for this condition. Typists and pianists may also be affected. Interestingly, frostbite predisposes to the development of RP in the body parts involved.
    3. Occlusive arterial disease. Atherosclerosis and thromboangiitis obliterans (Buerger's disease) may result in RP in the distribution of the narrowed blood vessels. Thrombotic or embolic occlusions of digital or larger proximal arteries are also in the working differential diagnosis.
    4. Nerve compression. RP can result from a thoracic outlet syndrome. Compression (e.g., by a cervical rib or a pectoralis minor tendon) of brachial plexus sympathetic fibers and the subclavian artery have been implicated. RP may also be seen in patients with the carpal tunnel syndrome.
    5. Drugs and chemicals. Ergot alkaloids have a direct vasoconstrictive action on blood vessels. Methysergide may cause intimal fibrosis. Exposure to vinyl chloride and bleomycin can cause a scleroderma-like illness with RP. Beta blockers, sympathomimetics, cocaine, cyclosporine, interferon-alfa, vinblastine, and cisplatin have been all implicated in the development of RP.
    6. Hematologic abnormalities. RP has been reported in cryoglobulinemia, cold agglutinin disease, polycythemia, and macroglobulinemia. Blood hyperviscosity is the presumed underlying mechanism.
    7. Other disorders associated with RP include malignancy, and hypothyroidism .

II. Diagnosis

  1. History. The diagnosis of RP is based on a history of the classic triad of sequential digital pallor, cyanosis, and rubor in response to cold exposure or emotional stimuli. However, white alone, white and blue-purple, or white and red color changes are frequently seen. Male sex and age above 40 suggest secondary RP. A thorough history including exposure to drugs, trauma, and occupational hazards should be taken to differentiate primary from secondary RP.
  2. Physical examination. Examination of patients with primary RP between attacks is unrevealing. Moreover, attempts to reproduce an attack during clinical evaluation are usually unsuccessful and not recommended. Nevertheless, the clinician should look for clues of an underlying disease. Asymmetric involvement and abnormal peripheral pulses should prompt vascular surgical evaluation and exclusion of thromboembolic disease (especially in an acute setting and history of trauma). Puffy hands, sclerodactyly, tendon friction rubs, and telangiectasia are features of SSc and scleroderma-overlap CTD syndromes. Similarly, nailfold capillary microscopy, performed with placement of grade B immersion oil on the nailfolds and a stereo-zoom microscope (or even an ophthalmoscope set at 40 diopters), may reveal important scleroderma-specific abnormalities (see above). The presence of digital trophic skin changes, ulcers, severe pain, and gangrene indicate a compromised resting blood flow, as would occur with a fixed arterial obstruction. Maneuvers to detect thoracic outlet compression or carpal tunnel syndrome should be undertaken.
  3. Laboratory studies
    1. A complete blood count with differential, urinalysis , and tests for ESR, ANA, and RF can help identify an underlying systemic disorder in the initial evaluation. Additional tests should be ordered accordingly . Evaluation for the presence of a hypercoagulable state, cryoglobulins, hypothyroidism, and anti-centromere and anti-topoisomerase antibodies may be necessary. Chest radiography might reveal a bony cervical rib or basal lung fibrosis. Echocardiography is useful for exclusion of thromboemboli or septic emboli, and nerve conduction studies for nerve compression syndromes.
    2. Vascular laboratory evaluation may include a Doppler study of vessels to assess the patency of the superficial palmar arch and proximal larger arteries. Additionally, finger photoplethysmography and finger blood pressure determination (with a pneumatic cuff placed around the proximal phalanx and a photoplethysmograph placed over the distal phalanx), performed at a warm ambient temperature to avoid vasoconstriction, may prove very useful. Abnormal photoplethysmographic waveforms and brachial-finger pressure gradients of more than 20 mm Hg indicate fixed arterial obstruction somewhere in the vascular pathway supplying the terminal phalanx.
    3. Arteriography (or magnetic resonance angiography) is necessary only when a proximal embolic source is suspected or microsurgical arterial reconstruction of the superficial palmar arch is contemplated. Sympathetic blockade is recommended prior to angiograpy in order to avoid reflex vasospasm due to vascular trauma.
  4. Differential diagnosis. RP, which is an episodic disorder, must be differentiated from processes characterized by persistent vasospastic ischemia. In the disorders described below, vasoconstriction is probably limited to arterioles and does not involve the digital arteries.
    1. Acrocyanosis, like RP, is exacerbated by low temperatures and emotional stress. However, cyanosis is not confined to the digits but extends diffusely to the hands or feet. Its idiopathic form is a benign disorder.
    2. Livedo reticularis, characterized by a persistent purple or blue mottling of the skin, predominantly involves the extremities; it is usually a benign condition. However, it may be vasculitic in nature (livedo reticularis with ulceration or atrophie blanche ) or secondary to a systemic disorder such as SLE or the antiphospholipid syndrome.

III. Treatment. Adequate reassurance and patient education on how to avoid cold exposure is often all that is needed for patients with mild primary RP. Temperature biofeedback, in combination with different relaxation techniques or conditioning treatment, has also been helpful for such patients. Severe primary RP compromising quality of life because of frequent uncomfortable attacks and the constant need to practice cold avoidance will usually respond to pharmacologic therapy with calcium channel blockers. Therapy of secondary RP should address both vasospasm and the underlying disorder. Notably, vasculitis will require corticosteroids or immunosuppressive therapy. Antiphospholipid syndrome, other thrombophilic disorders, and thromboembolic events require appropriate anticoagulation therapy . Severe involvement of large vessels (secondary to trauma, atherosclerosis, or vasculitis) will require vascular surgery. Microsurgical revascularization, if available, can be effectively employed for occlusive lesions affecting the wrist arteries and superficial palmar arch. Notably, these are frequently seen in SSc.

  1. General measures. Avoidance of cold temperatures and the use of warm clothing, mittens, and even electrically heated gloves cannot be overemphasized. Tobacco smoking should be discontinued. Repetitive traumatic injury to the extremities should be avoided. Beta blockers, if used, should be appropriately substituted. For acute and severe ischemic pain, which may further augment sympathetically mediated vasospasm, adequate analgesia will be necessary. Extreme care should be undertaken to prevent or treat infection (usually with Staphylococcus ) of ischemic ulcers.
  2. Drug therapy of vasospasm. Vasodilators are more helpful in cases in which the vasospastic component is prominent. If a significant occlusive component is present, the benefit may be less significant.
    1. Calcium channel blockers are the best-studied agents and the usual first choice. Some calcium channel blockers, in addition to causing vasodilation, may inhibit in vivo platelet activation and enhance the thrombolytic activity of blood. However, they can aggravate esophageal reflux or constipation. They should be avoided during pregnancy .
      1. Nifedipine can decrease the number and severity of episodes of RP. Side effects are common and include headache , tachycardia, flushing, light-headedness, and edema. The initial dosage is 10 mg orally three times daily with upward titration to the maximum tolerated dose. The slow-release preparations (30 or 60 mg once daily) are thought to have fewer side effects. Because amlodipine is very closely related to nifedipine, it is also used (5 to 10 mg daily).
      2. Diltiazem, another calcium channel inhibitor, may be efficacious in patients with primary or vibration-induced RP. The dosage is 30 mg three to four times daily.
    2. Alpha blockers
      1. Prazosin, an a 1 -adrenoreceptor blocker, is beneficial in primary RP, yet the clinical improvement may not be sustained with prolonged treatment. Syncope may occur with the first dose but can be prevented by giving the drug at bedtime and limiting the dose to 1 mg. Subsequent doses are better tolerated. Most patients can be managed on 1 to 2 mg orally three times daily.
      2. Phenoxybenzamine is a potent alpha blocker. The weak evidence supporting its use in RP and the high incidence of side effects (postural hypotension, palpitations, diarrhea, impotence) limit its clinical usefulness .
    3. Presynaptic sympathetic inhibitors , such as guanethidine and reserpine, have been largely replaced by other, better studied and tolerated agents.
    4. Nitrates. Topical nitroglycerin ointment and sustained-release transdermal glyceryl trinitrate patches can reduce the number and severity of attacks in both primary and secondary RP, but their use is limited by the high incidence of headaches .
    5. Prostaglandins, besides being potent vasodilators and platelet aggregation inhibitors, probably have additional biologic properties of longer- lasting benefit to microcirculation. Although they are effective when given intravenously, there is not yet sufficient evidence for the clinical usefulness of available oral prostaglandin preparations.
      1. Iloprost is a chemically stable prostacyclin analog. Recent controlled studies have shown that intravenous infusions of iloprost promote healing of digital ischemic ulcerations and may reduce the frequency and severity of RP attacks in patients with SSc. Improvement in microcirculation after 5-day iloprost infusion therapy (0.5 to 2 ng/kg per minute for 6 hours daily) can last for 2 to 4 weeks; thereafter, repeated monthly 1-day infusions may maintain these effects. Therapy is probably more effective in early ischemia, before extensive tissue damage has occurred. Side effects are common during infusion and include headaches, nausea, and jaw, thigh, or chest pains. Therapy should be avoided in pregnancy and in patients with coronary disease, stroke, or bleeding disorders. Iloprost is currently not available in the United States. Prostacyclin (prostaglandin I 2 ) itself has also been effective in RP secondary to SSc. It is approved for use in primary pulmonary hypertension where it is given continuously (via a portable infusion pump linked to a central vein) at a starting dose of 2 ng/kg per minute.
      2. Prostaglandin E 1 is probably less effective but better tolerated than iloprost. It requires a central intravenous line and has been given in infusions of 6 to 10 ng/kg per minute over a 72- hour period. It is available in the United states for maintaining the patency of the ductus arteriosus.
    6. Serotonin receptor inhibitors. Ketanserin, an antagonist of 5-hydroxytryptamine 2 receptors on vascular smooth muscle and platelets, may be effective in both primary RP and RP secondary to CTD. It is not available in the United States.
    7. The role of angiotensin-converting enzyme inhibitors in RP needs further exploration.
  3. Other drugs. Antiplatelet agents such as low-dose aspirin and pentoxifylline have been advocated by several experts, but there is little supporting evidence for their use in RP. Temporary improvement in skin blood flow has been observed with infusions of recombinant tissue plasminogen activator in SSc-associated RP.
  4. Sympathetic blocks and sympathectomy. Sympathectomy is not recommended for upper- extremity RP, as it does not offer long-term benefits. However, peripheral or proximal sympathetic blocks have a place in the acute management of severe digital ischemia (digit at imminent risk for tissue loss) in CTD, and they will often sufficiently stabilize the condition to allow maintenance therapy with a calcium channel blocker. For cases refractory to such treatment and to maximum pharmacologic therapy (including vasodilators and sometimes aspirin and heparin), digital sympathectomy (adventitial stripping) can be digit-saving, often with immediate restoration of blood flow. The technique, in experienced hands, is a relatively safe procedure. Alternatively, in such critical conditions, prostaglandin infusions can be tried first. For lower-extremity RP, lumbar sympathectomy is usually effective.
  5. Exercises to strengthen the shoulder muscles are highly recommended for thoracic outlet syndrome. Refractory cases will require surgical decompression .

IV. Prognosis. Primary RP has an excellent prognosis. However, as noted above, in a proportion of patients with apparent primary RP, especially those presenting with abnormalities on nailfold capillaroscopy or serology testing, a CTD will eventually develop. Careful clinical follow-up is warranted in such cases. The prognosis of secondary RP depends on the character of the underlying disease. The presence of fixed arterial obstructions on vascular laboratory evaluation not only increases the probability of transition to a CTD in a patient with RP and abnormal serology, but also strongly correlates with digital ulcerations (half of patients) and amputations (10% to 20% of patients).

Bibliography

Ceru S, et al. Effects of five-day versus one-day infusion of iloprost on the peripheral microcirculation in patients with systemic sclerosis. Clin Exp Rheumatol 1997;15:381.

Coffman JD. Raynaud's phenomenon. New York: Oxford University Press, 1989.

Landry GJ, et al. Long-term outcome of Raynaud's syndrome in a prospectively analyzed patient cohort. J Vasc Surg 1996;23:76.

LeRoy EC, Medsger TA Jr. Raynaud's phenomenon: a proposal for classification. Clin Exp Rheumatol 1992;10:485.

Maricq HR, et al. Geographic variation in the prevalence of Raynaud's phenomenon: a five-region comparison. J Rheumatol 1997;24:879.

Matucci Cerinic M, et al. New approaches to the treatment of Raynaud's phenomenon. Curr Opin Rheumatol 1997;9:544.

Spencer-Green G. Outcomes in primary Raynaud phenomenon. Arch Intern Med 1998;158:595.

Wigley FM, Flavahan NA. Raynaud's phenomenon. Rheum Dis Clin North Am 1996; 22:765.

Yee AMF, et al. Adventitial stripping: a digit-saving procedure in refractory Raynaud's phenomenon. J Rheumatol 1998;25:269.

Books@Ovid
Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders

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Manual of Rheumatology and Outpatient Orthopedic Disorders (LB Spiral Manuals)
Manual of Rheumatology and Outpatient Orthopedic Disorders (LB Spiral Manuals)
ISBN: N/A
EAN: N/A
Year: 2000
Pages: 315

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