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The diagnosis of Raynaud's phenomenon
The Diagnosis of RaynauA’s Phenomenon JAY D. COFFMAN,
MD
R
aynaud’s phenomenon is defined as the occurrence of episodic attacks of well-demarcated blanching or cyanosis of the digits on exposure to cold.‘** A red, reactive hyperemia phase may occur when the attack ends. Onset of symptoms in patients with the primary phenomenon usually occurs at between 15 and 45 years of age, although it may occur in much younger or older patients. Patients often complain that they always had cold hands and feet before the onset of classic vasospastic attacks. Most patients have involvement of the fingers and about 40% have attacks in the toes. Vasospastic attacks involving only the toes are uncommon. The nose, ears, face, and lips are affected in some patients, and may be more common in the primary disease. Many patients present with only one or two digits involved, but more digits experience attacks with each cold season. The thumbs are often spared. Numbness is usually present during the ischemic phases; a throbbing pain may occur in the reactive hyperemia phase. The primary phenomenon occurs most frequently in young women, the woman-to-man ratio being 4 : 1 in most series. The small prevalence dictates a search for a secondary cause in men. Few racial studies exist, but one report found an equal distribution among blacks and whites.3 Studies vary on the presence of color changes. In our experience, patients with the primary disease usually have the pallor phase with or without a red, reactive hyperemia phase. There is some indication that patients with only the cyanotic phase are more likely to have an
From the Peripheral Vascular Section, Evans Memorial Department of Clinical Research and Department of Medicine, Boston University Medical Center, Boston, Massachusetts. This work was supported by the National Heart, Lung, Blood Institute, grant HL26320. Address correspondence to Jay D. Cofj%an, MD, University Hospital, 88 East Newton Street, Room E411, Boston, MA 02118.
0 1994 by Elsevier Science Inc.
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underlying disease. 4 Cold exposure is overwhelmingly the most common cause of vasospastic attacks. We have rarely seen emotions as a precipitating factor, although other investigators have reported an 18 to 60% incidence.5*6 We have not encountered patients in whom tobacco smoking definitely induced attacks. Cold exposure plus pressure on the digits appears to be the most common factor; patients report attacks grasping a cold steer-‘ ing wheel on a cold morning, holding iced drinks, shopping for frozen foods in an air-conditioned supermarket, or carrying luggage. Vasospastic attacks are very difficult to induce in the doctor’s office in patients with the primary disease, although patients may present for the examination with an attack. Trophic changes of the digits have been described in 13% of women with primary Raynaud’s phenomenon,6 but in our experience they are uncommon. A few women develop ischemic lesions of the tips of the toes, confusing the diagnosis with chilblains. In the secondary phenomenon due to connective tissue diseases, ulcerations, scarring, fissuring, pitting, and chronic paronychia are very common. Patients with Raynaud’s phenomenon and sclerodactyly, ulcers, pits, or gangrene of the fingers should be strongly suspected of an underlying disease. In different studies the prevalence of Raynaud’s phenomenon has ranged from 4.6 to 30%. The most recent study reported a prevalence of 5.0% in a moderate climate but 16.8% in a cold climate.’ These studies did not differentiate between the prevalence of primary and secondary Raynaud’s phenomenon. Many patients have only one or two Raynaud’s attacks involving only one finger each cold season; these patients usually do not seek medical care.
Prognosis The prognosis in primary Raynaud’s phenomenon is very good. Even in connective tissue diseases such as sclero-
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Clinics in Dermatology 1994;12:283-289
derma, symptoms or signs of systemic disease may not appear for many years. In most studies,QB more than a third of patients with primary Raynaud’s phenomenon report no change in symptoms and another third improve. About 16% of patients report increasingly severe attacks, and the phenomenon disappears in about 10%. Onset of the vasospastic attacks at a younger age and the absence of trophic changes predict a good prognosis. Patients, who have abnormal laboratory studies but only Raynaud’s phenomenon and would otherwise fit the primary category also have a good prognosis.9 It is therefore difficult to predict prognosis for patients with Raynaud’s phenomenon and positive antinuclear antibodies. If nailfold capillary abnormalities are also seen by microscopy, patients are more likely to develop evidence of a secondary etiology in a few years.
Pathology In mild cases of primary Raynaud’s disease, pathologic findings of the digital arteries are probably absent.‘O In more severe cases with trophic lesions of the digits, intima1 hyperplasia, narrowing or occlusion of the lumen, or thrombi are present in the digital arteries. In patients with scleroderma, severe intimal hyperplasia with collagen, thromboses, adventitial fibrosis, and telangiectasia of the vasa vasorum may be present.” Other secondary etiologies of Raynaud’s phenomenon may show similar abnormalities.
Arteriography Arteriograms have been described as normal in patients with primary Raynaud’s disease,12 although some patients show diseased or occluded arteries. In most patients with connective tissue disease or vasculitis, there is narrowing or obstruction of digital arteries. In one study of patients with scleroderma, the ulnar artery was narrowed or occluded in just over 50% of patients while the radial artery was involved in only 2 of 31 patients.13
Pathophysiology Most evidence exists for an abnormal sensitivity of the digital arteries to cold. Lewis showed that local cooling produced ischemic attacks in single fingers and in sympathetically denervated tingers.14 The latter was recently reconfirmed.15 Since attacks could be relieved by proximal but not distal warming of a finger and an attack could occur with proximal cooling of a finger with the tip kept warm, Lewis surmised that the digital arteries and not the arterioles became vasospastic. Other investigators have presented some evidence for arteriolar involvement.’ The
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Figure 1. Percentage decreasesin total fingertip blood flow during intraarterial infusion of increasing dosesof the cyradrenoceptor agonist clonidine. Mean and standard errors are shown. Patients with Raynaud’s phenomenon had a significantly greater decreasein flow to clonidine than normal subjects. Reprinted courtesy of Blackwell Scientific Publications, Inc.r8
local fault theory is supported by the fact that reflex sympathetic vasoconstriction is enhanced in patients with Raynaud’s phenomenon by locally cooling the hand, but not in normal subjects. l6 It was postulated that cold temperatures sensitize the cY-adrenoceptors, which mediate vasoconstriction of vascular smooth muscle as has been shown to occur in in vitro experiments. Patients with primary Raynaud’s disease have increased binding capacity and affinity of a,-adrenoceptors of platelets.” Finally, patients with Raynaud’s phenomenon have an increased vasoconstrictor response in the digits to cy2-but not to cq-adrenoceptor agonists (Figures 1 and 2); however, they also have an increased sensitivity to 5-hydroxytryptamine (5-HT; Figure 3).‘* Evidence for overactivity of the sympathetic nervous system is not substantial. The most recent evidence is the demonstration of an exaggerated digital vasoconstriction with changes in posture in patients with primary Raynaud’s phenomenon and vibration-induced white finger with a normal local axon reflex.19 Several investigators have found decreased hand or finger blood flow in patients with the primary phenomenon in a cool environment compared to normal subjects. Normal vasodilatation in the patients during sympathetic inhibition does not support structural arterial disease and implicates the sympathetic nervous system control of blood vessel tone in the lower blood flow that occurs in a cool environment. Other investigators have been unable to demonstrate increased reflex sympathetic vasoconstriction in patients with Raynaud’s phenomenon, however, and microelec-
Clinics in Dermatology 1994;12:283-289
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THE DIAGNOSIS
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Figure 2. Percentagedecreasesin total fingertip blood flow during intraarterial infusions of increasing dosesof the cx,adrenoceptor agonist phenylephrine. Mean and standard errors are shown. Patients with Raynaud’s phenomenon and normal subjects showed similar decreasesin pow to phenylephrine. Reprinted courtesy of Blackwell Scientific Publications, Inc.“’
trode recordings of skin sympathetic nerve activity do not demonstrate an abnormality in patients with primary Raynaud’s phenomenon or vibration-induced white finger.20*2* If increased sensitivity of digital arteries in cold is present, then normal sympathetic nerve activity would aid in producing vasospastic attacks. A strong correlation of Raynaud’s phenomenon and migraine headaches in patients with variant angina or chest pains has been reported and confmned.22~23 A report of a family with vasospastic conditions in more than one circulatory system for three generations supports the correlation.24 Evidence for vasospasm in the pulmonary, heart, retinal, and renal circulation has been found in patients with Raynaud’s phenomenon. A generalized vascular abnormality may be present in some patients, but it is difficult to envision the defect since the neurogenie and humoral control of the various circulations are so different. Serotonin has also been implicated in the pathophysiology of Raynaud’s phenomenon since it was reported that methysergide, a serotonin inhibitor, reduced the intensity and duration of the response of patients to cold exposure of the hands. 25 Acute administration of ketanserin, a 5-HT, receptor antagonist, relieves vasospastic attacks but does not prevent them when given before stimuli that induce attacks.26 Some investigators, but not others, have found increased plasma free and intraplatelet levels of serotonin in patients with Raynaud’s phenomenon.27,2* However, intraarterial 5-HT does not produce blanching of the fingers but a reddish blue
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discoloration,‘* and in chronic studies ketanserin has produced variable therapeutic results in patients with Raynaud’s phenomenon. Two investigators have found lower brachial artery and digital blood pressures in patients with primary Raynaud’s phenomenon. 29*30This would predispose to vasospasm as transmural arterial distending forces are decreased and less external pressure or sympathetic stimulation is required to close the blood vessels and stop blood flow. Many other factors have been investigated in the pathogenesis of digital vasospasm. Platelets and their products could play a secondary role by aggravating vasospasm or occluding small vessels. A thromboxane receptor antagonist and a thromboxane synthase inhibitor did not change the response of finger pulsations to a cold challenge in patients with Raynaud’s phenomenon from that seen in normal subjects.31 Dazoxiben, an inhibitor of thromboxane synthase,32 indomethacin,33 and aspirin plus dipyridamole% have not proved therapeutically useful in patients. Plasma and blood viscosity have been measured, and reports are variable in patients with primary Raynaud’s disease, although viscosity may be elevated in some patients with Raynaud’s phenomenon secondary to connective tissue disease.35 Endothelin-1 levels have been found to be elevated in the plasma of patients with Raynaud’s phenomenon and to rise with the provocation of a cold stimulus.36 The levels were higher in diffuse compared to limited sclero-
Figure 3. Percentagedecreasesin total fingertip blood flow during intraarterial infusions of increasing dosesof 5hydroxytryptamine. Mean and standard errors are shown. Patients with Raynaud’s phenomenon had a significantly greater decreasein flow to 5-hydroxytryptamine than normal subjects. Reprinted courtesy of Blackwell Scientific Publications, Inc.18
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COPPMAN
derma and were inversely correlated with the pulmonary carbon monoxide diffusing capacity.37 They were considered useful for predicting prognosis and perhaps for reflecting endothelial damage. Other plasma markers of endothelial damage, von Willebrand factor and tissue plasminogen activator, have been reported as elevated in Raynaud’s phenomenon. One group found them raised only in systemic sclerosis and proposed they could be used to rule out primary Raynaud’s phenomenon.28 Evidence for increased polymorphonuclear cell activity and free radical activity was reported in primary and secondary Raynaud’s phenomenon, but the levels did not correlate with the severity of the Raynaud’s phenomenon.38 The significance of these findings is unknown. Hypersensitivity in skin blood flow of the hands to calcitonin gene-related peptide has been reported in patients with Raynaud’s phenomenon, which was not observed with other endogenous vasodilators.39 The investigators postulated a relative deficiency of the peptide, but further study is necessary. In summary, the pathophysiology of vasospastic attacks is still unknown but may be due to a combination of factors. In secondary Raynaud’s phenomenon, digital artery stenosis or obstruction with low distal blood flow and blood pressure, hyperviscosity, thickened vessel walls, and endothelial and platelet vasoconstrictor products may be important. In primary Raynaud’s phenomenon, local hypersensitivity of the digital arteries to cold and low blood pressure are probably most important, but abnormalities in the a,-adrenoceptors and 5-HT, receptors are also present.
Table 1. SecondaryCausesof Raynaud’s Phenomenon Common Causes Connective tissue diseases Sclerodenna Systemic lupus erythematosus Rheumatoid arthritis Polymyositis and dermatomyositis Sjiigren’s syndrome Mixed connective tissue disease Drw P-Adrenergic receptor blocking agents Ergot preparations Methysergide Vinblastine and bleomycin Amphetamines Imipramine Bromocriptine Clonidine cyc10sp0lin Carpal tunnel syndrome Thoracic outlet syndrome Traumatic vasospastic disease (vibration-induced white finger) Hypothenar hammer syndrome Obstructive arterial disease Thromboangiitis obliterans Arteriosclerosis obliterans Arterial emboli Uncommon Causes Cryoproteinemias Cold agglutinins Polycythemia Vinyl chloride disease Hepatitis B antlgenemia Vasculitis Hypothyroidism Arteriovenous Bstula Renal disease Reflex sympathetic dystrophy Neoplasms
Diagnosis The diagnosis of Raynaud’s phenomenon can be made if the patient has a characteristic attack during a physician’s visit or if the episodic, well-demarcated digital color changes are clearly described. The differential diagnosis in patients who complain of cold hands and feet or from acrocyanosis is usually not difficult. The real problem is in distinguishing primary from secondary Raynaud’s phenomenon. This is very important for decisions regarding treatment and forecasting prognosis for the patient. The history should be exhaustive in searching for symptoms of connective tissue disease, drug usage, toxic exposure, trauma to the hands or fingers including vibration exposure, positional symptoms in the arms, and symptoms of circulatory insufficiency of the limbs (Table 1).2 The physical examination is normal in the primary disease. Signs of connective tissue diseases should be sought, absent pulses should be determined, and carpal tunnel and thoracic outlet maneuvers performed. Nailfold capillaries should be examined under a mi-
Reprinted
courtesy of the American
Henrt Association.’
croscope. Normal capillaries are present in the primary disease but do not rule out the secondary phenomenon. Abnormalities of enlarged, tortuous capillary loops, sparsity of capillaries, and avascular areas may be seen in patients with connective tissue diseases.“O In scleroderma, mixed connective tissue disease, and dermatomyositis, enlarged and deformed capillary loops surrounded by avascular areas are characteristic. In systemic lupus erythematosus, abnormal capillary loops and a prominent subpapillary venous plexus may be present. Bushy capillary formations are seen most frequently in mixed connective tissue disease. The presence of antinuclear antibodies in a patient with Raynaud’s phenomenon usually indicates an underlying disease. Anticentromere antibodies are more common in the CREST syndrome (calcinosis, Raynaud’s
Clinics in Dermatology 1994;12:283-289
phenomenon, esophageal dysfunction, sclerodactyly, telangiectasias), whereas anti-SCL-70 are sometimes present in systemic sclerosis. A homogeneous pattern of antinuclear antibodies with antibodies to desoxyribonucleic acid is often present in systemic lupus erythematosus. Other antibodies have been described, but their usefulness in differentiating primary from secondary Raynaud’s phenomenon has not been demonstrated. The erythrocyte sedimentation rate is normal in patients with the primary disease. It may or may not be elevated in the connective tissue diseases. One-third of patients with scleroderma may have a normal test. Esophageal motility is often abnormal in patients with Raynaud’s phenomenon, and patients may complain of heartburn, regurgitation, or dysphagia. More than twothirds of patients with scleroderma have abnormal peristalsis of the lower two-thirds of the esophagus and the esophageal sphincter pressure may be decreased. Similar abnormalities may occur in patients with lupus erythematosus and with mixed connective tissue disease. Although some investigators have found normal esophageal motility in primary Raynaud’s disease,” others have reported esophageal abnormalities.42 Measurement of digital systolic blood pressure during graded local cooling with &hernia of the linger has been used as a diagnostic test for Raynaud’s phenomenon. In this test, fingertip laser Doppler measurements of red blood cell flux or instruments that detect finger pulsations have been used. Patients lose their digital systolic pressure or red cell flux stops at a higher temperature than in normal subjects. One group reported they could grade the severity of the disease by using different finger and room temperatures with and without arterial occlusion to study the level of finger systolic pressure disappearance measured by a laser Doppler. 43 Other investigators using different temperatures report low sensitivity and specificity for this test and failure to differentiate mild from severe Raynaud’s phenomenon.” The test is difficult to perform and time-consuming; it is therefore not usually used in practice settings. It cannot distinguish primary from secondary Raynaud’s phenomenon. Currently the best criteria for the diagnosis of primary Raynaud’s phenomenon are the following: 1. Vasospastic attacks should be episodic with welldemarcated color changes precipitated by cold or emotional stimuli. 2. Bilateral involvement of the extremities should be present and only the digits involved. 3. Gangrene usually should be absent or limited to the skin of the fingertips or toe tips. 4. There should be no evidence of an underlying disease that could be responsible for vasospastic attacks.
THE DIAGNOSIS
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There should be a history of symptoms for 2 years, The sedimentation rate should be normal. Antinuclear antibodies should be absent. Nailfold capillaroscopy should be normal.
Using similar criteria, a retrospective study of 240 patients with Raynaud’s phenomenon was able to classify 89% of the patients into primary or secondary Raynaud’s phenomenon. I5 One study reported that measuring antinuclear antibodies by immunofluorescence and immunoblotting had a positive predictive value of 65 and 71% and a negative predictive value of 93 and 83%, respectively, for the patient developing a connective tissue disease.46 Immunoblotting was most reliable for predicting systemic sclerosis, the CREST syndrome, and mixed connective tissue disease.
Relationship of Raynaud’s Phenomenon to Scleroderma It has been reported that approximately 90% of patients with scleroderma have Raynaud’s phenomenon.” How many patients have episodic attacks of well-demarcated color changes of the digits as opposed to continuous decreased blood flow to the digits with cyanosis on cold exposure is unknown. We have seen many patients with both conditions, indicating they are different entities. Raynaud’s phenomenon may be the first manifestation of scleroderma and precede other symptoms and signs by many years. This has led to the postulate that most cases of “primary” Raynaud’s phenomenon will eventually develop scleroderma. However, the prevalence of Raynaud’s phenomenon in the general population in some areas of the world far exceeds that of scleroderma, making this postulate highly unlikely. In a referral medical center, many patients, perhaps 50%, will test positive for scleroderrna or other connective tissue diseases, but this is a skewed population of the more severe cases of vasospasm, and the patients often have other symptoms. It is often difficult to rule out the diagnosis of scleroderma in patients with Raynaud’s phenomenon despite using strict criteria for the diagnosis of the primary disease. The presence of only a cyanotic ischemic phase of the vasospastic attacks, digital ulcers or gangrene, onset in older age groups, abnormal nailfold capillaries, or the presence of antinuclear antibodies have all been claimed to predict scleroderma. However, these features may all be absent even though scleroderma develops eventually. Therefore, the physician can never be certain an underlying connective tissue disease is not present. This fact may not be important for the patient with Raynaud’s phenomenon who has no other symptoms or signs. Even in the presence of a positive test for antinuclear antibodies,
288 COFFMAN
other symptoms and signs may not appear for many years.9 In the absence of a definitive treatment for scleroderma, the importance of early diagnosis is unclear. The patient should be informed of the abnormal tests and what they mean for two reasons: first, they should watch for the other manifestations of scleroderma and, second, another physician may do the test and confront the patient with the results, leading to depression or anxiety. It is known that a long history of Raynaud’s phenomenon precedes the more benign form of scleroderma, CREST syndrome, whereas diffuse scleroderma usually develops within a year of the onset of vasospastic attacks. Patients with a long duration of Raynaud’s phenomenon and positive antinuclear antibodies, especially the anticentromere antibody, may be reassured by this knowledge.
Conclusions Raynaud’s phenomenon is characterized by episodic attacks of well-demarcated blanching or cyanosis of the digits on exposure to cold. It may be primary (idiopathic) or secondary due to a variety of underlying causes. The pathophysiology of the vasospastic attacks is not known but may involve many factors. Diagnostic tests are not definitive. The prognosis is good in the primary disease but guarded in secondary cases.
Acknowledgments The authors acknowledge the invaluable assistance of May Jo Graziano in the preparation of this manuscript.
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Clinics in Dermatology 1994;12:283-289 9. Gerbracht DD, Steen VD, Ziegler GL, et al. Evolution of primary Raynaud’s phenomenon (Raynaud’s disease) to connective tissue disease. Arthritis Rheum 1985;28:87-92. 10. Lewis T. The pathological changes in the arteries supplying the fingers in warm-handed people and in cases of socalled Raynaud’s disease. CIin Sci 1938;3:288-311. 11. Rodnan GP, Myerowitz RL, Justh GO. Morphological changes in the digital arteries of patients with progressive systemic sclerosis (scleroderma) and Raynaud’s phenomenon. Medicine 1980;59:393-408. 12. Jeune R, Thivolet J. Etude arteriographique de la main au tours de 52 phenomenes de Raynaud d’etiologie diverse. Nouve Presse Med 1978;7:2619-23. 13. Dabrich L, Bookstein JJ, Zweifler A, et al. Digital arteries in patients with sclerodenna. Arch Intern Med 1972;130:
708-14. 14. Lewis T. Experiments relating to the peripheral mechanism involved in spasmodic arrest of the circulation in the fingers, a variety of Raynaud’s disease. Heart 1929;15:7101. 15. Friedman RR, Mayes MD, Sabharwal SC. Induction of vasospastic attacks despite digital nerve block in Raynaud’s disease and phenomenon. Circulation 1989;80:859-62. 16. Jamieson GG, Ludbrook J, Wilson A. Cold hypersensitivity in Raynaud’s phenomenon. Circulation 1971;44:254-64. 17. Edward JM, Phinney ES, Taylor LM Jr, et al. ar-Adrenergic receptor levels in obstructive and spastic Raynaud’s syndrome. J Vast Surg 1987;5:38-45. 18. Coffman JD, Cohen RA. err-Adrenergic and 5-HT, receptor hypersensitivity in Raynaud’s phenomenon. J Vast Med Biol 1990;2:100-05. 19. Olsen N, Petring OU, Rossing N. Exaggerated postural vasoconstrictor reflex in Raynaud’s phenomenon. Br Med J 1987;264:1186-88. 20. Fagius J, Blumbert H. Sympathetic outflow to the hand in patients with Raynaud’s phenomenon. Cardiovasc Res 1985;19:249-53. 21. Ishida G, Nasu Y, Nakashima K, et al. Sympathetic nerve activity in the skin in relation to vibration-induced white finger, Stand J Work Environ Health 1992;18:124-27. 22. Miller D, Waters DD, Wamica W, et al. Is variant angina the coronary manifestation of a generalized vasospastic disorder. New EngI J Med 1981;304:763-66. 23. O’Keeffe ST, Tsapatsaris NP, Beetham WP Jr. Increased prevalence of migraine and chest pain in patients with primary Raynaud’s disease. Ann Intern Med 1992;116: 985-89. 24. Krumholz HM, Goldberger AL. Systemic arterial vasospastic syndrome: Familial occurrence with variant angina. Am J Med 1992;92:344-45. 25. Halpern A, Kuhn P, Shaftel HE, et al. Raynaud’s disease, Raynaud’s phenomenon, and serotonin. Angiology 1960; 11:151-67. 26. Seibold JR, Terregino CA. Selective antagonism of Sr-serotone@ receptors relieves but does not prevent cold-
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39.
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MD
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aynaud’s phenomenon is defined as the occurrence of episodic attacks of well-demarcated blanching or cyanosis of the digits on exposure to cold.‘** A red, reactive hyperemia phase may occur when the attack ends. Onset of symptoms in patients with the primary phenomenon usually occurs at between 15 and 45 years of age, although it may occur in much younger or older patients. Patients often complain that they always had cold hands and feet before the onset of classic vasospastic attacks. Most patients have involvement of the fingers and about 40% have attacks in the toes. Vasospastic attacks involving only the toes are uncommon. The nose, ears, face, and lips are affected in some patients, and may be more common in the primary disease. Many patients present with only one or two digits involved, but more digits experience attacks with each cold season. The thumbs are often spared. Numbness is usually present during the ischemic phases; a throbbing pain may occur in the reactive hyperemia phase. The primary phenomenon occurs most frequently in young women, the woman-to-man ratio being 4 : 1 in most series. The small prevalence dictates a search for a secondary cause in men. Few racial studies exist, but one report found an equal distribution among blacks and whites.3 Studies vary on the presence of color changes. In our experience, patients with the primary disease usually have the pallor phase with or without a red, reactive hyperemia phase. There is some indication that patients with only the cyanotic phase are more likely to have an
From the Peripheral Vascular Section, Evans Memorial Department of Clinical Research and Department of Medicine, Boston University Medical Center, Boston, Massachusetts. This work was supported by the National Heart, Lung, Blood Institute, grant HL26320. Address correspondence to Jay D. Cofj%an, MD, University Hospital, 88 East Newton Street, Room E411, Boston, MA 02118.
0 1994 by Elsevier Science Inc.
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underlying disease. 4 Cold exposure is overwhelmingly the most common cause of vasospastic attacks. We have rarely seen emotions as a precipitating factor, although other investigators have reported an 18 to 60% incidence.5*6 We have not encountered patients in whom tobacco smoking definitely induced attacks. Cold exposure plus pressure on the digits appears to be the most common factor; patients report attacks grasping a cold steer-‘ ing wheel on a cold morning, holding iced drinks, shopping for frozen foods in an air-conditioned supermarket, or carrying luggage. Vasospastic attacks are very difficult to induce in the doctor’s office in patients with the primary disease, although patients may present for the examination with an attack. Trophic changes of the digits have been described in 13% of women with primary Raynaud’s phenomenon,6 but in our experience they are uncommon. A few women develop ischemic lesions of the tips of the toes, confusing the diagnosis with chilblains. In the secondary phenomenon due to connective tissue diseases, ulcerations, scarring, fissuring, pitting, and chronic paronychia are very common. Patients with Raynaud’s phenomenon and sclerodactyly, ulcers, pits, or gangrene of the fingers should be strongly suspected of an underlying disease. In different studies the prevalence of Raynaud’s phenomenon has ranged from 4.6 to 30%. The most recent study reported a prevalence of 5.0% in a moderate climate but 16.8% in a cold climate.’ These studies did not differentiate between the prevalence of primary and secondary Raynaud’s phenomenon. Many patients have only one or two Raynaud’s attacks involving only one finger each cold season; these patients usually do not seek medical care.
Prognosis The prognosis in primary Raynaud’s phenomenon is very good. Even in connective tissue diseases such as sclero-
203
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COFFMAN
Clinics in Dermatology 1994;12:283-289
derma, symptoms or signs of systemic disease may not appear for many years. In most studies,QB more than a third of patients with primary Raynaud’s phenomenon report no change in symptoms and another third improve. About 16% of patients report increasingly severe attacks, and the phenomenon disappears in about 10%. Onset of the vasospastic attacks at a younger age and the absence of trophic changes predict a good prognosis. Patients, who have abnormal laboratory studies but only Raynaud’s phenomenon and would otherwise fit the primary category also have a good prognosis.9 It is therefore difficult to predict prognosis for patients with Raynaud’s phenomenon and positive antinuclear antibodies. If nailfold capillary abnormalities are also seen by microscopy, patients are more likely to develop evidence of a secondary etiology in a few years.
Pathology In mild cases of primary Raynaud’s disease, pathologic findings of the digital arteries are probably absent.‘O In more severe cases with trophic lesions of the digits, intima1 hyperplasia, narrowing or occlusion of the lumen, or thrombi are present in the digital arteries. In patients with scleroderma, severe intimal hyperplasia with collagen, thromboses, adventitial fibrosis, and telangiectasia of the vasa vasorum may be present.” Other secondary etiologies of Raynaud’s phenomenon may show similar abnormalities.
Arteriography Arteriograms have been described as normal in patients with primary Raynaud’s disease,12 although some patients show diseased or occluded arteries. In most patients with connective tissue disease or vasculitis, there is narrowing or obstruction of digital arteries. In one study of patients with scleroderma, the ulnar artery was narrowed or occluded in just over 50% of patients while the radial artery was involved in only 2 of 31 patients.13
Pathophysiology Most evidence exists for an abnormal sensitivity of the digital arteries to cold. Lewis showed that local cooling produced ischemic attacks in single fingers and in sympathetically denervated tingers.14 The latter was recently reconfirmed.15 Since attacks could be relieved by proximal but not distal warming of a finger and an attack could occur with proximal cooling of a finger with the tip kept warm, Lewis surmised that the digital arteries and not the arterioles became vasospastic. Other investigators have presented some evidence for arteriolar involvement.’ The
RM-ANOVA,
p=O.O48
100 0.125
0.25 Clonidine
0.5 (pglmin)
Figure 1. Percentage decreasesin total fingertip blood flow during intraarterial infusion of increasing dosesof the cyradrenoceptor agonist clonidine. Mean and standard errors are shown. Patients with Raynaud’s phenomenon had a significantly greater decreasein flow to clonidine than normal subjects. Reprinted courtesy of Blackwell Scientific Publications, Inc.r8
local fault theory is supported by the fact that reflex sympathetic vasoconstriction is enhanced in patients with Raynaud’s phenomenon by locally cooling the hand, but not in normal subjects. l6 It was postulated that cold temperatures sensitize the cY-adrenoceptors, which mediate vasoconstriction of vascular smooth muscle as has been shown to occur in in vitro experiments. Patients with primary Raynaud’s disease have increased binding capacity and affinity of a,-adrenoceptors of platelets.” Finally, patients with Raynaud’s phenomenon have an increased vasoconstrictor response in the digits to cy2-but not to cq-adrenoceptor agonists (Figures 1 and 2); however, they also have an increased sensitivity to 5-hydroxytryptamine (5-HT; Figure 3).‘* Evidence for overactivity of the sympathetic nervous system is not substantial. The most recent evidence is the demonstration of an exaggerated digital vasoconstriction with changes in posture in patients with primary Raynaud’s phenomenon and vibration-induced white finger with a normal local axon reflex.19 Several investigators have found decreased hand or finger blood flow in patients with the primary phenomenon in a cool environment compared to normal subjects. Normal vasodilatation in the patients during sympathetic inhibition does not support structural arterial disease and implicates the sympathetic nervous system control of blood vessel tone in the lower blood flow that occurs in a cool environment. Other investigators have been unable to demonstrate increased reflex sympathetic vasoconstriction in patients with Raynaud’s phenomenon, however, and microelec-
Clinics in Dermatology 1994;12:283-289
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THE DIAGNOSIS
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Figure 2. Percentagedecreasesin total fingertip blood flow during intraarterial infusions of increasing dosesof the cx,adrenoceptor agonist phenylephrine. Mean and standard errors are shown. Patients with Raynaud’s phenomenon and normal subjects showed similar decreasesin pow to phenylephrine. Reprinted courtesy of Blackwell Scientific Publications, Inc.“’
trode recordings of skin sympathetic nerve activity do not demonstrate an abnormality in patients with primary Raynaud’s phenomenon or vibration-induced white finger.20*2* If increased sensitivity of digital arteries in cold is present, then normal sympathetic nerve activity would aid in producing vasospastic attacks. A strong correlation of Raynaud’s phenomenon and migraine headaches in patients with variant angina or chest pains has been reported and confmned.22~23 A report of a family with vasospastic conditions in more than one circulatory system for three generations supports the correlation.24 Evidence for vasospasm in the pulmonary, heart, retinal, and renal circulation has been found in patients with Raynaud’s phenomenon. A generalized vascular abnormality may be present in some patients, but it is difficult to envision the defect since the neurogenie and humoral control of the various circulations are so different. Serotonin has also been implicated in the pathophysiology of Raynaud’s phenomenon since it was reported that methysergide, a serotonin inhibitor, reduced the intensity and duration of the response of patients to cold exposure of the hands. 25 Acute administration of ketanserin, a 5-HT, receptor antagonist, relieves vasospastic attacks but does not prevent them when given before stimuli that induce attacks.26 Some investigators, but not others, have found increased plasma free and intraplatelet levels of serotonin in patients with Raynaud’s phenomenon.27,2* However, intraarterial 5-HT does not produce blanching of the fingers but a reddish blue
COFFMAN PHENOMENON
OF RAYNAUD’S
285
discoloration,‘* and in chronic studies ketanserin has produced variable therapeutic results in patients with Raynaud’s phenomenon. Two investigators have found lower brachial artery and digital blood pressures in patients with primary Raynaud’s phenomenon. 29*30This would predispose to vasospasm as transmural arterial distending forces are decreased and less external pressure or sympathetic stimulation is required to close the blood vessels and stop blood flow. Many other factors have been investigated in the pathogenesis of digital vasospasm. Platelets and their products could play a secondary role by aggravating vasospasm or occluding small vessels. A thromboxane receptor antagonist and a thromboxane synthase inhibitor did not change the response of finger pulsations to a cold challenge in patients with Raynaud’s phenomenon from that seen in normal subjects.31 Dazoxiben, an inhibitor of thromboxane synthase,32 indomethacin,33 and aspirin plus dipyridamole% have not proved therapeutically useful in patients. Plasma and blood viscosity have been measured, and reports are variable in patients with primary Raynaud’s disease, although viscosity may be elevated in some patients with Raynaud’s phenomenon secondary to connective tissue disease.35 Endothelin-1 levels have been found to be elevated in the plasma of patients with Raynaud’s phenomenon and to rise with the provocation of a cold stimulus.36 The levels were higher in diffuse compared to limited sclero-
Figure 3. Percentagedecreasesin total fingertip blood flow during intraarterial infusions of increasing dosesof 5hydroxytryptamine. Mean and standard errors are shown. Patients with Raynaud’s phenomenon had a significantly greater decreasein flow to 5-hydroxytryptamine than normal subjects. Reprinted courtesy of Blackwell Scientific Publications, Inc.18
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Clinics in Dermatology 2994;12:283-289
COPPMAN
derma and were inversely correlated with the pulmonary carbon monoxide diffusing capacity.37 They were considered useful for predicting prognosis and perhaps for reflecting endothelial damage. Other plasma markers of endothelial damage, von Willebrand factor and tissue plasminogen activator, have been reported as elevated in Raynaud’s phenomenon. One group found them raised only in systemic sclerosis and proposed they could be used to rule out primary Raynaud’s phenomenon.28 Evidence for increased polymorphonuclear cell activity and free radical activity was reported in primary and secondary Raynaud’s phenomenon, but the levels did not correlate with the severity of the Raynaud’s phenomenon.38 The significance of these findings is unknown. Hypersensitivity in skin blood flow of the hands to calcitonin gene-related peptide has been reported in patients with Raynaud’s phenomenon, which was not observed with other endogenous vasodilators.39 The investigators postulated a relative deficiency of the peptide, but further study is necessary. In summary, the pathophysiology of vasospastic attacks is still unknown but may be due to a combination of factors. In secondary Raynaud’s phenomenon, digital artery stenosis or obstruction with low distal blood flow and blood pressure, hyperviscosity, thickened vessel walls, and endothelial and platelet vasoconstrictor products may be important. In primary Raynaud’s phenomenon, local hypersensitivity of the digital arteries to cold and low blood pressure are probably most important, but abnormalities in the a,-adrenoceptors and 5-HT, receptors are also present.
Table 1. SecondaryCausesof Raynaud’s Phenomenon Common Causes Connective tissue diseases Sclerodenna Systemic lupus erythematosus Rheumatoid arthritis Polymyositis and dermatomyositis Sjiigren’s syndrome Mixed connective tissue disease Drw P-Adrenergic receptor blocking agents Ergot preparations Methysergide Vinblastine and bleomycin Amphetamines Imipramine Bromocriptine Clonidine cyc10sp0lin Carpal tunnel syndrome Thoracic outlet syndrome Traumatic vasospastic disease (vibration-induced white finger) Hypothenar hammer syndrome Obstructive arterial disease Thromboangiitis obliterans Arteriosclerosis obliterans Arterial emboli Uncommon Causes Cryoproteinemias Cold agglutinins Polycythemia Vinyl chloride disease Hepatitis B antlgenemia Vasculitis Hypothyroidism Arteriovenous Bstula Renal disease Reflex sympathetic dystrophy Neoplasms
Diagnosis The diagnosis of Raynaud’s phenomenon can be made if the patient has a characteristic attack during a physician’s visit or if the episodic, well-demarcated digital color changes are clearly described. The differential diagnosis in patients who complain of cold hands and feet or from acrocyanosis is usually not difficult. The real problem is in distinguishing primary from secondary Raynaud’s phenomenon. This is very important for decisions regarding treatment and forecasting prognosis for the patient. The history should be exhaustive in searching for symptoms of connective tissue disease, drug usage, toxic exposure, trauma to the hands or fingers including vibration exposure, positional symptoms in the arms, and symptoms of circulatory insufficiency of the limbs (Table 1).2 The physical examination is normal in the primary disease. Signs of connective tissue diseases should be sought, absent pulses should be determined, and carpal tunnel and thoracic outlet maneuvers performed. Nailfold capillaries should be examined under a mi-
Reprinted
courtesy of the American
Henrt Association.’
croscope. Normal capillaries are present in the primary disease but do not rule out the secondary phenomenon. Abnormalities of enlarged, tortuous capillary loops, sparsity of capillaries, and avascular areas may be seen in patients with connective tissue diseases.“O In scleroderma, mixed connective tissue disease, and dermatomyositis, enlarged and deformed capillary loops surrounded by avascular areas are characteristic. In systemic lupus erythematosus, abnormal capillary loops and a prominent subpapillary venous plexus may be present. Bushy capillary formations are seen most frequently in mixed connective tissue disease. The presence of antinuclear antibodies in a patient with Raynaud’s phenomenon usually indicates an underlying disease. Anticentromere antibodies are more common in the CREST syndrome (calcinosis, Raynaud’s
Clinics in Dermatology 1994;12:283-289
phenomenon, esophageal dysfunction, sclerodactyly, telangiectasias), whereas anti-SCL-70 are sometimes present in systemic sclerosis. A homogeneous pattern of antinuclear antibodies with antibodies to desoxyribonucleic acid is often present in systemic lupus erythematosus. Other antibodies have been described, but their usefulness in differentiating primary from secondary Raynaud’s phenomenon has not been demonstrated. The erythrocyte sedimentation rate is normal in patients with the primary disease. It may or may not be elevated in the connective tissue diseases. One-third of patients with scleroderma may have a normal test. Esophageal motility is often abnormal in patients with Raynaud’s phenomenon, and patients may complain of heartburn, regurgitation, or dysphagia. More than twothirds of patients with scleroderma have abnormal peristalsis of the lower two-thirds of the esophagus and the esophageal sphincter pressure may be decreased. Similar abnormalities may occur in patients with lupus erythematosus and with mixed connective tissue disease. Although some investigators have found normal esophageal motility in primary Raynaud’s disease,” others have reported esophageal abnormalities.42 Measurement of digital systolic blood pressure during graded local cooling with &hernia of the linger has been used as a diagnostic test for Raynaud’s phenomenon. In this test, fingertip laser Doppler measurements of red blood cell flux or instruments that detect finger pulsations have been used. Patients lose their digital systolic pressure or red cell flux stops at a higher temperature than in normal subjects. One group reported they could grade the severity of the disease by using different finger and room temperatures with and without arterial occlusion to study the level of finger systolic pressure disappearance measured by a laser Doppler. 43 Other investigators using different temperatures report low sensitivity and specificity for this test and failure to differentiate mild from severe Raynaud’s phenomenon.” The test is difficult to perform and time-consuming; it is therefore not usually used in practice settings. It cannot distinguish primary from secondary Raynaud’s phenomenon. Currently the best criteria for the diagnosis of primary Raynaud’s phenomenon are the following: 1. Vasospastic attacks should be episodic with welldemarcated color changes precipitated by cold or emotional stimuli. 2. Bilateral involvement of the extremities should be present and only the digits involved. 3. Gangrene usually should be absent or limited to the skin of the fingertips or toe tips. 4. There should be no evidence of an underlying disease that could be responsible for vasospastic attacks.
THE DIAGNOSIS
5. 6. 7. 8.
OF RAYNAUD’S
COFFMAN PHENOMENON
287
There should be a history of symptoms for 2 years, The sedimentation rate should be normal. Antinuclear antibodies should be absent. Nailfold capillaroscopy should be normal.
Using similar criteria, a retrospective study of 240 patients with Raynaud’s phenomenon was able to classify 89% of the patients into primary or secondary Raynaud’s phenomenon. I5 One study reported that measuring antinuclear antibodies by immunofluorescence and immunoblotting had a positive predictive value of 65 and 71% and a negative predictive value of 93 and 83%, respectively, for the patient developing a connective tissue disease.46 Immunoblotting was most reliable for predicting systemic sclerosis, the CREST syndrome, and mixed connective tissue disease.
Relationship of Raynaud’s Phenomenon to Scleroderma It has been reported that approximately 90% of patients with scleroderma have Raynaud’s phenomenon.” How many patients have episodic attacks of well-demarcated color changes of the digits as opposed to continuous decreased blood flow to the digits with cyanosis on cold exposure is unknown. We have seen many patients with both conditions, indicating they are different entities. Raynaud’s phenomenon may be the first manifestation of scleroderma and precede other symptoms and signs by many years. This has led to the postulate that most cases of “primary” Raynaud’s phenomenon will eventually develop scleroderma. However, the prevalence of Raynaud’s phenomenon in the general population in some areas of the world far exceeds that of scleroderma, making this postulate highly unlikely. In a referral medical center, many patients, perhaps 50%, will test positive for scleroderrna or other connective tissue diseases, but this is a skewed population of the more severe cases of vasospasm, and the patients often have other symptoms. It is often difficult to rule out the diagnosis of scleroderma in patients with Raynaud’s phenomenon despite using strict criteria for the diagnosis of the primary disease. The presence of only a cyanotic ischemic phase of the vasospastic attacks, digital ulcers or gangrene, onset in older age groups, abnormal nailfold capillaries, or the presence of antinuclear antibodies have all been claimed to predict scleroderma. However, these features may all be absent even though scleroderma develops eventually. Therefore, the physician can never be certain an underlying connective tissue disease is not present. This fact may not be important for the patient with Raynaud’s phenomenon who has no other symptoms or signs. Even in the presence of a positive test for antinuclear antibodies,
288 COFFMAN
other symptoms and signs may not appear for many years.9 In the absence of a definitive treatment for scleroderma, the importance of early diagnosis is unclear. The patient should be informed of the abnormal tests and what they mean for two reasons: first, they should watch for the other manifestations of scleroderma and, second, another physician may do the test and confront the patient with the results, leading to depression or anxiety. It is known that a long history of Raynaud’s phenomenon precedes the more benign form of scleroderma, CREST syndrome, whereas diffuse scleroderma usually develops within a year of the onset of vasospastic attacks. Patients with a long duration of Raynaud’s phenomenon and positive antinuclear antibodies, especially the anticentromere antibody, may be reassured by this knowledge.
Conclusions Raynaud’s phenomenon is characterized by episodic attacks of well-demarcated blanching or cyanosis of the digits on exposure to cold. It may be primary (idiopathic) or secondary due to a variety of underlying causes. The pathophysiology of the vasospastic attacks is not known but may involve many factors. Diagnostic tests are not definitive. The prognosis is good in the primary disease but guarded in secondary cases.
Acknowledgments The authors acknowledge the invaluable assistance of May Jo Graziano in the preparation of this manuscript.
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THE DIAGNOSIS
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
OF RAYNAUD’S
COFFMAN PHENOMENON
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