• Save
Acs0624 Raynaud Phenomenon
Upcoming SlideShare
Loading in...5
×

Like this? Share it with your network

Share
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
    Be the first to like this
No Downloads

Views

Total Views
1,270
On Slideshare
1,270
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
0
Comments
0
Likes
0

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide

Transcript

  • 1. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 24 RAYNAUD PHENOMENON — 1 24 RAYNAUD PHENOMENON Tina R. Desai, M.D., F.A.C.S., and Ryan Headley, M.D. Raynaud phenomenon is an episodic, exaggerated vascular Pathophysiology of Raynaud Phenomenon], but an attack may response to cold or emotional stimuli, typically involving the fin- also be elicited by generalized cooling of the entire body. In addi- gers.The classic triphasic color change, first described by Maurice tion, attacks may be precipitated by any stimulation of the sympa- Raynaud in 1862, consists of initial pallor (secondary to vaso- thetic nervous system, especially at times of emotional stress. spasm), followed first by cyanosis (from deoxygenation of the sta- As a rule, Raynaud phenomenon is more likely to affect the tic blood) and then by rubor (as blood flow to the digits is restored hands than the feet. It is characterized by the sudden occurrence and reactive hyperemia ensues).1 This classic manifestation of of cold digits in association with sharply demarcated pale skin— Raynaud phenomenon occurs in as many as two thirds of affect- the so-called ischemic phase. Eventually, the skin may become ed patients; however, less common variants of the phenomenon cyanotic. Subsequently, rapid restoration of blood flow to the dig- (e.g., pallor followed by cyanosis alone and pallor followed by its results in reactive hyperemia—the reperfusion phase. Attacks rubor alone) also exist. typically start in a single digit and spread symmetrically to other Raynaud phenomenon occurs throughout the world. Overall, it digits, eventually involving both hands. Other sites may be involved tends to be more common in colder climates. In warmer areas of as well—notably, the ears, the nose, the nipples, the face, and the the United States and Spain, the prevalence ranges from 3% to knees. Ischemic attacks may be accompanied by mottling of the 5%, whereas in cooler areas, the prevalence ranges from 15% to 20%.2-4 In a study of the African-American population, the preva- lence was 3%.5 Table 1 Conditions Associated with Raynaud Phenomenon20 Classification Systemic sclerosis syndrome (scleroderma) Raynaud phenomenon is generally classified as either primary or Systemic lupus erythematosus Dermatomyositis or polymyositis secondary. Primary Raynaud phenomenon occurs as an isolated Rheumatoid arthritis finding in an otherwise healthy individual; secondary Raynaud Rheumatologic diseases Takayasu arteritis phenomenon is caused by an associated disease (in most cases, an Giant cell arteritis autoimmune disease) or by identifiable environmental or chemical Thromboangiitis obliterans exposure [see Table 1].6 The two types are distinguished from each Primary biliary cirrhosis other on the basis of clinical criteria, and the distinction has signif- Vibration (hand/arm vibration syndrome) icant prognostic implications. Mechanical injury Frostbite With primary Raynaud phenomenon, the typical age of onset is 15 to 30 years, symptoms are generally symmetrical and less severe, Recurrent trauma or injury Crutch pressure to large vessels Thoracic outlet syndrome patients are more likely to be female, and multiple family members may be affected.7 With secondary Raynaud phenomenon, the typ- Arterial diseases Brachiocephalic atherosclerosis ical age of onset is greater, symptoms are usually more severe, and Migraine or vascular headache a systemic inflammatory disorder is commonly involved. In fact, Vasospastic disorders Prinzmetal angina Raynaud phenomenon is a prominent component of many autoimmune disorders, occurring in 90% of patients with sclero- Carcinoid syndrome derma, 10% to 45% of patients with systemic lupus erythematosus Endocrine disorders Pheochromocytoma (SLE), one third of patients with Sjögren syndrome, 20% of pa- Hypothyroidism tients with dermatomyositis or polymyositis, and 10% to 20% of Ovarian cancer Malignant diseases patients with rheumatoid arthritis.8 In 0% to 13% of patients who Angiocentric lymphoma present with primary Raynaud phenomenon, an identifiable con- Cryoglobulins nective tissue disorder develops within a few years after presenta- Cold agglutinins tion.9,10 The best predictors of transition to such a disorder are (1) Abnormal blood elements Paraproteinemia serologic findings that are positive for autoantibody and (2) sugges- Polycythemia tive physical findings (e.g., abnormal nailfold capillary patterns, Parvovirus B19 cutaneous telangectasias, puffy fingers, and sclerodactyly).6,10 Infections Helicobacter pylori Bleomycin, vinblastine Clinical Evaluation and Investigative Studies Polyvinyl chloride Chemicals or drugs Beta blockers CHARACTERISTIC FINDINGS Ergots (e.g., methysergide) Interferon alfa, beta Exacerbation of Raynaud phenomenon typically occurs after Tegafur direct exposure of an extremity to cold temperatures [see Sidebar
  • 2. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 24 RAYNAUD PHENOMENON — 2 skin on the arms and legs. During the ischemic phase, patients may complain of paresthesias and clumsiness in the involved extremities. In the most severe cases of secondary Raynaud phe- Pathophysiology of Raynaud Phenomenon nomenon, critical ischemia may cause painful digital ulceration. Raynaud phenomenon should be differentiated from simple Blood flow to the skin is regulated by a complex interaction between the endothelium, vascular smooth muscle, circulating hormones, and “cold hands” (a more common and benign condition). In patients neural plexus. Patients with Raynaud phenomenon demonstrate an with Raynaud phenomenon, cold hands occur in conjunction exaggerated vasomotor response to otherwise benign stimuli, no- with clearly distinguished skin-color changes. Moreover, recovery tably cold exposure. Normally, on exposure to cold, blood flow to the takes longer than it does in patients who merely have cold hands. skin is reduced in an effort to preserve core temperature. This natural The guidelines for diagnosing Raynaud phenomenon are based response is mediated primarily by the sympathetic nervous system on a history of color change on exposure to cold or other stimuli. via the neurotransmitter norepinephrine, which causes contraction of vascular smooth muscle in the cutaneous arterial beds. This cold- A history of repeated episodes of biphasic skin-color change on induced vasoconstriction of cutaneous vascular smooth muscle exposure to cold is indicative of Raynaud phenomenon. A histo- appears to be mediated specifically by the alpha2 receptor.40 ry of uniphasic skin-color change with paresthesias on exposure It has been suggested that the cold-induced vasoconstriction to cold is suggestive. In the absence of any skin-color change, seen in primary Raynaud phenomenon is the result of exaggerated Raynaud phenomenon is ruled out.11 Generally, additional diag- activity of the alpha2 receptors. This suggestion was supported by nostic tests are unnecessary; however, both evaluation of digital the results of experiments that blocked the cold-induced vasocon- pressure response to cooling and laser Doppler assessment of skin striction in primary Raynaud phenomenon by delivering alpha2 re- ceptor antagonists locally.41 The mechanism of this Raynaud-specif- perfusion pressure have been employed in this setting. There is ic hyperactive response has not been fully elucidated, though there is evidence to suggest that laser Doppler assessment of skin perfu- evidence to indicate that the response may, in part, be attributable to sion pressure is capable of distinguishing between normal control increased activity in the protein tyrosine kinase signal transduction subjects, persons with primary Raynaud phenomenon, and per- pathway.42 Endothelial derangements may also contribute to the sons with secondary Raynaud phenomenon.12-14 pathogenesis of primary Raynaud phenomenon through increased Raynaud phenomenon should also be differentiated from carpal plasma concentrations of endothelin and decreased levels of nitric oxide.43,44 tunnel syndrome and other neuropathies, which may cause cold In secondary Raynaud phenomenon, it is generally accepted sensitivity but do not induce the skin-color changes characteristic that vascular damage from the underlying disease (especially in the of Raynaud phenomenon. Patients who have asymmetrical, per- case of scleroderma) is responsible for the disruption of normal va- sistent, or positional symptoms should undergo a full evaluation somotor homeostasis. Activated or damaged endothelial cells exac- for possible large vessel occlusive disease, embolism, or thoracic out- erbate vasospasm and further damage perfusion by mediating the let compression, any of which might lead to hand-color changes. proliferation and contraction of smooth muscle cells; enhancement of procoagulant activity and reduction of fibrinolysis promote the for- Raynaud phenomenon may also be a reflection of a more general- mation of intravascular microthrombi, and the release of chemotactic ized vasospastic disorder (e.g., migraine headache or Prinzmetal and adhesion factors activates local inflammatory processes.20 angina).15,16 HISTORY AND PHYSICAL EXAMINATION Once a diagnosis of Raynaud phenomenon has been estab- lished—or, at least, strongly suspected—a thorough history and “hairpin” capillary loops. However, the pattern seen in patients physical examination can help distinguish between primary and with Raynaud phenomenon secondary to an underlying cause secondary forms of the condition.The presence of specific symp- (e.g., scleroderma, dermatomyositis, or undifferentiated connec- toms of connective tissue disease (particularly arthralgia, myalgia, tive tissue disease) often includes enlarged capillary loops , with and dry mucous membranes), extended exposure to vibrating evidence of angiogenesis, architectural derangements, and areas machinery, or antecedent use of certain medications is suggestive of decreased vascularity.19 Serologic markers provide additional of secondary Raynaud phenomenon. The earliest specific diag- support for the diagnosis of secondary Raynaud phenomenon: nostic criteria for primary Raynaud phenomenon were described the anti-Smith antibody is specific for SLE, and the anti-topoiso- by Allen and Brown in 1932.17 More current criteria take advan- merase and anti–RNA polymerase antibodies are highly specific tage of modern diagnostic tools and serologic testing. Primary for scleroderma-spectrum disorders. Among experts, there is lit- Raynaud phenomenon is suspected when attacks are symmetrical tle doubt that patients with Raynaud phenomenon who test pos- and episodic, when the history and the physical examination itive for autoantibodies are at higher risk for the eventual devel- reveal no evidence of tissue gangrene or a possible underlying opment of a connective tissue disease.20 causative condition, when antinuclear antibody titers and eryth- rocyte sedimentation rates are normal, and when nailfold capil- Management lary examination yields unremarkable results.18 Management of Raynaud phenomenon generally consists of TESTING FOR SUSPECTED SECONDARY RAYNAUD lifestyle modification and medical treatment, with surgical PHENOMENON options limited to severe or refractory cases. Nonpharmacologic If secondary Raynaud phenomenon is suspected on the basis treatment generally suffices for primary Raynaud phenomenon, of the history and the physical examination, more specific testing but it is often inadequate for management of secondary Raynaud is appropriate. A particularly helpful test is nailfold capillaroscopy. phenomenon, which is usually more severe. Mild forms of Raynaud The bases of the fingernails of the fourth and fifth digits are phenomenon are managed with lifestyle modification, including examined with a handheld ophthalmoscope set to 10 to 40 maintenance of total body warmth (as well as warmth of hands diopters after a drop of immersion oil is placed on each nailfold. and fingers), avoidance of cold and emotional stress, cessation of The normal vascular pattern, seen in healthy control subjects and smoking, discontinuance of the use of vibrating tools, and avoid- patients with primary Raynaud phenomenon, consists of delicate ance of vasoconstricting substances (e.g., caffeine, cocaine, beta
  • 3. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 24 RAYNAUD PHENOMENON — 3 blockers, and decongestants). Biofeedback training has also been plasminogen activator and with low-molecular-weight heparin; shown to be of some utility in reducing symptoms of Raynaud however, these agents were found to carry significant bleeding phenomenon, though several studies have questioned its value, risks and thus have not been widely accepted for treatment of especially in comparison to that of medical management.21,22 Raynaud phenomenon.28,33 Calcium channel blockers are the vasodilators most commonly For refractory, severe Raynaud phenomenon, surgical manage- used to treat Raynaud phenomenon. Nifedipine, diltiazem, felodi- ment, most often involving some form of sympathectomy, is rec- pine, and amlodipine are all effective, though they tend to be more ommended. Both central and distal sympathectomy have been effective in patients with the primary form of the condition than in employed for this purpose; initial success rates are good, but there those with the secondary form. One meta-analysis found short-act- is a high incidence of recurrent symptoms. ing nifedipine, 10 to 20 mg three or four times a day, to be moder- For many years, open cervicothoracic sympathectomy was ately effective at reducing symptoms in patients with Raynaud phe- commonly performed for symptomatic treatment of Raynaud nomenon and scleroderma.23 A large clinical study found sustained- phenomenon (which was thought to result from an overactive release nifedipine to be useful as well.22 Despite some variability in sympathetic response), but the results were mixed.34,35 The open the published reports, calcium channel blockers remain the first form of the procedure was associated with substantial morbidity choice for medical treatment after failure of nonmedical treatment. and frequent recurrence of symptoms, and as a result, it has now Other vasodilators have also been shown to be effective. In one been largely abandoned. Some surgeons have advocated perform- study, losartan, an angiotensin receptor blocker, proved to be more ing thoracoscopic sympathectomy[see 4:10 Video-Assisted Thoracic effective than nifedipine in reducing the frequency and severity of Surgery] to treat severe Raynaud phenomenon that is refractory episodes of both primary and secondary Raynaud phenomenon.24 to medical management, but the benefits and durability of this Topical nitrates provide a degree of benefit as well.20 Because sero- approach have not been established. In this procedure, the ipsilat- tonin may be partially involved in the pathogenesis of Raynaud eral pleural space is approached thoracoscopically, with the patient phenomenon, a number of studies have focused on the use of sero- under general anesthesia. The sympathetic chain is identified as it tonin reuptake inhibitors and serotonin receptor antagonists.25 In a courses down the ribs near the costovertebral junction, and the small open-label trial that included both patients with primary second through fourth thoracic sympathetic ganglia lying be- Raynaud phenomenon and patients with the secondary form of the tween the ribs are cauterized. Bilateral sympathectomy may be condition, fluoxetine was more effective than nifedipine in reduc- performed in a sequential fashion during the same operation. Ap- ing the severity and frequency of attacks over a 6-week period; the proximately 90% of patients experience immediate relief of symp- effect was most pronounced in female patients and in patients with toms after thoracoscopic sympathectomy, but the majority also primary Raynaud phenomenon.26 In another study, ketanserin, a experience recurrence of symptoms.36,37 Proponents of this proce- selective serotonin receptor antagonist that is no longer available in dure argue that these recurrent symptoms are not as severe as the the United States, significantly reduced the number of attacks over original preoperative symptoms and that patients who undergo the a 3-month period.27 Intravenous prostaglandins have also been operation as treatment of ulceration exhibit continued long-term used with success. In one report, iloprost, given as a 5-day infusion, healing. Nonetheless, in our view, it is advisable to reserve thora- was beneficial in severe cases of Raynaud phenomenon, mitigating coscopic sympathectomy for selected cases of Raynaud phenome- symptoms and enhancing the healing of ischemic ulcers28; unfor- non that are refractory to medical management. tunately, iloprost is also unavailable in the United States. Of the I.V. At present, localized digital sympathectomy using microsurgical prostaglandins currently available in the United States, alprostadil techniques is generally preferred to proximal sympathectomy for (prostaglandin E1 [PGE1]) and epoprostenol (PGI2) have achieved, treatment of nonhealing ulcerations in patients with severe, refrac- at best, mixed results,29,30 whereas prazosin has been employed tory Raynaud phenomenon.38 This procedure involves stripping the with some success against primary and secondary Raynaud phe- adventitia, along with digital sympathetic fibers, from the involved nomenon (though its effectiveness seems to be limited in patients digital arteries, with the patient under either regional or general with scleroderma).31 anesthesia. In one small study of seven patients, it was suggested Some authors have advocated low-dose aspirin therapy for that this digital sympathectomy could be extended to include the Raynaud phenomenon, but to date, trials of antiplatelet therapy palmar arch, the radial and ulnar arteries proximal to the wrist, have yielded disappointing results.28 In a placebo-controlled, ran- and the nerve of Henle, which is responsible for the sympathetic domized trial published in 2003, cilostazol increased blood vessel innervation of the distal ulnar artery.39 The investigators found diameter in patients with primary and secondary Raynaud phe- that by 1.5 years after adventitial stripping of the proximal radial nomenon but did not bring about any improvement in symp- and ulnar arteries with resection of the nerve of Henle, all ischemic toms.32 In smaller studies, some success was achieved with tissue ulcerations had resolved. References 1. Bowling JC, Dowd PM: Raynaud’s disease. 4. Maricq HR, Carpentier PH, Weinrich MC, et al: tion of Raynaud’s phenomenon: a longterm Lancet 361:2078, 2003 Geographic variation in the prevalence of prospective study. J Rheumatol 22:2226, 1995 2. Riera G,Vilardell M,Vaque J, et al: Prevalence of Raynaud’s phenomenon: a 5 region comparison. 7. Freedman RR, Mayes MD: Familial aggregation Raynaud’s phenomenon in a healthy Spanish J Rheumatol 24:879, 1997 of primary Raynaud’s disease. Arthritis Rheum population. J Rheumatol 20:66, 1993 5. Gelber AC, Wigley FM, Stallings RY, et al: 39:1189, 1996 3. Maricq HR, Carpentier PH, Weinrich MC, et al: Symptoms of Raynaud’s phenomenon in an 8. Khan F: Vascular abnormalities in Raynaud’s Geographic variation in the prevalence of inner-city African-American community: preva- phenomenon. Scott Med J 44:4, 1999 Raynaud’s phenomenon: Charleston, SC, USA, lence and self-reported cardiovascular comor- 9. De Angelis R, Del Medico P, Blasetti P, et al: vs Tarentaise, Savoie, France. J Rheumatol bidity. J Clin Epidemiol 52:441, 1999 Raynaud’s phenomenon: clinical spectrum of 20:70, 1993 6. Luggen M, Belhorn L, Evans T, et al: The evolu- 118 patients. Clin Rheumatol 22:279, 2003
  • 4. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 24 RAYNAUD PHENOMENON — 4 10. Spencer-Green G: Outcomes in primary Raynaud parison of sustained-release nifedipine and tem- diseases: new understanding and the potential phenomenon: a meta-analysis of the frequency, perature biofeedback for treatment of primary for new directions. J Rheumatol 16:1184, 1989 rates, and predictors of transition to secondary Raynaud’s phenomenon: results from a random- 34. de Trafford JC, Lafferty K, Potter CE, et al: An diseases. Arch Intern Med 158:595, 1998 ized clinical trial with one-year follow-up. Arch epidemiological survey of Raynaud’s phenome- 11. Brennan P, Silman A, Black C, et al: Validity and Intern Med 160:1101, 2000 non. Eur J Vasc Surg 2:167, 1988 reliability of three methods used in the diagnosis 23. Thompson AE, Shea B, Welch V, et al: Calcium- 35. van de Wal HJ, Skotnicki SH, Wijn PF, et al: of Raynaud’s phenomenon.The UK Scleroderma channel blockers for Raynaud’s phenomenon in Thoracic sympathectomy as a therapy for upper Study Group. Br J Rheumatol 32:357, 1993 systemic sclerosis. Arthritis Rheum 44:1841, extremity ischemia: a long-term follow-up study. 12. Maricq HR, Weinrich MC, Valter I, et al: Digital 2001 Thorac Cardiovasc Surg 33:181, 1985 vascular responses to cooling in subjects with 24. Dziadzio M, Denton CP, Smith R, et al: Losar- cold sensitivity, primary Raynaud’s phenome- tan therapy for Raynaud’s phenomenon and scle- 36. Matsumoto Y, Ueyama T, Endo M, et al: En- non, or scleroderma spectrum disorders. J Rheu- roderma: clinical and biochemical findings in a doscopic thoracic sympathicotomy for Raynaud’s matol 23:2068, 1996 fifteen-week, randomized, parallel-group, con- phenomenon. J Vasc Surg 36:57, 2002 13. Jennings JR, Maricq HR, Canner J, et al: A ther- trolled trial. Arthritis Rheum 42:2646, 1999 37. Adams DCR, Wood SJ, Tulloh BR, et al: Endo- mal vascular test for distinguishing between pa- 25. Seibold JR: Serotonin and Raynaud’s phenome- scopic transthoracic sympathectomy: experience tients with Raynaud’s phenomenon and healthy non. J Cardiovasc Pharmacol 7(suppl 7):S95, in the southwest of England. Eur J Vasc Surg controls. Raynaud’s Treatment Study Investiga- 1985 6:558, 1992 tors. Health Psychol 18:421, 1999 38. O’Brien BM, Kumar PA, Mellow CG, et al: 26. Coleiro B, Marshall SE, Denton CP, et al: 14. Kanetaka T, Komiyama T, Onozuka A, et al: Treatment of Raynaud’s phenomenon with the Radical microarteriolysis in the treatment of Laser Doppler skin perfusion pressure in the selective serotonin reuptake inhibitor fluoxetine. vasospastic disorders of the hand, especially scle- assessment of Raynaud’s phenomenon. Eur J Rheumatology (Oxford) 40:1038, 2001 roderma. J Hand Surg [Br] 17:447, 1992 Vasc Endovasc Surg 27:414, 2004 39. Balogh B, Mayer W, Vesely M, et al: Adventitial 27. Coffman JD, Clement DL, Creager MA, et al: 15. Miller D, Waters DD, Warnica W, et al: Is variant International study of ketanserin in Raynaud’s stripping of the radial and ulnar arteries in angina the coronary manifestation of a general- phenomenon. Am J Med 87:264, 1989 Raynaud’s disease. J Hand Surg [Am] 27:1073, ized vasospastic disorder? N Engl J Med 2002 304:763, 1981 28. Hummers LK, Wigley FM: Management of Raynaud’s phenomenon and digital ischemic 40. Ekenvall L, Lindblad LE, Norbeck O, et al: 16. O’Keeffe ST, Tsapatsaris NP, Beetham WP Jr: lesions in scleroderma. Rheum Dis Clin North alpha-Adrenoceptors and cold-induced vasocon- Increased prevalence of migraine and chest pain Am 29:293, 2003 striction in human finger skin. Am J Physiol in patients with primary Raynaud disease. Ann 255:H1000, 1988 Intern Med 116:985, 1992 29. Mohrland JS, Porter JM, Smith EA, et al: A mul- ticlinic, placebo-controlled, double-blind study 41. Freedman RR, Baer RP, Mayes MD: Blockade of 17. Allen E, Brown G: Raynaud’s disease: a critical of prostaglandin E1 in Raynaud’s syndrome. Ann vasospastic attacks by α2-adrenergic but not α1- review of the minimal requisites for diagnosis. Rheum Dis 44:754, 1985 adrenergic antagonists in idiopathic Raynaud’s Am J Med Sci 183:187, 1932 disease. Circulation 92:1448, 1995 30. Badesch DB, Tapson VF, McGoon MD, et al: 18. LeRoy EC, Medsger TA Jr: Raynaud’s phenom- Continuous intravenous epoprostenol for pul- 42. Furspan PB, Chatterjee S, Freedman RR: enon: a proposal for classification. Clin Exp monary hypertension due to the scleroderma Increased tyrosine phosphorylation mediates the Rheumatol 10:485, 1992 spectrum of disease: a randomized, controlled cooling-induced contraction and increased vas- 19. Cutolo M, Grassi W, Matucci Cerinic M: Ray- trial. Ann Intern Med 132:425, 2000 cular reactivity of Raynaud’s disease. Arthritis naud’s phenomenon and the role of capillaros- 31. Russell IJ, Lessard JA: Prazosin treatment of Rheum 50:1578, 2004 copy. Arthritis Rheum 48:3023, 2003 Raynaud’s phenomenon: a double blind single 43. Turton EP, Kent PJ, Kester RC: The aetiology of 20. Block JA, Sequeira W: Raynaud’s phenomenon. crossover study. J Rheumatol 12:94, 1985 Raynaud’s phenomenon. Cardiovasc Surg 6:431, Lancet 357:2042, 2001 32. Rajagopalan S, Pfenninger D, Somers E, et al: 1998 21. Freedman RR, Ianni P, Wenig P: Behavioral Effects of cilostazol in patients with Raynaud’s 44. Zamora MR, O’Brien RF, Rutherford RB, et al: treatment of Raynaud’s disease: long-term fol- syndrome. Am J Cardiol 92:1310, 2003 Serum endothelin-1 concentrations and cold pro- low-up. J Consult Clin Psychol 53:136, 1985 33. Hart DA, Fritzler MJ: Regulation of plasmino- vocation in primary Raynaud’s phenomenon. 22. Raynaud’s Treatment Study Investigators. Com- gen activators and their inhibitors in rheumatic Lancet 336:1144, 1990