Raynaud's phenomenon: Pathogenesis and management

Journal of the American Academy of Dermatology

Volumn 59, Issue 4, 2008, Pages 633-653

  Bakst, Richard ^a   Merola, Joseph F ^a   Franks Jr , Andrew G ^a   Sanchez, Miguel ^a  

^a NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLSALICYLIC ACID; ALPHA ADRENERGIC RECEPTOR BLOCKING AGENT; ALPHA TOCOPHEROL; AMLODIPINE; ARGININE; BLEOMYCIN; CALCIUM CHANNEL BLOCKING AGENT; CISPLATIN; CYCLOSPORIN; DILTIAZEM; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DIPYRIDAMOLE; ENDOTHELIN RECEPTOR ANTAGONIST; FELODIPINE; GLYCERYL TRINITRATE; GRISEOFULVIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; NICOTINIC ACID; NIFEDIPINE; NITRIC OXIDE; NITROPRUSSIDE SODIUM; PENTOXIFYLLINE; PHOSPHODIESTERASE INHIBITOR; PLACEBO; PROSTAGLANDIN; SEROTONIN UPTAKE INHIBITOR; SILDENAFIL; SLO NIACIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; VERAPAMIL; VINBLASTINE;

CERVICAL SYMPATHECTOMY; CHEMICAL SYMPATHECTOMY; CLINICAL TRIAL; DEBRIDEMENT; DISEASE CLASSIFICATION; DRUG WITHDRAWAL; ENDOTHELIAL DYSFUNCTION; ERECTILE DYSFUNCTION; FIBRINOLYSIS; FLUSHING; GASTROINTESTINAL TOXICITY; HEADACHE; HEMATOLOGIC DISEASE; HEREDITY; HUMAN; JAW PAIN; LEG EDEMA; LIFESTYLE MODIFICATION; LOW DRUG DOSE; NAUSEA; NEUROLOGIC DISEASE; PAIN; PATHOGENESIS; PERIPHERAL OCCLUSIVE ARTERY DISEASE; PREVALENCE; PRIORITY JOURNAL; PULMONARY HYPERTENSION; RAYNAUD PHENOMENON; REVIEW; SIDE EFFECT; SYMPATHECTOMY; THROMBOCYTE ACTIVATION; UNSPECIFIED SIDE EFFECT; VASCULAR DISEASE; VASCULAR SURGERY; VASOCONSTRICTION; VASODILATATION;

ADULT; FIBRINOLYSIS; HUMANS; PLATELET ACTIVATION; RAYNAUD DISEASE; REACTIVE OXYGEN SPECIES; SYMPATHECTOMY;

EID: 51349153708     PISSN: 01909622     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.jaad.2008.06.004     Document Type: Review

References (167)

1. Raynaud M. Local asphyxia and symmetrical gangrene of extremities 1862. New researches on the nature and treatment of local asphyxia of the extremities 1874. Translated by Barlow (1888), New Sydenham Society, London
2. Maricq H.R., Weinrich M.C., Keil J.E., and LeRoy E.C. Prevalence of Raynaud phenomenon in the general population: a preliminary study by questionnaire. J Chronic Dis 39 (1986) 423-427
3. Freedman R.R., and Mayes M.D. Familial aggregation of primary Raynaud's disease. Arthritis Rheum 39 (1996) 1189-1191
4. Fraenkel L. Raynaud's phenomenon: epidemiology and risk factors. Curr Rheumatol Rep 4 (2002) 123-128
5. Maricq H.R., Carpentier P.H., Weinrich M.C., Keil J.E., Palesch Y., Biro C., et al. Geographic variation in the prevalence of Raynaud's phenomenon: a 5 region comparison. J Rheumatol 24 (1997) 879-889
6. Hutchison J. Raynaud's phenomenon. Med Press 123 (1901) 403-405
7. Lewis T. Experiments relating to the peripheral mechanisms involved in spasmodic arrest of the circulation in the fingers, a variety of Raynaud's disease. Heart 15 (1929) 7-101
8. Allen E.V., and Brown G.E. Raynaud's disease: a critical review of minimal requisites for diagnosis. Am J Med Sci 183 (1932) 187-200
9. LeRoy E.C., and Medsger Jr. T.A. Raynaud's phenomenon: a proposal for classification. Clin Exp Rheumatol 10 (1992) 485-488
10. Hummers L.K., and Wigley F.M. Management of Raynaud's phenomenon and digital ischemic lesions in scleroderma. Rheum Dis Clin North Am 29 (2003) 293-313
11. Block J.A., and Sequeira W. Raynaud's phenomenon. Lancet 357 (2001) 2042-2048
12. ter Borg E.J., Peirsma-Wichers G., Smit A.J., Kallenberg C.G., and Wouda A.A. Serial nailfold capillary microscopy in primary Raynaud's phenomenon and scleroderma. Semin Arthritis Rheum 24 (1994) 40-47
13. Kallenberg C.G., Wouda A.A., Hoet M.H., and van Venrooij W.J. Development of connective tissue disease in patients presenting with Raynaud's phenomenon: a six year follow up with emphasis on the predictive value of antinuclear antibodies as detected by immunoblotting. Ann Rheum Dis 47 (1988) 634-641
14. Spencer-Green G., Alter D., and Welch H.G. Test performance in systemic sclerosis: anti-centromere and anti-Scl-70 antibodies. Am J Med 103 (1997) 242-248
15. Landry G.J., Edwards J.M., McLafferty R.B., Taylor Jr. L.M., and Porter J.M. Long-term outcome of Raynaud's syndrome in a prospectively analyzed patient cohort. J Vasc Surg 23 (1996) 76-86
16. Lewis T., and Pickering G.W. Observations upon maladies in which the blood supply to the digits cease intermittently or permanently, and upon bilateral gangrene of digits; observations relevant to so-called Raynaud's disease. Clin Sci 1 (1934) 327
17. Herrick A.L. Pathogenesis of Raynaud's phenomenon. Rheumatology 44 (2005) 587-596
18. Rajagopalan S., Pfenninger D., Kehrer C., Chakrabarti A., Somers E., Pavlic R., et al. Increased asymmetric dimethylarginine and endothelin 1 levels in secondary Raynaud's phenomenon: implications for vascular dysfunction and progression of disease. Arthritis Rheum 48 (2003) 1992-2000
19. Yamamoto T., Katayama I., and Nishioka K. Nitric oxide production and inducible nitric oxide synthase expression in systemic sclerosis. J Rheumatol 25 (1998) 314-317
20. Takagi K., Kawaguchi Y., Hara M., Sugiura T., Harigai M., and Kamatani N. Serum nitric oxide (NO) levels in systemic sclerosis patients: correlation between NO levels and clinical features. Clin Exp Immunol 134 (2003) 538-544
21. Matucci Cerinic M., and Kahaleh M.B. Beauty and the beast: the nitric oxide paradox in systemic sclerosis. Rheumatology 41 (2002) 843-847
22. Dooley A., Gao B., Bradley N., Abraham D.J., Black C.M., Jacobs M.J., et al. Abnormal nitric oxide metabolism in systemic sclerosis: increased levels of nitrated proteins and asymmetric dimethylarginine. Rheumatology 45 (2006) 676-684
23. Kirchengast M., and Munter K. Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling. Proc Soc Exp Biol Med 221 (1999) 312-325
24. Sakurai T., and Goto K. Endothelins: vascular actions and clinical implications. Drugs 46 (1993) 795-804
25. Vancheeswaran R., Azam A., Black C., and Dashwood M.R. Localization of endothelin-1 and its binding sites in scleroderma skin. J Rheumatol 21 (1994) 1268-1276
26. Zamora M.R., O'Brien R.F., Rutherford R.B., and Weil J.V. Serum endothelin-1 concentrations and cold provocation in primary Raynaud's phenomenon. Lancet 336 (1990) 1144-1147
27. Smyth A.E., Bell A.L., Bruce I.N., McGrann S., and Allen J.A. Digital vascular responses and serum endothelin-1 concentrations in primary and secondary Raynaud's phenomenon. Ann Rheum Dis 59 (2000) 870-874
28. Duprez D.A. Role of the renin-angiotensin-aldosterone system in vascular remodeling and inflammation: a clinical review. J Hypertens 24 (2006) 983-991
29. Kawaguchi Y., Takagi K., Hara M., Fukasawa C., Sugiura T., Nishimagi E., et al. Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via angiotensin II type 1 receptors. Arthritis Rheum 50 (2004) 216-226
30. Bukhari M., Herrick A.L., Moore T., Manning J., and Jayson M.I. Increased nailfold capillary dimensions in primary Raynaud's phenomenon and systemic sclerosis. Br J Rheumatol 35 (1996) 1127-1131
31. Cooke J.P., and Marshall J.M. Mechanisms of Raynaud's disease. Vasc Med 10 (2005) 293-307
32. Wigley F.M., and Flavahan N.A. Raynaud's phenomenon. Rheum Dis Clin North Am 22 (1996) 765-781
33. Herrick A.L. Vascular function in systemic sclerosis. Curr Opin Rheumatol 12 (2000) 527-533
34. Silverstein J.L., Steen V.D., Medsger Jr. T.A., and Falanga V. Cutaneous hypoxia in patients with systemic sclerosis (scleroderma). Arch Dermatol 124 (1988) 1379-1382
35. Freemont A.J., Hoyland J., Fielding P., Hodson N., and Jayson M.I. Studies of the microvascular endothelium in uninvolved skin of patients with systemic sclerosis: direct evidence for a generalized microangiopathy. Br J Dermatol 126 (1992) 561-568
36. Prescott R.J., Freemont A.J., Jones C.J., Hoyland J., and Fielding P. Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 166 (1992) 255-263
37. Sgonc R., Gruschwitz M.S., Boeck G., Sepp N., Gruber J., and Wick G. Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95. Arthritis Rheum 43 (2000) 2550-2562
38. Flavahan N.A., and Vanhoutte P.M. Endothelial cell signaling and endothelial dysfunction. Am J Hypertens 8 Suppl (1995) 28S-41S
39. LeRoy E.C. Systemic sclerosis: a vascular perspective. Rheum Dis Clin North Am 22 (1996) 675-694
40. Flavahan N.A., Flavahan S., Mitra S., and Chotani M.A. The vasculopathy of Raynaud's phenomenon and scleroderma. Rheum Dis Clin North Am 29 (2003) 275-291
41. Rajkumar V.S., Sundberg C., Abraham D.J., Rubin K., and Black C.M. Activation of microvascular pericytes in autoimmune Raynaud's phenomenon and systemic sclerosis. Arthritis Rheum 42 (1999) 930-941
42. Freedman R.R., and Ianni P. Role of cold and emotional stress in Raynaud's disease and scleroderma. Br Med J (Clin Res Ed) 287 (1983) 1499-1502
43. Droste H., Wollersheim H., Reyenga J., and Thien T. Vascular and humoral sympathetic nervous system reactivity during mental arithmetic in primary Raynaud's phenomenon. Int Angiol 9 (1990) 84-89
44. Halperin J.L., Cohen R.A., and Coffman J.D. Digital vasodilatation during mental stress in patients with Raynaud's disease. Cardiovasc Res 17 (1983) 671-677
45. Martinez R.M., Saponaro A., Dragagna G., Santoro L., Leopardi N., Russo R., et al. Cutaneous circulation in Raynaud's phenomenon during emotional stress: a morphological and functional study using capillaroscopy and laser-Doppler. Int Angiol 11 (1992) 316-320
46. Edwards C.M., Marshall J.M., and Pugh M. Lack of habituation of the pattern of cardiovascular response evoked by sound in subjects with primary Raynaud's disease. Clin Sci (Colch) 95 (1998) 249-260
47. Edwards C.M., Marshall J.M., and Pugh M. The cutaneous vasoconstrictor response to venous stasis is normal in subjects with primary Raynaud's disease. Clin Auton Res 9 (1999) 255-262
48. Bunker C.B., Goldsmith P.C., Leslie T.A., Hayes N., Foreman J.C., and Dowd P.M. Calcitonin gene-related peptide, endothelin-1, the cutaneous microvasculature and Raynaud's phenomenon. Br J Dermatol 134 (1996) 399-406
49. Bunker C.B., Terenghi G., Springall D.R., Polak J.M., and Dowd P.M. Deficiency of calcitonin gene-related peptide in Raynaud's phenomenon. Lancet 336 (1990) 1530-1533
50. Bunker C.B., Reavley C., O'Shaughnessy D.J., and Dowd P.M. Calcitonin gene-related peptide in treatment of severe peripheral vascular insufficiency in Raynaud's phenomenon. Lancet 342 (1993) 80-83
51. Generini S., Seibold J.R., and Matucci-Cerinic M. Estrogens and neuropeptides in Raynaud's phenomenon. Rheum Dis Clin North Am 31 (2005) 177-186
52. Stephens D.P., Saad A.R., Bennett L.A., Kosiba W.A., and Johnson J.M. Neuropeptide Y antagonism reduces reflex cutaneous vasoconstriction in humans. Am J Physiol Heart Circ Physiol 287 (2004) H1404-H1409
53. Flavahan N.A., and Vanhoutte P.M. Effect of cooling on alpha-1 and alpha-2 adrenergic responses in canine saphenous and femoral veins. J Pharmacol Exp Ther 238 (1986) 139-147
54. Flavahan N.A., Cooke J.P., Shepherd J.T., and Vanhoutte P.M. Human postjunctional alpha-1 and alpha-2 adrenoreceptors: differential distribution in arteries of the limbs. J Pharmacol Exp Ther 241 (1987) 361-365
55. Chotani M.A., Flavahan S., Mitra S., Daunt D., and Flavahan N.A. Silent alpha(2C)-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries. Am J Physiol Heart Circ Physiol 278 (2000) H1075-H1083
56. Jeyaraj S.C., Chotani M.A., Mitra S., Gregg H.E., Flavahan N.A., and Morrison K.J. Cooling evokes redistribution of alpha2C-adrenoreceptors from Golgi to plasma membrane in transfected human embryonic kidney 293 cells. Mol Pharmacol 60 (2001) 1195-2000
57. Bailey S.R., Eid A.H., Mitra S., Flavahan S., and Flavahan N.A. Rho kinase mediates cold-induced constriction of cutaneous arteries: role of alpha2C-adrenoceptor translocation. Circ Res 94 (2004) 1367-1374
58. Bailey S.R., Mitra S., Flavahan S., and Flavahan N.A. Reactive oxygen species from smooth muscle mitochondria initiate cold-induced constriction of cutaneous arteries. Am J Physiol Heart Circ Physiol 289 (2005) H243-H250
59. Chotani M.A., Mitra S., Eid A.H., Han S.A., and Flavahan N.A. Distinct cAMP signaling pathways differently regulate alpha2C-adrenoreceptor expression: role in serum induction in human arteriolar smooth muscle cells. Am J Physiol Heart Circ Physiol 288 (2003) H69-H76
60. Furspan P.B., Chatterjee S., and Freedman R.R. Increased tyrosine phosphorylation mediates the cooling-induced contraction and increased vascular reactivity of Raynaud's disease. Arthritis Rheum 50 (2004) 1578-1585
61. Furspan P.B., Chatterjee S., Mayes M.D., and Freedman R.R. Cooling-induced contraction and protein tyrosine kinase activity of isolated arterioles in secondary Raynaud's phenomenon. Rheumatology 44 (2005) 488-494
62. Susol E., MacGregor A.J., Barrett J.H., Wilson H., Black C., Welsh K., et al. A two-stage, genome-wide screen for susceptibility loci in primary Raynaud's phenomenon. Arthritis Rheum 43 (2000) 1641-1646
63. Fagundus D.M., and LeRoy E.C. Cytokines and systemic sclerosis. Clin Dermatol 12 (1994) 407-417
64. Lau C.S., McLaren M., Saniabadi A., and Belch J.J. Increased whole blood platelet aggregation in patients with Raynaud's phenomenon with or without systemic sclerosis. Scand J Rheumatol 22 (1993) 97-101
65. Silveri F., De Angelis R., Poggi A., Muti S., Bonapace G., Argentati F., et al. Relative roles of endothelial cell damage and platelet activation in primary Raynaud's phenomenon (RP) and RP secondary to systemic sclerosis. Scand J Rheumatol 30 (2001) 290-296
66. Hutton R.A., Mikhailidis D.P., Bernstein R.M., Jeremy J.Y., Hughes G.R., and Dandona P. Assessment of platelet function in patients with Raynaud's syndrome. J Clin Pathol 37 (1984) 182-187
67. Reilly I.A., Roy L., and Fitzgerald G.A. Biosynthesis of thromboxane in patients with systemic sclerosis and Raynaud's phenomenon. Br Med J (Clin Res Ed) 292 (1986) 1037-1039
68. Biondi M.L., Marasini B., Bianchi E., and Agostoni A. Plasma free and intraplatelet serotonin in patients with Raynaud's phenomenon. Int J Cardiol 19 (1988) 335-339
69. Herrick A.L., Illingworth K., Blann A., Hay C.R., Hollis S., and Jayson M.I. Von Willebrand factor, thrombomodulin, thromboxane, b-thromboglobulin and markers of fibrinolysis in primary Raynaud's phenomenon and systemic sclerosis. Ann Rheum Dis 55 (1996) 122-127
70. Coffman J.D., and Cohen R.A. Plasma levels of 5-hydroxtryptamine during sympathetic stimulation and in Raynaud's phenomenon. Clin Sci (Colch) 86 (1994) 269-273
71. Lau C.S., McLaren M., Mackay I., and Belch J.J. Baseline plasma fibrinolysis and its correlation with clinical manifestations in patients with Raynaud's phenomenon. Ann Rheum Dis 52 (1993) 443-448
72. Ames P.R., Lupoli S., Alves J., Atsumi T., Edwards C., Iannaccone L., et al. The coagulation/fibrinolysis balance in systemic sclerosis: evidence for a hematological stress syndrome. Br J Rheumatol 36 (1997) 1045-1050
73. Herrick A.L., and Matucci Cerinic M. The emerging problem of oxidative stress and the role of antioxidants in systemic sclerosis. Clin Exp Rheumatol 19 (2001) 4-8
74. Herrick A.L., Rieley F., Schofield D., Hollis S., Braganza J.M., and Jayson M.I. Micronutrient antioxidant status in patients with primary Raynaud's phenomenon and systemic sclerosis. J Rheumatol 21 (1994) 1477-1483
75. Fraenkel L., Zhang Y., Chaisson C.E., Evans S.R., Wilson P.W., and Felson D.T. The association of estrogen replacement therapy and the Raynaud phenomenon in postmenopausal women. Ann Intern Med 129 (1998) 208-211
76. Lafferty K., De Trafford J.C., Potter C., Roberts V.C., and Cotton L.T. Reflex vascular responses in the finger to contralateral thermal stimuli during the normal menstrual cycle: a hormonal basis to Raynaud's phenomenon?. Clin Sci (Colch) 69 (1985) 639-645
77. Momoi H., Ikomi F., and Ohhashi T. Estrogen-induced augmentation of endothelium-dependent nitric oxide-mediated vasodilation in isolated rat cerebral small arteries. Jpn J Physiol 53 (2003) 193-203
78. Huang A., Sun D., Wu Z., Yan C., Carroll M.A., Jiang H., et al. Estrogen elicits cytochrome P450-mediated flow-induced dilation of arterioles in NO deficiency: role of PI3K-Akt phosphorylation in genomic regulation. Circ Res 94 (2004) 245-252
79. Lekakis J., Papamichael C., Mavrikakis M., Voutsas A., and Stamatelopoulos S. Effect of long-term estrogen therapy on brachial arterial endothelium-dependent vasodilation in women with Raynaud's phenomenon secondary to systemic sclerosis. Am J Cardiol 82 (1998) 1555-1557
80. Lekakis J., Mavrikakis M., Papamichael C., Papazoglou S., Economou O., Scotiniotis I., et al. Short-term estrogen administration improves abnormal endothelial function in women with systemic sclerosis and Raynaud's phenomenon. Am Heart J 136 (1998) 905-912
81. Smyth A.E., Hughes A.E., Bruce I.N., and Bell A.L. A case-control study of candidate vasoactive mediator genes in primary Raynaud's phenomenon. Rheumatology 38 (1999) 1094-1098
82. Zhou X., Tan F.K., Wang N., Xiong M., Maghidman S., Reveille J.D., et al. Genome-wide association study for regions of systemic sclerosis susceptibility in a Choctaw Indian population with high disease prevalence. Arthritis Rheum 48 (2003) 2585-2592
83. Kinney E.L., Nicholas G.G., Gallo J., Pontoriero C., and Zelis R. The treatment of severe Raynaud's phenomenon with verapamil. J Clin Pharmacol 22 (1982) 74-76
84. Smith C.R., and Rodeheffer R.J. Treatment of Raynaud's phenomenon with calcium channel blockers. Am J Med 78 (1985) 39-42
85. Smith C.R., and Rodeheffer R.J. Raynaud's phenomenon: pathophysiologic features and treatment with calcium-channel blockers. Am J Cardiol 55 (1985) 154B-157B
86. Rhedda A., McCans J., Willan A.R., and Ford P.M. A double blind placebo controlled crossover randomized trial of diltiazem in Raynaud's phenomenon. J Rheumatol 12 (1985) 724-727
87. Vayssairat M., Capron L., Fiessinger J.N., Mathieu J.F., and Housset E. Calcium channel blockers and Raynaud's disease. Ann Intern Med 95 (1981) 243
88. da Costa J., Gomes J.A., Espirito Santo J., and Queiros M. Inefficacy of diltiazem in the treatment of Raynaud's phenomenon with associated connective tissue disease: a double blind placebo controlled study. J Rheumatol 14 (1987) 858-859
89. Thompson A.E., and Pope J.E. Calcium channel blockers for primary Raynaud's phenomenon: a meta-analysis. Rheumatology 44 (2005) 145-150
90. Thompson A.E., Shea B., Welch V., Fenlon D., and Pope J.E. Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis. Arthritis Rheum 44 (2001) 1841-1847
91. Fredrick M.W., Wise R., Haythornthwaite J., Rand C., Smith E.A., Maricq H.R., et al. Comparison of sustained-release nifedipine and temperature biofeedback for treatment of primary Raynaud phenomenon: results from a randomized clinical trial with 1-year follow-up. Arch Intern Med 160 (2000) 1101-1108
92. Kahan A., Bour B., Couturier D., Amor B., and Menkes C.J. Nifedipine and esophageal dysfunction in progressive systemic sclerosis: a controlled manometric study. Arthritis Rheum 28 (1985) 490-495
93. Gaine S. Pulmonary hypertension. JAMA 284 (2000) 3160-3168
94. Teh L.S., Manning J., Moore T., Tully M.P., O'Reilly D., and Jayson M.I. Sustained-release transdermal glyceryl trinitrate patches as a treatment for primary and secondary Raynaud's phenomenon. Br J Rheumatol 34 (1995) 636-641
95. Franks Jr. A.G. Topical glyceryl trinitrate as adjunctive treatment in Raynaud's disease. Lancet 1 (1982) 76-77
96. Khan F., Litchfield S.J., McLaren M., Veale D.J., Littleford R.C., and Belch J.J. Oral L-arginine supplementation and cutaneous vascular responses in patients with primary Raynaud's phenomenon. Arthritis Rheum 40 (1997) 352-357
97. Khan F., and Belch J.J. Skin blood flow in patients with systemic sclerosis and Raynaud's phenomenon: effects of oral L-arginine supplementation. J Rheumatol 26 (1999) 2389-2394
98. Freedman R.R., Girgis R., and Mayes M.D. Acute effect of nitric oxide on Raynaud's phenomenon in scleroderma. Lancet 354 (1999) 739
99. Fishman A.P. Pulmonary hypertension-beyond vasodilator therapy. N Engl J Med 338 (1998) 321-322
100. Stratton R., Shiwen X., Martini G., Holmes A., Leask A., Haberberger T., et al. Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients. J Clin Invest 108 (2001) 241-250
101. Wigley F.M., Seibold J.R., Wise R.A., McCloskey D.A., and Dole W.P. Intravenous iloprost treatment of Raynaud's phenomenon and ischemic ulcers secondary to systemic sclerosis. J Rheumatol 19 (1992) 1407-1414
102. Wigley F.M., Wise R.A., Seibold J.R., McCloskey D.A., Kujala G., Medsger Jr. T.A., et al. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study. Ann Intern Med 120 (1994) 199-206
103. Scorza R., Caronni M., Mascagni B., Berruti V., Bazzi S., Micallef E., et al. Effects of long-term cyclic iloprost therapy in systemic sclerosis with Raynaud's phenomenon: a randomized, controlled study. Clin Exp Rheumatol 19 (2001) 503-508
104. Zulian F., Corona F., Gerloni V., Falcini F., Buoncompagni A., Scarazatti M., et al. Safety and efficacy of iloprost for the treatment of ischemic digits in pediatric connective tissue diseases. Rheumatology 43 (2004) 229-233
105. Badesch D.B., Tapson V.F., McGoon M.D., Brundage B.H., Rubin L.J., Wigley F.M., et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med 132 (2000) 425-434
106. Clifford P.C., Martin M.F., Sheddon E.J., Kirby J.D., Baird R.N., and Dieppe P.A. Treatment of vasospastic disease with prostaglandin E1. Br Med J 281 (1980) 1031-1034
107. Opitz C.F., Wensel R., Winkler J., Halank M., Bruch L., Kleber F.X., et al. Clinical efficacy and survival with first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension. Eur Heart J 18 (2005) 1895-1902
108. Black C.M., Halkier-Sorensen L., Belch J.J., Ullman S., Madhok R., Smit A.J., et al. Oral iloprost in Raynaud's phenomenon secondary to systemic sclerosis: a multicentre, placebo-controlled, dose-comparison study. Br J Rheumatol 37 (1998) 952-960
109. Wigley F.M., Korn J.H., Csuka M.E., Medsger Jr. T.A., Rothfield N.F., Ellman M., et al. Oral iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study. Arthritis Rheum 41 (1998) 670-677
110. Vayssairat M. Controlled multicenter double blind trial of an oral analog of prostacyclin in the treatment of primary Raynaud's phenomenon: French Microcirculation Society multicenter group for the study of vascular acrosyndromes. J Rheumatol 23 (1996) 1917-1920
111. Vayssairat M. Preventive effect of an oral prostacyclin analog, beraprost sodium, on digital necrosis in systemic sclerosis: French Microcirculation Society multicenter group for the study of vascular acrosyndromes. J Rheumatol 26 (1999) 2173-2178
112. Wilkins M.R., Paul G.A., Strange J.W., Tunariu N., Gin-Sing W., Banya W.A., et al. Sildenafil versus endothelin receptor antagonist for pulmonary hypertension (SERAPH) study. Am J Respir Crit Care Med 171 (2005) 1292-1297
113. Lichtenstein J.R. Use of sildenafil citrate in Raynaud's phenomenon: comment on the article by Thompson, et al. Arthritis Rheum 28 (2003) 282-283
114. Kumana C.R., Cheung G.T., and Lau C.S. Sever digital ischemia treated with phosphodiesterase inhibitors. Ann Rheum Dis 63 (2004) 1522-1524
115. Fries R., Shariat K., von Wilmowsky H., and Bohm M. Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy. Circulation 112 (2005) 2980-2985
116. Rajagopalan S., Pfenninger D., Somers E., Kehrer C., Chakrabarti A., Mukherjee D., et al. Effects of cilostazol in patients with Raynaud's syndrome. Am J Cardiol 92 (2003) 1310-1315
117. Mancini G.B., Henry G.C., Macaya C., O'Neill B.J., Pucillo A.L., Carere R.G., et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease: the TREND (trial on reversing endothelial dysfunction) study. Circulation 94 (1996) 258-265
118. Weber K.T., Brilla C.G., and Janicki J.S. Cardioreparation with lisinopril in the management of hypertension and heart failure. Cardiology 79 (1991) 62-73
119. Challenor V.F., Waller D.G., Hayward R.A., Griffin M.J., and Roath O.S. Subjective and objective assessment of enalapril in primary Raynaud's phenomenon. Br J Clin Pharmacol 31 (1991) 477-480
120. Janini S.D., Scott D.G., Coppock J.S., Bacon P.A., and Kendall M.J. Enalapril in Raynaud's phenomenon. J Clin Pharm Ther 13 (1988) 145-150
121. Dziadzio M., Denton C.P., Smith R., Howell K., Blann A., Bowers E., et al. Losartan therapy for Raynaud's phenomenon and scleroderma: clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum 42 (1999) 2646-2655
122. Rey J., Cretel E., Jean R., Pastor M.J., and Durand J.M. Serotonin reuptake inhibitors, Raynaud's phenomenon and erythromelalgia. Rheumatology 42 (2003) 601-602
123. Garcia-Porrua C., Margarinos C.C., and Gonzalez-Gay M.A. Raynaud's phenomenon and serotonin reuptake inhibitors. J Rheumatol 31 (2004) 2090
124. Coleiro B., Marshall S.E., Denton C.P., Howell K., Blann A., Welsh K.I., et al. Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology 40 (2001) 1038-1043
125. Pope J., Fenlon D., Thompson A., Shea B., Furst D., Wells G., et al. Ketanserin for Raynaud's phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev 2 (2000) CD000954
126. Rubin L.J., Badesch D.B., Barst R.J., Galie N., Black C.M., Keogh A., et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 346 (2003) 896-903
127. Denton C.P., Humbert M., Rubin L., and Black C.M. Bosentan therapy for pulmonary arterial hypertension related to connective tissue disease: a subgroup analysis of the pivotal clinical trials and their open-label extensions. Ann Rheum Dis 65 (2006) 1336-1340
128. Korn J.H., Mayes M., Matucci Cerinic M., Rainisio M., Pope J., Hachulla E., et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 50 (2004) 3985-3993
129. Humbert M., and Cabane J. Successful treatment of systemic sclerosis digital ulcers and pulmonary arterial hypertension with endothelin receptor antagonist bosentan. Rheumatology 42 (2003) 191-193
130. Ramos-Casals M., Brito-Zeron P., Nardi N., Claver G., Risco G., Parraga F.D., et al. Successful treatment of severe Raynaud's phenomenon with bosentan in four patients with systemic sclerosis. Rheumatology 43 (2004) 1454-1456
131. Launay D., Diot E., Pasquier E., Mouthon L., Boullanger N., Fain O., et al. Bosentan for treatment of active digital ulcers in patients with systemic sclerosis. [French]. Presse Med 35 (2006) 587-592
132. Patheon, Inc. Tracleer. Available from: URL:http://www.fda.gov/medwatch/SAFETY/2003/03Oct_PI/Tracleer_PI.pdf. Accessed October 25, 2006.
133. Suntharalingam J., Hodgkins D., Cafferty F.H., Hughes R.J., and Pepke-Zaba J. Does rapid dose titration affect the hepatic safety profile of Bosentan?. Vasc Pharmacol 44 (2006) 508-512
134. Patheon, Inc. Tracleer. Available from: URL:http://www.fda.gov/MedWatch/safety/2006/TracleerPI_012006.pdf. Accessed October 25, 2006.
135. Pope J., Fenlon D., Thompson A., Shea B., Furst D., Wells G., et al. Prazosin for Raynaud's phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev 2 (2000) CD000956
136. Wise R.A., Wigley F.M., White B., Leatherman G., Zhong J., Krasa H., et al. Efficacy and tolerability of a selective alpha(2C)-adrenergic receptor blocker in recovery from cold-induced vasospasm in scleroderma patients: a single-center, double-blind, placebo-controlled, randomized crossover study. Arthritis Rheum 50 (2004) 3994-4001
137. Rikitake Y., and Liao J.K. ROCKs as therapeutic targets in cardiovascular diseases. Expert Rev Cardiovasc Ther 3 (2005) 441-451
138. Masumoto A., Mohri M., Shimokawa H., Urakami L., Usui M., and Takeshita A. Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation 105 (2002) 1545-1547
139. Tanaka K., Minami H., Kota M., Kuwamura K., and Kohmura E. Treatment of cerebral vasospasm with intra-arterial fasudil hydrochloride. Neurosurgery 56 (2005) 214-223
140. Fukumoto Y., Matoba T., Ito A., Tanaka H., Kishi T., Hayashidani S., et al. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart 91 (2005) 391-392
141. Ishikura K., Yamada N., Ito M., Ota S., Nakamura M., Isaka N., et al. Beneficial acute effects of rho-kinase inhibitor in patients with pulmonary arterial hypertension. Circ J 70 (2006) 174-178
142. Denton C.P., Howell K., Stratton R.J., and Black C.M. Long-term low molecular weight heparin therapy for severe Raynaud's phenomenon: a pilot study. Clin Exp Rheumatol 18 (2000) 499-502
143. Cukierman T., Elinav E., Korem M., and Chajek-Shaul T. Low dose warfarin treatment for calcinosis in patients with systemic sclerosis. Ann Rheum Dis 63 (2004) 1341-1343
144. Lakshminarayanan S., Vazquez-Abad D., Maestrello S.J., and Waterman J.R. Treatment of severe Raynaud's phenomenon and ischemic ulcerations with tissue plasminogen activator. Clin Exp Rheumatol 17 (1999) 260
145. Fritzler M.J., and Hart D.A. Prolonged improvement of Raynaud's phenomenon and scleroderma after recombinant tissue plasminogen activator therapy. Arthritis Rheum 33 (1990) 274-276
146. Bridges A.J., and Spadone D.P. Tissue plasminogen activator treatment of digital thrombosis in severe Raynaud's phenomenon-a case report. Angiology 44 (1993) 566-569
147. Sambo P., Amico D., Giacomelli R., Matucci-Cerinic M., Salsano F., Valentini G., et al. Intravenous N-acetylcysteine for treatment of Raynaud's phenomenon secondary to systemic sclerosis: a pilot study. J Rheumatol 28 (2001) 2257-2262
148. Denton C.P., Bunce T.D., Dorado M.B., Roberts Z., Wilson H., Howell K., et al. Probucol improves symptoms and reduces lipoprotein oxidation susceptibility in patients with Raynaud's phenomenon. Rheumatology 38 (1999) 309-315
149. Herrick A.L., Hollis S., Schofield D., Rieley F., Blann A., Griffin K., et al. A double-blind placebo-controlled trial of antioxidant therapy in limited cutaneous systemic sclerosis. Clin Exp Rheumatol 18 (2000) 349-356
150. Morris J.L., Jobling P., and Gibbins I.L. Differential inhibition by botulinum neurotoxin A of cotransmitters released from autonomic vasodilator neurons. Am J Physiol Heart Circ Physiol 281 (2001) H2124-H2132
151. Van Beek A.L., Lim P.K., Gear A.J., and Pritzker M.R. Management of vasospastic disorders with botulinum toxin A. Plast Reconstr Surg 119 (2007) 217-226
152. de Trafford J.C., Lafferty K., Potter C.E., Roberts V.C., and Cotton L.T. An epidemiological survey of Raynaud's phenomenon. Eur J Vasc Surg 2 (1988) 167-170
153. Gordon A., Zechmeister K., and Collin J. The role of sympathectomy in current surgical practice. Eur J Vasc Surg 8 (1994) 129-137
154. Matsumoto Y., Ueyama T., Endo M., Sasaki H., Kasashima F., Abe Y., et al. Endoscopic thoracic sympathicotomy for Raynaud's phenomenon. J Vasc Surg 36 (2002) 57-61
155. Flatt A.E. Digital artery sympathectomy. J Hand Surg [Am] 5 (1980) 550-556
156. Balogh B., Mayer W., Vesely M., Mayer S., Partsch H., and Piza-Katzer H. Adventitial stripping of the radial and ulnar arteries in Raynaud's disease. J Hand Surg [Am] 6 (2002) 1073-1080
157. Drake D.B., Kesler R.W., and Morgan R.F. Digital sympathectomy for refractory Raynaud's phenomenon in an adolescent. J Rheumatol 19 (1992) 1286-1288
158. Yee A.M., Hotchkiss R.N., and Paget S.A. Adventitial stripping: a digit saving procedure in refractory Raynaud's phenomenon. J Rheumatol 25 (1998) 269-276
159. Egloff D.V., Mifsud R.P., and Verdan C. Superselective digital sympathectomy in Raynaud's phenomenon. Hand 15 (1983) 110-114
160. Tomaino M.M., Goitz R.J., and Medsger T.A. Surgery for ischemic pain and Raynaud's' phenomenon in scleroderma: a description of treatment protocol and evaluation of results. Microsurgery 21 (2001) 75-79
161. Taylor M.H., McFadden J.A., Bolster M.B., and Silver R.M. Ulnar artery involvement in systemic sclerosis (scleroderma). J Rheumatol 29 (2002) 102-106
162. Tomaino M.M. Digital arterial occlusion in scleroderma: is there a role for digital arterial reconstruction?. J Hand Surg [Br] 25 (2000) 611-613
163. Palesch Y.Y., Valter I., Carpentier P.H., and Maricq H.R. Association between cigarette and alcohol consumption and Raynaud's phenomenon. J Clin Epidemiol 52 (1999) 321-328
164. Harrison B.J., Silman A.J., Hider S.L., and Herrick A.L. Cigarette smoking as a significant risk factor for digital vascular disease in patients with systemic sclerosis. Arthritis Rheum 46 (2002) 3312-3316
165. Goldberg J., and Dlesk A. Successful treatment of Raynaud's phenomenon with pentoxifylline. Arthritis Rheum 29 (1986) 1055-1056
166. Charles C.R., and Carmick E.S. Skin temperature changes in Raynaud's disease after griseofulvin. Arch Dermatol 101 (1970) 331-336
167. Allen B.R. Griseofulvin in Raynaud's phenomenon. Lancet 2 (1971) 840-841