CREST Syndrome Clinical Presentation
- Author: Jeanie C Yoon, MD; Chief Editor: Dirk M Elston, MD more...
In the typical course of limited scleroderma, the patient first notices Raynaud phenomenon. Over time (usually years), fingers become puffy, then the skin thickens slowly. Internal organ manifestations are delayed for many years.
Calcinosis is the pathologic calcification of soft tissues. The calcific deposits can be subclinical. When symptomatic, they can be tender and painful. They can ulcerate, drain a white chalky substance, and become secondarily infected. Inflammatory reactions intermittently occur at the site of calcinosis. Paraspinal calcifications rarely occur, causing local pain, radiculopathy, and diffuse weakness.
Maurice Raynaud defined Raynaud phenomenon in 1862. He observed episodes of pallor, cyanosis, and/or rubor on the hands bilaterally in response to cold or emotional stress, in the setting of normal proximal arterial pulsations, and without gangrene.
Patients occasionally describe color changes proximally as far as the wrist. Less frequently, the feet are involved. Rarely, the nose and ears can be affected. Involved skin is cool during the attack, but the proximal skin is warm. Color changes are often accompanied by symptoms that can include pain and paresthesias. The phenomenon lasts minutes to hours, and the patient is symptom-free between episodes.
While the entire intestine can be involved in scleroderma, esophageal involvement is most common and most often clinically relevant.
According to Akesson and Wollheim from 1989, dysmotility is common. Cine-esophagram and radionuclide transit time studies demonstrate hypomotility in as many as 75-86% of patients with CREST syndrome. All patients have normal motility of the proximal esophagus, which primarily is striated muscle.
In 1987, Zamost et al correlated esophageal symptoms with anatomic and physiologic measurements in 53 patients with scleroderma. The prevalence of esophagitis and strictures (41%) in this patient population is higher than in otherwise healthy patients with gastroesophageal reflux disease. Abnormal motility was a significant predictor of erosive esophagitis; 70% of patients with dysmotility had gross or microscopic evidence of erosive esophagitis. No patients with normal motility had erosive esophagitis. Symptoms of heartburn and dysphagia were more common in patients with erosive esophagitis. Heartburn alone did not predict esophagitis; half the patients without this complication still experienced heartburn. Additionally, dysphagia did not predict the presence of stricture.
Barrett esophagitis, a complication of gastroesophageal reflux, has been found in scleroderma patients, perhaps at a higher rate (37% in patients with scleroderma vs 4-13% in patients without scleroderma). Esophageal adenocarcinoma, a malignant transformation of Barrett esophagitis, has also been documented in scleroderma patients.
Another potential complication of esophageal dysmotility and gastroesophageal reflux is occult aspiration and pulmonary disease. In 1989, Johnson et al examined 13 patients with systemic sclerosis using endoscopy, laryngoscopy, esophageal manometry, 24-hour esophageal pH monitoring, pulmonary function testing, and aspiration scanning. All 13 patients had endoscopic evidence of reflux. Twelve patients had abnormal laryngeal examination findings suggestive of aspiration; however, in this group, 1 patient had no evidence of proximal reflux by pH monitoring and 2 patients had normal aspiration scan results. Nonetheless, an inverse relationship was found between diffusing capacity of lung for carbon dioxide and esophageal reflux scores, indicating that gastroesophageal reflux potentially contributes to diminished pulmonary function.
Sclerodactyly means thickening of the skin of the digits of the hands and feet. Three phases of skin changes are seen in scleroderma: the edematous phase, indurative phase, and atrophic phase.
Patients with early scleroderma present with puffy edema in the fingers and may report morning stiffness or arthralgias. The edematous phase is usually short (ie, months, but occasionally years).
In the indurative phase, the skin becomes thickened. Patients may report pruritus. The skin appears shiny and tight. Skin creases are lost. Erythema may be present. In limited scleroderma, this process continues slowly for many years.
Late in the course of scleroderma, the skin becomes fragile and lax as it enters the atrophic phase.
Patients with limited scleroderma find that the advancement of skin disease occurs slowly, over many years. By definition, skin involvement remains distal to the elbows and knees, although it can involve the face and neck.
Telangiectases are lesions formed by collections of dilated blood vessels.
In scleroderma patients, telangiectases occur on the face, upper trunk, and hands.
They also occur on mucosal surfaces (eg, lips) and throughout the GI tract and may be symptomatic. These were the most common cause of bleeding in a series of 144 patients with scleroderma (diffuse and limited disease). Telangiectases were associated with recurrent GI bleeding in 7 patients in this group. This bleeding can be chronic and cause anemia.
Arthralgias are common (90% of patients), but erosive arthritis is rare. Proximal muscle weakness can occur.
Pulmonary hypertension most often occurs in the absence of interstitial fibrosis in approximately 3-14% of CREST syndrome patients. It is a very late event and the prognosis is poor, with a mortality rate of 50% after 2 years. Symptoms heralding this phenomenon include dyspnea on exertion and cough.
Myocardial involvement is rare in patients with limited scleroderma; however, patchy fibrosis in the myocardium can occur and typically is asymptomatic. Significant myocardial involvement manifests as dyspnea on exertion, fatigue, and palpitations. Arrhythmias and conduction abnormalities can occur.
Primary biliary cirrhosis may be associated with CREST syndrome.[39, 40]
Renal crises rarely occur in persons with limited scleroderma (1%); they manifest accelerated hypertension, renal failure, and microangiopathic hemolytic anemia.
Entrapment neurologic syndromes (eg, carpal tunnel syndrome) occur. Autonomic dysfunction of the GI tract also occurs.
Sicca symptoms are present in approximately 35% of patients. Of patients with sicca symptoms, half have anti-Ro (SSA) or anti-La (SSB) antibodies.
Scleroderma is associated with an increased risk of cancer, in particular lung cancer.
In scleroderma, calcific deposits are found predominantly in the extremities, around joints, and around bony prominences. Osteonecrosis has also been reported.
Deposits typically are found in the flexor surfaces of the hands and the extensor surfaces of the forearms and knees.
The deposits rest in the dermis but can be found in deeper periarticular tissues.
Triphasic color changes of pallor, cyanosis, and erythema represent phases of vasoconstriction, slow blood flow, and reperfusion, respectively.
Color changes extend proximally from the tips of digits to various levels, with a well-demarcated border.
The earliest change in the distal esophagus (primarily smooth muscle) is an uncoordinated disorganized pattern of contractions resulting in low amplitude or absent peristalsis.
Lower esophageal sphincter (LES) pressure typically is lower than in healthy controls, and incomplete relaxation of the LES occurs.
The process typically begins in the distal fingers and advances proximally.
The process also may occur on the face, over the forehead, and around the mouth. Facial involvement can lead to a mauskopf (mouse head) appearance. Lips become thinner, and radial furrowing develops around the mouth. The oral aperture is reduced in size (microstomia). Wrinkles over the forehead diminish.
These are flat and nonpulsatile and typically have a rectangular or elongated shape. The vessels are so close together that they appear as discrete mats.
The cause of limited scleroderma is yet to be determined. Studies of genetic factors show only rare occasions of multicase families. HLA associations are present but are not strong. These include HLA-DRB*01, HLADRB*11, HLA-A*30, and HLA-A*32 showing increased susceptibility to scleroderma and HLA-DRB*07, HLA-B*57, and HLA-Cw*14 being protective.
The predominance of cases occurring in women after their childbearing years and the similar clinical presentation of scleroderma to graft versus host disease has suggested the importance of fetal/maternal microchimerism in the etiology of scleroderma.
Environmental factors also are likely important. Some similarities in clinical presentation occur with L-tryptophan and rapeseed oil exposure. Certain occupations have been linked to an increased risk to systemic sclerosis, including female teachers, female textile workers, and construction workers. Exposure to silica, synthetic adhesives, solvents (including chlorinated solvents, aromatic solvents, white spirit, toluene, trichloroethylene, formaldehyde, vinyl chloride, and cleaning products) have been implicated in a higher risk of developing systemic sclerosis. Interestingly, the use of vibrating tools was also found to increase the risk of systemic sclerosis.[45, 46]
The pathogenesis of calcinosis, Raynaud phenomenon, esophageal dysmotility, and sclerodactyly are described in more detail.
Ultrastructural study of calcifications from patients with CREST syndrome demonstrates calcium apatite crystals. Serum calcium, phosphorus, and alkaline phosphatase levels typically are normal; therefore, the calcifications are considered dystrophic.
Elevated levels of gamma-carboxyglutamic acid (Gla), a calcium-binding amino acid found in vitamin K–dependent clotting factors, are present in the urine and the involved tissues of patients with calcinosis. Gla and other calcium-binding proteins may be deposited abnormally in soft tissues during clotting. The occurrence of calcinosis at sites of repeated trauma appears to support this idea.
Microvascular abnormalities and dysfunction are central to the pathogenesis of scleroderma-associated Raynaud phenomenon.
Endothelial injury is believed to result in intimal hyperplasia and fibrosis, concentric narrowing of digital arteries by as much as 75-80%, and occlusion by intravascular thrombi.
Resting blood flow in fingers was lower in scleroderma patients compared with normal controls as measured by laser Doppler flowmeter. Arteries from scleroderma patients have significantly increased sensitivity to alpha2-adenoreceptor–mediated vasoconstriction. Whether this is a consequence or cause of endothelial cell injury and dysfunction is unclear.
Endothelin, a naturally occurring peptide, has been implicated as a pathologic mediator of vasoconstriction, fibrosis, vascular hypertrophy, and inflammation in patients with Raynaud syndrome.
The earliest abnormality in the involved gut of scleroderma patients is dysmotility secondary to nerve injury, perhaps resulting from arteriolar changes in the vasa nervorum or compressive nerve damage via collagen deposits. Smooth muscle atrophy occurs later (and often marks the beginning of symptoms).
The predilection for smooth muscle rather than striated muscle atrophy explains the distribution of anatomic involvement. The proximal esophagus primarily is striated muscle and remains essentially uninvolved. The esophagus typically is weakly responsive to prokinetic therapy, until, according to Sjogren, the final stage of the disease (fibrotic infiltration of muscle) halts the response to medications.
The consequences of esophageal dysmotility are reflux and its complications. The reduced LES pressure in patients with scleroderma likely allows acid reflux, which is exacerbated by delayed clearance of acid from the esophagus because of abnormal distal motility. This creates an environment in which stricture, Barrett esophagus, adenocarcinoma, or aspiration may supervene.
The relationship of Raynaud phenomenon to esophageal dysmotility is interesting. Cold-induced vasospasm of the hands also results in esophageal dysmotility, and reversal of this vasospasm with reserpine reverses both peripheral Raynaud phenomenon and abnormalities in esophageal motility (as reported by Sjogren in 1994); however, patients with primary Raynaud phenomenon do not tend to have esophageal dysmotility. Therefore, the significance of these observations remains to be determined.
The development of sclerodactyly begins with a perivascular inflammatory infiltrate in the dermis. The trigger for this inflammatory process is not known.
The edematous phase of skin involvement results from mucopolysaccharide, glycoprotein, and collagen (types I and III) deposition in the dermis.
As collagen deposition continues, the dermis becomes more sclerotic than edematous. Meanwhile, a similar process occurs in small arteries. Mucinous deposition occurs in the intima. The adventitia is infiltrated first with inflammatory cells, and then it becomes fibrotic. This process results in narrowing of the artery and then arterial collapse or thrombosis. The tissue then becomes ischemic.
Years after the onset of skin changes, fibrosis usually subsides, leaving atrophic skin.
Meyer O. [From Thibierge-Weissenbach syndrome (1910) to anti-centromere antibodies (1980). Clinical and biological features of scleroderma]. Ann Med Interne (Paris). 1999 Jan. 150(1):47-52. [Medline].
Winterbauer RH. Multiple telangiectasia, Raynaud's phenomenon, sclerodactyly, and subcutaneous calcinosis: A syndrome mimicking hereditary hemorrhagic telangiectasia. Bull Johns Hopkins Hosp. 1964 Jun. 114:361-83. [Medline].
Frayha RA, Scarola JA, Shulman LE. Calcinosis in scleroderma: A reevaluation of the CRST syndrome, abstracted. Arthritis Rheum. 1973. 16:542.
Velayos EE, Masi AT, Stevens MB, Shulman LE. The 'CREST' syndrome. Comparison with systemic sclerosis (scleroderma). Arch Intern Med. 1979 Nov. 139(11):1240-4. [Medline].
Rodnan GP, Jablonska S, Medsger TA. Classification and nomenclature of progressive systemic sclerosis (scleroderma). Clin Rheum Dis. 1979. 5:5-13.
Barnett AJ, Miller MH, Littlejohn GO. A survival study of patients with scleroderma diagnosed over 30 years (1953-1983): the value of a simple cutaneous classification in the early stages of the disease. J Rheumatol. 1988 Feb. 15(2):276-83. [Medline].
Tuffanelli DL, Winkelmann RK. Diffuse systemic scleroderma. A comparison with acrosclerosis. Ann Intern Med. 1962 Aug. 57:198-203. [Medline].
Ferri C, Valentini G, Cozzi F, Sebastiani M, Michelassi C, La Montagna G, et al. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine (Baltimore). 2002 Mar. 81(2):139-53. [Medline].
Scussel-Lonzetti L, Joyal F, Raynauld JP, Roussin A, Rich E, Goulet JR, et al. Predicting mortality in systemic sclerosis: analysis of a cohort of 309 French Canadian patients with emphasis on features at diagnosis as predictive factors for survival. Medicine (Baltimore). 2002 Mar. 81(2):154-67. [Medline].
LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988 Feb. 15(2):202-5. [Medline].
Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am. 1996 Nov. 22(4):751-64. [Medline].
Nadashkevich O, Davis P, Fritzler MJ. A proposal of criteria for the classification of systemic sclerosis. Med Sci Monit. 2004 Nov. 10(11):CR615-21. [Medline].
Maricq HR, Valter I. A working classification of scleroderma spectrum disorders: a proposal and the results of testing on a sample of patients. Clin Exp Rheumatol. 2004 Jan-Feb. 22(3 Suppl 33):S5-13. [Medline].
Wollheim FA. Classification of systemic sclerosis. Visions and reality. Rheumatology (Oxford). 2005 Oct. 44(10):1212-6. [Medline].
Postiglione L, Montagnani S, Riccio A, Montuori N, Sciorio S, Ladogana P, et al. Enhanced expression of the receptor for granulocyte macrophage colony stimulating factor on dermal fibroblasts from scleroderma patients. J Rheumatol. 2002 Jan. 29(1):94-101. [Medline].
Kawakami T, Soma Y, Mizoguchi M, Saito R. Immunohistochemical expression of transforming growth factor beta3 in calcinosis in a patient with systemic sclerosis and CREST syndrome. Br J Dermatol. 2000 Nov. 143(5):1098-100. [Medline].
Postiglione L, Ladogana P, Montagnani S, di Spigna G, Castaldo C, Turano M, et al. Effect of granulocyte macrophage-colony stimulating factor on extracellular matrix deposition by dermal fibroblasts from patients with scleroderma. J Rheumatol. 2005 Apr. 32(4):656-64. [Medline].
Kikuchi K, Kadono T, Furue M, Tamaki K. Tissue inhibitor of metalloproteinase 1 (TIMP-1) may be an autocrine growth factor in scleroderma fibroblasts. J Invest Dermatol. 1997 Mar. 108(3):281-4. [Medline].
de Oliveira JG, Guedes AC, Lanna CC, Coelho LF, Prados RZ, Feghali C, et al. Protease nexin-1 messenger RNA levels are not affected by serum or interferon beta in cultured systemic sclerosis fibroblasts. Arch Dermatol Res. 2002 Jan. 293(11):584-9. [Medline].
Helmbold P, Fiedler E, Fischer M, Marsch WCh. Hyperplasia of dermal microvascular pericytes in scleroderma. J Cutan Pathol. 2004 Jul. 31(6):431-40. [Medline].
LeRoy EC. Systemic sclerosis. A vascular perspective. Rheum Dis Clin North Am. 1996 Nov. 22(4):675-94. [Medline].
Klareskog L, Gustafsson R, Scheynius A, Hällgren R. Increased expression of platelet-derived growth factor type B receptors in the skin of patients with systemic sclerosis. Arthritis Rheum. 1990 Oct. 33(10):1534-41. [Medline].
Nelson JL. Microchimerism and the pathogenesis of systemic sclerosis. Curr Opin Rheumatol. 1998 Nov. 10(6):564-71. [Medline].
Mayes MD, Lacey JV Jr, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003 Aug. 48(8):2246-55. [Medline].
Arnett FC, Howard RF, Tan F, Moulds JM, Bias WB, Durban E, et al. Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype. Arthritis Rheum. 1996 Aug. 39(8):1362-70. [Medline].
Steen VD, Powell DL, Medsger TA Jr. Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum. 1988 Feb. 31(2):196-203. [Medline].
Pakunpanya K, Verasertniyom O, Vanichapuntu M, Pisitkun P, Totemchokchyakarn K, Nantiruj K, et al. Incidence and clinical correlation of anticentromere antibody in Thai patients. Clin Rheumatol. 2006 May. 25(3):325-8. [Medline].
Silman AJ, Newman J. Epidemiology of systemic sclerosis. Curr Opin Rheumatol. 1996 Nov. 8(6):585-9. [Medline].
Alamanos Y, Tsifetaki N, Voulgari PV, Siozos C, Tsamandouraki K, Alexiou GA, et al. Epidemiology of systemic sclerosis in northwest Greece 1981 to 2002. Semin Arthritis Rheum. 2005 Apr. 34(5):714-20. [Medline].
Allcock RJ, Forrest I, Corris PA, Crook PR, Griffiths ID. A study of the prevalence of systemic sclerosis in northeast England. Rheumatology (Oxford). 2004 May. 43(5):596-602. [Medline].
Le Guern V, Mahr A, Mouthon L, Jeanneret D, Carzon M, Guillevin L. Prevalence of systemic sclerosis in a French multi-ethnic county. Rheumatology (Oxford). 2004 Sep. 43(9):1129-37. [Medline].
Englert H, Small-McMahon J, Davis K, O'Connor H, Chambers P, Brooks P. Systemic sclerosis prevalence and mortality in Sydney 1974-88. Aust N Z J Med. 1999 Feb. 29(1):42-50. [Medline].
Akesson A, Wollheim FA. Organ manifestations in 100 patients with progressive systemic sclerosis: a comparison between the CREST syndrome and diffuse scleroderma. Br J Rheumatol. 1989 Aug. 28(4):281-6. [Medline].
Zamost BJ, Hirschberg J, Ippoliti AF, Furst DE, Clements PJ, Weinstein WM. Esophagitis in scleroderma. Prevalence and risk factors. Gastroenterology. 1987 Feb. 92(2):421-8. [Medline].
Johnson DA, Drane WE, Curran J, Cattau EL Jr, Ciarleglio C, Khan A, et al. Pulmonary disease in progressive systemic sclerosis. A complication of gastroesophageal reflux and occult aspiration?. Arch Intern Med. 1989 Mar. 149(3):589-93. [Medline].
Lachter J, Suissa A, Schiff E, Rosner I. Anemia in CREST syndrome. Isr Med Assoc J. 2003 Jun. 5(6):449. [Medline].
Meyer O. [Crest Syndrome]. Ann med Interne (Paris). 2002. 153(3):183-188. [Medline].
Mavrogeni S, Bratis C, Manoussakis M. Coronary artery abnormalities in CREST syndrome revealed by cardiovascular magnetic resonance imaging. Can J Cardiol. 2011 May-Jun. 27(3):390.e5-7. [Medline].
Kouraklis G, Glinavou A, Karatzas G. Primary biliary cirrhosis accompanied by CREST syndrome. South Med J. 2002 Sep. 95(9):1058-9. [Medline].
Tojo J, Ohira H, Suzuki T, Takeda I, Shoji I, Kojima T, et al. Clinicolaboratory characteristics of patients with primary biliary cirrhosis associated with CREST symptoms. Hepatol Res. 2002 Mar. 22(3):187-195. [Medline].
Hill CL, Nguyen AM, Roder D, Roberts-Thomson P. Risk of cancer in patients with scleroderma: a population based cohort study. Ann Rheum Dis. 2003 Aug. 62(8):728-31. [Medline].
Desai K, Mian NZ. Osteonecrosis of multiple joints in a patient with limited scleroderma/CREST syndrome. J Clin Rheumatol. 2015 Apr. 21 (3):169-70. [Medline].
Sjogren RW. Gastrointestinal motility disorders in scleroderma. Arthritis Rheum. 1994 Sep. 37(9):1265-82. [Medline].
Gladman DD, Kung TN, Siannis F, Pellett F, Farewell VT, Lee P. HLA markers for susceptibility and expression in scleroderma. J Rheumatol. 2005 Aug. 32(8):1481-7. [Medline].
Bovenzi M, Barbone F, Pisa FE, Betta A, Romeo L, Tonello A, et al. A case-control study of occupational exposures and systemic sclerosis. Int Arch Occup Environ Health. 2004 Jan. 77(1):10-6. [Medline].
Maître A, Hours M, Bonneterre V, Arnaud J, Arslan MT, Carpentier P, et al. Systemic sclerosis and occupational risk factors: role of solvents and cleaning products. J Rheumatol. 2004 Dec. 31(12):2395-401. [Medline].
Mayes MD. Endothelin and endothelin receptor antagonists in systemic rheumatic disease. Arthritis Rheum. 2003 May. 48(5):1190-9. [Medline].
Anastasopoulos G, Marinis A, Konstantinidis C, Theodosopoulos T, Fragulidis G, Vassiliou I. Adenocarcinoma of the third portion of the duodenum in a man with CREST syndrome. World J Surg Oncol. 2008 Oct 1. 6:106. [Medline]. [Full Text].
Lauritano D, Bussolati A, Baldoni M, Leonida A. Scleroderma and CREST syndrome: a case report in dentistry. Minerva Stomatol. 2011 Sep. 60(9):443-66. [Medline].
van Paassen P, Damoiseaux J, Tervaert JW. Laboratory assessment in musculoskeletal disorders. Best Pract Res Clin Rheumatol. 2003 Jun. 17(3):475-94. [Medline].
Aeschlimann A, Meyer O, Bourgeois P, Haim T, Belmatoug N, Palazzo E, et al. Anti-Scl-70 antibodies detected by immunoblotting in progressive systemic sclerosis: specificity and clinical correlations. Ann Rheum Dis. 1989 Dec. 48(12):992-7. [Medline].
Gonzalez R, Storr M, Bloching H, Seige M, Ott R, Allescher HD. Autoantibody profile in progressive systemic sclerosis as markers for esophageal involvement. J Clin Gastroenterol. 2001 Feb. 32(2):123-7. [Medline].
Bar-Sever Z, Mukamel M, Harel L, Hardoff R. Scintigraphic evaluation of calcinosis in juvenile dermatomyositis with Tc-99m MDP. Clin Nucl Med. 2000 Dec. 25(12):1013-6. [Medline].
Strumia R. Videodermatoscopy: a useful tool for diagnosing cutaneous dystrophic calcifications. Dermatol Online J. 2005. 11(1):28. [Medline].
Ling TC, Johnston BT. Esophageal investigations in connective tissue disease: which tests are most appropriate?. J Clin Gastroenterol. 2001 Jan. 32(1):33-6. [Medline].
Joslin N. Early identification key to scleroderma treatment. Nurse Pract. 2004 Jul. 29(7):24-39; quiz 40-1. [Medline].
Rus V, White B. Systemic sclerosis: multiple therapies control morbidity. J Musculoskel Med. 2002. 19:110-121.
Samuelson UK, Ahlmen EM. Development and evaluation of a patient education program for persons with systemic sclerosis (scleroderma). Arthritis Care Res. 2000 Jun. 13(3):141-8. [Medline].
Legendre C, Allanore Y, Ferrand I, Kahan A. Evaluation of depression and anxiety in patients with systemic sclerosis. Joint Bone Spine. 2005 Oct. 72(5):408-11. [Medline].
Matsuura E, Ohta A, Kanegae F, Haruda Y, Ushiyama O, Koarada S, et al. Frequency and analysis of factors closely associated with the development of depressive symptoms in patients with scleroderma. J Rheumatol. 2003 Aug. 30(8):1782-7. [Medline].
Farge D, Passweg J, van Laar JM, Marjanovic Z, Besenthal C, Finke J, et al. Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR Registry. Ann Rheum Dis. 2004 Aug. 63(8):974-81. [Medline].
Thomas-Golbanov CK, Wilke WS, Fessler BJ, Hoffman GS. Open label trial of tamoxifen in scleroderma. Clin Exp Rheumatol. 2003 Jan-Feb. 21(1):99-102. [Medline].
Fink CW, Cook JD. Spontaneous resolution of calcinosis in childhood dermatomyositis. Arthritis Rheum. 1986. 29(suppl):S91.
Merlino G, Germano S, Carlucci S. Surgical management of digital calcinosis in CREST syndrome. Aesthetic Plast Surg. 2013 Dec. 37 (6):1214-9. [Medline].
Hazen PG, Walker AE, Carney JF, Stewart JJ. Cutaneous calcinosis of scleroderma. Successful treatment with intralesional adrenal steroids. Arch Dermatol. 1982 May. 118(5):366-7. [Medline].
Vayssairat M, Hidouche D, Abdoucheli-Baudot N, Gaitz JP. Clinical significance of subcutaneous calcinosis in patients with systemic sclerosis. Does diltiazem induce its regression?. Ann Rheum Dis. 1998 Apr. 57(4):252-4. [Medline].
Berger RG, Featherstone GL, Raasch RH, McCartney WH, Hadler NM. Treatment of calcinosis universalis with low-dose warfarin. Am J Med. 1987 Jul. 83(1):72-6. [Medline].
Cukierman T, Elinav E, Korem M, Chajek-Shaul T. Low dose warfarin treatment for calcinosis in patients with systemic sclerosis. Ann Rheum Dis. 2004 Oct. 63(10):1341-3. [Medline].
Lassoued K, Saiag P, Anglade MC, Roujeau JC, Touraine RL. Failure of warfarin in treatment of calcinosis universalis. Am J Med. 1988 Apr. 84(4):795-6. [Medline].
Boulman N, Slobodin G, Rozenbaum M, Rosner I. Calcinosis in rheumatic diseases. Semin Arthritis Rheum. 2005 Jun. 34(6):805-12. [Medline].
Rabens SF, Bethune JE. Disodium etidronate therapy for dystrophic cutaneous calcification. Arch Dermatol. 1975 Mar. 111(3):357-61. [Medline].
Metzger AL, Singer FR, Bluestone R, Pearson CM. Failure of disodium etidronate in calcinosis due to dermatomyositis and scleroderma. N Engl J Med. 1974 Dec 12. 291(24):1294-6. [Medline].
Ambler GR, Chaitow J, Rogers M, McDonald DW, Ouvrier RA. Rapid improvement of calcinosis in juvenile dermatomyositis with alendronate therapy. J Rheumatol. 2005 Sep. 32(9):1837-9. [Medline].
Robertson LP, Marshall RW, Hickling P. Treatment of cutaneous calcinosis in limited systemic sclerosis with minocycline. Ann Rheum Dis. 2003 Mar. 62(3):267-9. [Medline].
Taborn J, Bole GG, Thompson GR. Colchicine suppression of local and systemic inflammation due to calcinosis universalis in chronic dermatomyositis. Ann Intern Med. 1978 Nov. 89(5 Pt 1):648-9. [Medline].
Kalajian AH, Perryman JH, Callen JP. Intravenous immunoglobulin therapy for dystrophic calcinosis cutis: unreliable in our hands. Arch Dermatol. 2009 Mar. 145(3):334; author reply 335. [Medline].
Goodfield MJ, Hume A, Rowell NR. The effect of simple warming procedures on finger blood flow in systemic sclerosis. Br J Dermatol. 1988 May. 118(5):661-8. [Medline].
Freedman RR. Quantitative measurements of finger blood flow during behavioral treatments for Raynaud''s disease. Psychophysiology. 1989 Jul. 26(4):437-41. [Medline].
Karavidas MK, Tsai PS, Yucha C, McGrady A, Lehrer PM. Thermal biofeedback for primary Raynaud's phenomenon: a review of the literature. Appl Psychophysiol Biofeedback. 2006 Sep. 31(3):203-16. [Medline].
Meyrick Thomas RH, Rademaker M, Grimes SM, MacKay A, Kovacs IB, Cook ED, et al. Nifedipine in the treatment of Raynaud's phenomenon in patients with systemic sclerosis. Br J Dermatol. 1987 Aug. 117(2):237-41. [Medline].
Thompson AE, Pope JE. Calcium channel blockers for primary Raynaud's phenomenon: a meta-analysis. Rheumatology (Oxford). 2005 Feb. 44(2):145-50. [Medline].
Fischer M, Reinhold B, Falck H, Torok M, Alexander K. Topical nitroglycerin ointment in Raynaud's phenomenon. Z Kardiol. 1985 May. 74(5):298-302. [Medline].
Anderson ME, Moore TL, Hollis S, Jayson MI, King TA, Herrick AL. Digital vascular response to topical glyceryl trinitrate, as measured by laser Doppler imaging, in primary Raynaud's phenomenon and systemic sclerosis. Rheumatology (Oxford). 2002 Mar. 41(3):324-8. [Medline].
Teh LS, Manning J, Moore T, Tully MP, O'Reilly D, Jayson MI. Sustained-release transdermal glyceryl trinitrate patches as a treatment for primary and secondary Raynaud's phenomenon. Br J Rheumatol. 1995 Jul. 34(7):636-41. [Medline].
Torley HI, Madhok R, Capell HA, Brouwer RM, Maddison PJ, Black CM, et al. A double blind, randomised, multicentre comparison of two doses of intravenous iloprost in the treatment of Raynaud's phenomenon secondary to connective tissue diseases. Ann Rheum Dis. 1991 Nov. 50(11):800-4. [Medline].
Milio G, Corrado E, Genova C, Amato C, Raimondi F, Almasio PL, et al. Iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis and the quality of life: a new therapeutic protocol. Rheumatology (Oxford). 2006 Aug. 45(8):999-1004. [Medline].
Kaminaga T, Takada K, Kutomi K, Imai E, Furui S. Improvement in cold-induced Raynaud's syndrome with administration of ticlopidine hydrochloride detected by Tc-99m DTPA human serum albumin scintigraphy. Clin Nucl Med. 2002 Feb. 27(2):131-2. [Medline].
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. 2003 Dec 1. 92(11):1310-5. [Medline].
Dean SM, Satiani B. Three cases of digital ischemia successfully treated with cilostazol. Vasc Med. 2001 Nov. 6(4):245-8. [Medline].
Bridges AJ, Spadone DP. Tissue plasminogen activator treatment of digital thrombosis in severe Raynaud's phenomenon--a case report. Angiology. 1993 Jul. 44(7):566-9. [Medline].
Denton CP, Howell K, Stratton RJ, Black CM. Long-term low molecular weight heparin therapy for severe Raynaud's phenomenon: a pilot study. Clin Exp Rheumatol. 2000 Jul-Aug. 18(4):499-502. [Medline].
Jacobs MJ, Jörning PJ, Van Rhede van der Kloot EJ, Kitslaar PJ, Lemmens HA, Slaaf DW, et al. Plasmapheresis in Raynaud's phenomenon in systemic sclerosis: a microcirculatory study. Int J Microcirc Clin Exp. 1991 Feb. 10(1):1-11. [Medline].
O'Reilly MJ, Talpos G, Roberts VC, White JM, Cotton LT. Controlled trial of plasma exchange in treatment of Raynaud's syndrome. Br Med J. 1979 Apr 28. 1(6171):1113-5. [Medline].
Koo AP. Therapeutic apheresis in autoimmune and rheumatic diseases. J Clin Apher. 2000. 15(1-2):18-27. [Medline].
Dziadzio M, Denton CP, 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. 1999 Dec. 42(12):2646-55. [Medline].
Pancera P, Sansone S, Secchi S, Covi G, Lechi A. The effects of thromboxane A2 inhibition (picotamide) and angiotensin II receptor blockade (losartan) in primary Raynaud's phenomenon. J Intern Med. 1997 Nov. 242(5):373-6. [Medline].
Wood HM, Ernst ME. Renin-angiotensin system mediators and Raynaud's phenomenon. Ann Pharmacother. 2006 Nov. 40(11):1998-2002. [Medline].
Baumhaekel M, Scheffler P, Boehm M. Use of tadalafil in a patient with a secondary Raynaud's phenomenon not responding to sildenafil. Microvasc Res. 2005 May. 69(3):178-9. [Medline].
Gore J, Silver R. Oral sildenafil for the treatment of Raynaud's phenomenon and digital ulcers secondary to systemic sclerosis. Ann Rheum Dis. 2005 Sep. 64(9):1387. [Medline].
Caglayan E, Huntgeburth M, Karasch T, Weihrauch J, Hunzelmann N, Krieg T, et al. Phosphodiesterase type 5 inhibition is a novel therapeutic option in Raynaud disease. Arch Intern Med. 2006 Jan 23. 166(2):231-3. [Medline].
Wise RA, Wigley FM, 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. 2004 Dec. 50(12):3994-4001. [Medline].
Johnson S, Iazzetta J, Dewar C. Severe Raynaud's phenomenon with yohimbine therapy for erectile dysfunction. J Rheumatol. 2003 Nov. 30(11):2503-5. [Medline].
Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002 Mar 21. 346(12):896-903. [Medline].
Coleiro B, Marshall SE, Denton CP, Howell K, Blann A, Welsh KI, et al. Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology (Oxford). 2001 Sep. 40(9):1038-43. [Medline].
Garcia-Porrua C, Margarinos CC, Gonzalez-Gay MA. Raynaud's phenomenon and serotonin reuptake inhibitors. J Rheumatol. 2004 Oct. 31(10):2090; author reply 2090-1. [Medline].
Herrick AL. Treatment of Raynaud's phenomenon: new insights and developments. Curr Rheumatol Rep. 2003 Apr. 5(2):168-74. [Medline].
Wang SJ, La JL, Chen DY, Chen YH, Hsieh TY, Lin WY. Effects of cisapride on oesophageal transit of solids in patients with progressive systemic sclerosis. Clin Rheumatol. 2002 Feb. 21(1):43-5. [Medline].
Hulshof MM, Bouwes Bavinck JN, Bergman W, Masclee AA, Heickendorff L, Breedveld FC, et al. Double-blind, placebo-controlled study of oral calcitriol for the treatment of localized and systemic scleroderma. J Am Acad Dermatol. 2000 Dec. 43(6):1017-23. [Medline].
Clements PJ, Furst DE, Wong WK, Mayes M, White B, Wigley F, et al. High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, double-blind, randomized, controlled clinical trial. Arthritis Rheum. 1999 Jun. 42(6):1194-203. [Medline].
Alam M, Dover JS, Arndt KA. Treatment of facial telangiectasia with variable-pulse high-fluence pulsed-dye laser: comparison of efficacy with fluences immediately above and below the purpura threshold. Dermatol Surg. 2003 Jul. 29(7):681-4; discussion 685. [Medline].
Saddic N, Miller JJ, Miller OF 3rd, Clarke JT. Surgical debridement of painful fingertip calcinosis cutis in CREST syndrome. Arch Dermatol. 2009 Feb. 145(2):212-3. [Medline].
Melone CP Jr, McLoughlin JC, Beldner S. Surgical management of the hand in scleroderma. Curr Opin Rheumatol. 1999 Nov. 11(6):514-20. [Medline].
Chamberlain AJ, Walker NP. Successful palliation and significant remission of cutaneous calcinosis in CREST syndrome with carbon dioxide laser. Dermatol Surg. 2003 Sep. 29(9):968-70. [Medline].
Bottomley WW, Goodfield MJ, Sheehan-Dare RA. Digital calcification in systemic sclerosis: effective treatment with good tissue preservation using the carbon dioxide laser. Br J Dermatol. 1996 Aug. 135(2):302-4. [Medline].
Medsger TA. Systemic sclerosis (scleroderma): Clinical aspects. Koopman WJ, ed. Arthritis and Allied Conditions: A Textbook of Rheumatology. 13th ed. Williams and Wilkins; 1997. 1433-64.