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CREST Syndrome

  • Author: Jeanie C Yoon, MD; Chief Editor: Dirk M Elston, MD  more...
Updated: Oct 15, 2015


CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome is a member of the heterogeneous group of sclerodermas, and its name is an acronym for the cardinal clinical features of the syndrome.

In 1910, Thibierge and Weissenbach described the first case report of what was later called CRST (calcinosis cutis, Raynaud phenomenon, sclerodactyly, and telangiectasia) syndrome in English by Winterbauer who, in 1964, described a series of 8 patients with the features that make up the abbreviation CRST.[1, 2] Although he noted esophageal dysmotility in 4 of 8 patients, he did not include this feature in his original description of CRST syndrome. Frayha et al[3] noted the frequent occurrence of esophageal dysmotility and suggested that the acronym CREST may be more appropriate. Velayos et al[4] reviewed 13 patients with CREST and CRST syndromes and found the syndromes equivalent.

The 1980 American College of Rheumatology Classification Criteria for Rheumatic Diseases is the most widely used system for systemic scleroderma. Because it was designed for research applications and not for clinical diagnosis, it has been criticized for its low sensitivity in identifying early disease and milder forms of systemic scleroderma such as CREST syndrome. Several authors recognized this limitation and responded by categorizing patients with scleroderma syndromes into 2 groups: those with diffuse cutaneous scleroderma and those with a limited form of scleroderma.[5, 6, 7]

Others have shown that visceral involvement, poorer prognosis, and higher mortality are all more common in patients with diffuse disease.[8, 9, 10, 11] Several new classification systems may better categorize the wide spectrum of systemic scleroderma.

In 2004, Nadashkevich et al[12] proposed the classification criteria (1) autoantibodies to centromere proteins, Scl-70 (topo I) and fibrillarin; (2) bibasilar pulmonary fibrosis; (3) contractures of the digital joints or the prayer sign; (4) dermal thickening proximal to the wrists; (5) calcinosis cutis; (6) Raynaud phenomenon (at least a 2-phase color change); (7) esophageal distal hypomotility or reflux esophagitis; (8) sclerodactyly or nonpitting digital edema; and (9) telangiectasias, which can be remembered by the abbreviation ABCDCREST. Fulfilling 3 or more criteria indicates definite systemic scleroderma with a sensitivity and specificity as high as 99% and 100%, respectively.

Also in 2004, Maricq and Valter[13] had a complex but potentially very useful proposal for classifying the scleroderma spectrum disorders; however, in 2005, Wollheim[14] reported that without substantial independent confirmatory work, this classification system may not gain widespread acceptance in its present form.

The Maricq and Valter[13] proposed classification for scleroderma spectrum disease is as follows:

  • Type I - Diffuse skin involvement proximal to elbows/knees; includes trunk
  • Type II - Intermediate skin involvement proximal to the metacarpal phalangeal/metatarsal phalangeal joints, distal to the elbows/knees; trunk not involved
  • Type III - Digital sclerodactyly only (meets American College of Rheumatology minor criteria but excludes those without skin involvement)
  • Type IV - Scleroderma sine scleroderma (capillary pattern or pitting scars and visceral involvement; no anticentromere antibodies; no telangiectasia)
  • Type V - Undifferentiated connective-tissue disease with 2 of 3 of the following scleroderma features: sclerodactyly, pitting scars, or scleroderma capillary pattern; or one of these features along with one of the following: Raynaud phenomenon, pulmonary fibrosis, or visceral involvement (esophagus, heart, kidney); but do not meet the criteria for groups III and IV; no anticentromere antibodies; no telangiectasia
  • Type VI - CREST; no skin involvement, or sclerodactyly only, telangiectasia is required with one or more other acronyms; or anticentromere antibodies are required with any 2 or more acronyms


Three primary pathologic features are found in scleroderma and include increased collagen deposition, perivascular mononuclear cell infiltration, and vascular abnormalities.

The pathologic hallmark of scleroderma is progressive fibrosis of tissues. Collagen (types I, III, IV, and VII), fibronectin, glycosaminoglycans, and proteoglycans are deposited in the interstitium and in the intima of small arteries.[15] Fibrosis is found in clinically affected and unaffected tissue.

Skin fibroblasts in patients with scleroderma act as if they are persistently activated. Higher levels of COL1A2 mRNA (gene encoding alpha-2 chain of type I procollagen) are found in the dermis of scleroderma patients compared with patients without scleroderma, and down-regulation of fibroblast collagen synthesis by collagen amino-terminal peptides is impaired.

Mononuclear infiltration probably precedes fibrosis of tissues. Histologic specimens from patients with disease duration of less than 2 years show mononuclear infiltration near blood vessels and dermal appendages. While this inflammatory infiltrate can accompany fibrosis in tissues, it can also be present without fibrosis, suggesting that it is an early event in the pathogenesis of scleroderma.

CD4 lymphocytes predominate in the inflammatory infiltrate. Suppressor T cells are diminished in number. Macrophages are present in higher numbers, as are eosinophils, basophils, mast cells, and B cells. These cells secrete a variety of cytokines, the balance of which is important in the pathogenesis of fibrosis.

Several cytokines have been implicated in the development of fibrosis. Transforming growth factor-beta (TGF-beta) stimulates collagen synthesis, and plasma levels of this cytokine are elevated in scleroderma patients (both limited and diffuse scleroderma). Fibroblasts from the skin of scleroderma patients express increased amounts of mRNA for TGF-beta and secrete higher levels of TGF-beta. Furthermore, these fibroblasts are not as sensitive as normal fibroblasts to stimulation by exogenous TGF-beta, suggesting that they are already maximally stimulated. TGF-beta3 in particular has been suggested as having a major role in the pathogenesis of the calcinosis often seen in persons with systemic sclerosis.[16]

Sera from patients with systemic scleroderma contain enhanced concentrations of granulocyte macrophage colony-stimulating factor (GM-CSF). Incubating GM-CSF with dermal fibroblasts from systemic scleroderma patients decreases type I collagen mRNA levels and collagen synthesis while increasing the production of other extracellular matrix proteins such as fibronectin and tenascin.[17]

Interleukin 4, a potent stimulator of collagen synthesis, is overexpressed in scleroderma skin. Scleroderma patients have normal or reduced levels of interferon-gamma (IFN-gamma), an inhibitor of collagen synthesis, in the skin. Interleukin 4 is produced by T helper-2 (TH2) cells, and IFN-gamma is produced by T helper-1 (TH1) cells. Scleroderma fibroblasts may be responding to an imbalance in these usual regulatory cytokines as a result of a predominance of TH2 cell activity.

Other cytokine perturbations have been demonstrated. Scleroderma fibroblasts secrete a higher basal level of connective tissue growth factor (CTGF) than normal fibroblasts. Scleroderma fibroblasts are less responsive to tumor necrosis factor-alpha, which normally acts to suppress CTGF expression.

Serum tissue inhibitor of metalloproteinase-1 (TIMP-1) levels are elevated in scleroderma patients compared with normal controls. This may allow progressive fibrosis to result because of a relative lack of collagenase activity. TIMP-1 may behave as an autocrine growth factor in the fibrotic process of scleroderma.[18] Recently, the protease nexin-1 gene (PN1) has been found to be overexpressed in systemic sclerosis fibroblasts. PN1 plays an important role in the regulation of cell growth, differentiation, and cell death by modulating proteolytic activity; in vitro evidence suggests it inhibits metalloproteinase activation.[19]

Vascular abnormalities are also likely to be an early contributor to the pathogenesis of scleroderma. Pericytes, the smooth muscle–like mural cells of capillaries and venules, synthesize matrix components and fibroblast-activating cytokines; thus, they are potential mediators of pathological changes in scleroderma. Pericyte density is increased in the microvasculature of the peripheral zones of active disease.[20] Clinically, microvascular changes are apparent in the nailfold capillaries as larger tufted capillaries and areas of dropout. The vasospastic phenomenon of Raynaud is present in most scleroderma patients.

Endothelial cell injury and dysfunction, intimal proliferation, thrombocytosis, elevated factor VIII-von Willebrand factor levels, and vasospasm are found in scleroderma patients and result in vascular compromise. Elevated levels of platelet-derived growth factor (PDGF) and increased expression of PDGF type-B receptors are found in the skin of scleroderma patients.[21, 22] Ischemia is an important contributor to end organ damage in scleroderma patients.

Animal models of scleroderma may help identify abnormalities in human scleroderma. The tight skin mouse model of scleroderma (Tsk1) is characterized by increased collagen deposition in the skin and some internal organs, as well as antinuclear antibody (ANA) production. The defect is a heterozygous mutation in the fibrillin-1 gene. A 1996 haplotype analysis of Choctaw Native Americans (who have a 50-fold increase in the prevalence of scleroderma) has demonstrated linkage between the fibrillin gene locus and the scleroderma phenotype. How a defect in fibrillin, an extracellular matrix component, may be involved in the pathogenesis of scleroderma is unclear.

An avian model, the UCD-200 chicken, develops fibrosis of the skin and internal organs and the presence of ANAs. Affected chickens develop vascular occlusion and severe perivascular lymphocytic infiltration of the skin and internal organs. These studies suggest that early pathogenetic events in scleroderma are endothelial abnormalities. Antiendothelial cell antibodies trigger both apoptosis and increased adhesion molecule expression on endothelial cells, resulting in perivascular accumulation of mononuclear cells.

In summary, while the primary trigger for CREST syndrome is not known, a reasonable speculation is that vascular endothelial cell abnormalities incite mononuclear infiltration, and the resulting perturbations in TH1 and/or TH2 cell and cytokine balance result in abnormal fibroblast activity and increased collagen deposition.

Nelson[23] has suggested the role of microchimerism in the pathogenesis of scleroderma, because of the similarity of scleroderma to chronic graft versus host disease and the frequent onset of scleroderma in women after their childbearing years. Microchimerism indeed occurs to a greater degree in persons with scleroderma or other autoimmune disorders than in healthy patients. A causal linkage between microchimerism and autoimmune disorders has not been demonstrated.




United States

The incidence of systemic sclerosis approximates 2.7-19.3 new cases per million adults per year. The prevalence is 253-286 cases per million persons.[24] The highest prevalence has been reported in a Choctaw Native American Group in Oklahoma (660 cases per million, based on 14 cases).[25] The apparent increase in both incidence and prevalence over the past 50 years is most likely an artifact of better classification, earlier diagnosis, and improved survival. Some serum antibody studies suggest that CREST syndrome may account for 22-25% of all cases of systemic sclerosis; however, epidemiologic studies specifically looking at CREST syndrome are lacking.[24, 25, 26, 27]


In other countries, the incidence of systemic sclerosis is slightly lower than in the United States. In Iceland, systemic sclerosis occurs In 3.8 patients per million per year; a high percentage of patients in this population have limited forms of scleroderma. The incidence in Russia is 7 cases per million adults per year, in England is 3.7 cases per million per year, in Greece is 11 cases per million per year, and in New Zealand is 2.3 cases per million per year. Disease prevalence is slightly lower in other countries compared with the United States; in Greece it is 154 cases per million, in the United Kingdom is it 82 cases per million, in France it is 158 cases per million, and in Australia it is 86-233 cases per million.[11, 28, 24, 29, 30, 31, 32]


Both the prevalence and incidence of systemic sclerosis is higher in blacks than in whites. The prevalence of diffuse disease among black patients is nearly twice that of white patients. Survival for black patients versus nonblack patients is marginally worse during the first 12 years after diagnosis, but, in general, survival for both groups is comparable.[24]

Some Choctaw Native American and Thai populations are more likely to have diffuse disease, while some European and white Australian groups have more limited disease.


Females have a greater incidence of scleroderma than males. This difference appears greater during childbearing years. Mayes et al[24] reported an overall female-to-male ratio of 4.6:1.


The usual age of onset of scleroderma is approximately 30-65 years. Black women tend to present at an earlier age.

Contributor Information and Disclosures

Jeanie C Yoon, MD Clinical Instructor, Department of General Internal Medicine, University of Washington School of Medicine

Jeanie C Yoon, MD is a member of the following medical societies: American College of Physicians, Society of Hospital Medicine

Disclosure: Nothing to disclose.


Gregory J Raugi, MD, PhD Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle School of Medicine; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle

Gregory J Raugi, MD, PhD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, American College of Rheumatology

Disclosure: Received income in an amount equal to or greater than $250 from: XOMA; Biogen/IDEC; Novartis; Janssen Biotech, Abbvie, CSL pharma<br/>Received honoraria from UpToDate for author/editor; Received honoraria from JAMA Dermatology for associate editor and intermittent author; Received royalty from Elsevier for book author/editor; Received dividends from trust accounts, but I do not control these accounts, and have directed our managers to divest pharmaceutical stocks as is fiscally prudent from Stock holdings in various trust accounts include some pharmaceutical companies and device makers for i inherited these trust accounts; for: Celgene; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.


The authors and editors of Medscape Reference wish to thank Dr. Bruce Gilliland for assistance in reviewing the manuscript and Dr. Jan V. Hirschmann and Dr. Netayna Sandler for their images.

The authors and editors of Medscape Reference also gratefully acknowledge the contributions of previous authors, Mary A. Wemple, MD, and Kyle L. Horner, MD, MS, to the development and writing of this article.

  1. 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].

  2. 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].

  3. Frayha RA, Scarola JA, Shulman LE. Calcinosis in scleroderma: A reevaluation of the CRST syndrome, abstracted. Arthritis Rheum. 1973. 16:542.

  4. 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].

  5. Rodnan GP, Jablonska S, Medsger TA. Classification and nomenclature of progressive systemic sclerosis (scleroderma). Clin Rheum Dis. 1979. 5:5-13.

  6. 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].

  7. Tuffanelli DL, Winkelmann RK. Diffuse systemic scleroderma. A comparison with acrosclerosis. Ann Intern Med. 1962 Aug. 57:198-203. [Medline].

  8. 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].

  9. 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].

  10. 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].

  11. Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am. 1996 Nov. 22(4):751-64. [Medline].

  12. 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].

  13. 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].

  14. Wollheim FA. Classification of systemic sclerosis. Visions and reality. Rheumatology (Oxford). 2005 Oct. 44(10):1212-6. [Medline].

  15. 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].

  16. 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].

  17. 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].

  18. 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].

  19. 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].

  20. 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].

  21. LeRoy EC. Systemic sclerosis. A vascular perspective. Rheum Dis Clin North Am. 1996 Nov. 22(4):675-94. [Medline].

  22. 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].

  23. Nelson JL. Microchimerism and the pathogenesis of systemic sclerosis. Curr Opin Rheumatol. 1998 Nov. 10(6):564-71. [Medline].

  24. 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].

  25. 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].

  26. 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].

  27. 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].

  28. Silman AJ, Newman J. Epidemiology of systemic sclerosis. Curr Opin Rheumatol. 1996 Nov. 8(6):585-9. [Medline].

  29. 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].

  30. 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].

  31. 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].

  32. 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].

  33. 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].

  34. 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].

  35. 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].

  36. Lachter J, Suissa A, Schiff E, Rosner I. Anemia in CREST syndrome. Isr Med Assoc J. 2003 Jun. 5(6):449. [Medline].

  37. Meyer O. [Crest Syndrome]. Ann med Interne (Paris). 2002. 153(3):183-188. [Medline].

  38. 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].

  39. Kouraklis G, Glinavou A, Karatzas G. Primary biliary cirrhosis accompanied by CREST syndrome. South Med J. 2002 Sep. 95(9):1058-9. [Medline].

  40. 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].

  41. 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].

  42. 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].

  43. Sjogren RW. Gastrointestinal motility disorders in scleroderma. Arthritis Rheum. 1994 Sep. 37(9):1265-82. [Medline].

  44. 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].

  45. 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].

  46. 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].

  47. Mayes MD. Endothelin and endothelin receptor antagonists in systemic rheumatic disease. Arthritis Rheum. 2003 May. 48(5):1190-9. [Medline].

  48. 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].

  49. 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].

  50. van Paassen P, Damoiseaux J, Tervaert JW. Laboratory assessment in musculoskeletal disorders. Best Pract Res Clin Rheumatol. 2003 Jun. 17(3):475-94. [Medline].

  51. 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].

  52. 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].

  53. 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].

  54. Strumia R. Videodermatoscopy: a useful tool for diagnosing cutaneous dystrophic calcifications. Dermatol Online J. 2005. 11(1):28. [Medline].

  55. 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].

  56. Joslin N. Early identification key to scleroderma treatment. Nurse Pract. 2004 Jul. 29(7):24-39; quiz 40-1. [Medline].

  57. Rus V, White B. Systemic sclerosis: multiple therapies control morbidity. J Musculoskel Med. 2002. 19:110-121.

  58. 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].

  59. 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].

  60. 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].

  61. 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].

  62. 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].

  63. Fink CW, Cook JD. Spontaneous resolution of calcinosis in childhood dermatomyositis. Arthritis Rheum. 1986. 29(suppl):S91.

  64. Merlino G, Germano S, Carlucci S. Surgical management of digital calcinosis in CREST syndrome. Aesthetic Plast Surg. 2013 Dec. 37 (6):1214-9. [Medline].

  65. 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].

  66. 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].

  67. 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].

  68. 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].

  69. 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].

  70. Boulman N, Slobodin G, Rozenbaum M, Rosner I. Calcinosis in rheumatic diseases. Semin Arthritis Rheum. 2005 Jun. 34(6):805-12. [Medline].

  71. Rabens SF, Bethune JE. Disodium etidronate therapy for dystrophic cutaneous calcification. Arch Dermatol. 1975 Mar. 111(3):357-61. [Medline].

  72. 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].

  73. 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].

  74. 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].

  75. 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].

  76. 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].

  77. 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].

  78. Freedman RR. Quantitative measurements of finger blood flow during behavioral treatments for Raynaud''s disease. Psychophysiology. 1989 Jul. 26(4):437-41. [Medline].

  79. 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].

  80. 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].

  81. Thompson AE, Pope JE. Calcium channel blockers for primary Raynaud's phenomenon: a meta-analysis. Rheumatology (Oxford). 2005 Feb. 44(2):145-50. [Medline].

  82. 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].

  83. 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].

  84. 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].

  85. 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].

  86. 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].

  87. 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].

  88. 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].

  89. Dean SM, Satiani B. Three cases of digital ischemia successfully treated with cilostazol. Vasc Med. 2001 Nov. 6(4):245-8. [Medline].

  90. 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].

  91. 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].

  92. 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].

  93. 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].

  94. Koo AP. Therapeutic apheresis in autoimmune and rheumatic diseases. J Clin Apher. 2000. 15(1-2):18-27. [Medline].

  95. 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].

  96. 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].

  97. Wood HM, Ernst ME. Renin-angiotensin system mediators and Raynaud's phenomenon. Ann Pharmacother. 2006 Nov. 40(11):1998-2002. [Medline].

  98. 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].

  99. 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].

  100. 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].

  101. 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].

  102. 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].

  103. 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].

  104. 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].

  105. 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].

  106. Herrick AL. Treatment of Raynaud's phenomenon: new insights and developments. Curr Rheumatol Rep. 2003 Apr. 5(2):168-74. [Medline].

  107. 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].

  108. 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].

  109. 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].

  110. 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].

  111. 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].

  112. Melone CP Jr, McLoughlin JC, Beldner S. Surgical management of the hand in scleroderma. Curr Opin Rheumatol. 1999 Nov. 11(6):514-20. [Medline].

  113. 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].

  114. 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].

  115. 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.

Calcinosis on dorsal forearm.
Close-up view of calcinosis.
Raynaud phenomenon showing pallor of most of the finger tips with a violaceous discoloration (hyperemia) of the thumb tip.
Sclerodactyly (also with Raynaud phenomenon).
Telangiectasia of the face.
Telangiectasia of the lip.
Telangiectasia of the finger.
Close-up view of telangiectasia.
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