CREST Syndrome - a Limited Form of Systemic Scleroderma: a Case Report and Literature Review

Open access

Abstract

Systemic scleroderma (SSc) is a multisystem disease with microvascular abnormalities, autoimmune disorders, excessive collagen production and deposition, and fibrosis of the skin and internal organs. According to the simplest, though incomplete classification, there are two forms of SSc: diffuse and limited (formerly acrosclerosis). CREST syndrome is a subtype of limited SSc, characterized by: calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia. We present a patient with all the features of the CREST syndrome, which appeared at the age of 43 and lasted for 23 years. The patient presented with a gradual development of symptoms during the first ten years, from Raynaud’s phenomenon, skin sclerosis, calcinosis, telangiectasia, and esophageal dysmotility. The diagnosis was based on clinical findings and relevant diagnostic procedures. The article presents a literature review on the epidemiology, etiology, pathophysiology, clinical manifestations, various attempts at classification, diagnostic criteria, and therapeutic modalities.

When classifying systemic scleroderma into two main types — diffuse and limited, with CREST syndrome as a variant of the latter, it should be pointed out that both types represent clinical forms of systemic sclerosis, share similar visceral involvement, laboratory abnormalities and course which is variable, as was the case in our patient.

1. Karadaglić Đ, Pavlović M. Sklerodermija. In: Karadaglć Đ, editor. Dermatologija. Beograd: Vojnoizdavački zavod, Versalpress Beograd; 2000. p. 1721-41.

2. Jimenez SA, Derk CT. Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis. Ann Intern Med 2004; 140: 37-50.

3. Fabri M, Hunzelmann N. Differential diagnosis of scleroderma and pseudoscleroderma. J Dtsch Dermatol Ges 2007;5(11):977-84.

4. Mavrogeni S, Bratis C, Manoussakis M. Coronary artery abnormalities in CREST syndrome revealed by cardiovascular magnetic resonance imaging. Can J Cardiol 2011;27:390e5-7.

5. Tuffanelli DL, Winkelman RK. Diffuse systemic scleroderma. A comparison with acrosclerosis. Ann Intern Med 1962;57:198-203.

6. Barnnett AJ. Scleroderma (progressive systemic sclerosis): progress and course based on a personal series of 118 cases. Med J Aust 1978;2:129-34.

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

8. Giordano M, Valentini G, Migliaresi S, Picillo U, Vatti M. Different antibody patterns and different prognoses in patient with scleroderma with various extent of skin sclerosis. J Rheumatol 1986;13:911-6.

9. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988;15:202-5.

10. Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980;23:581-90.

11. Drake LA, Dinehart SM, Farmer ER, Goltz RW, Graham GF, Hordinsky MK, et al. Guidelines of care for scleroderma and sclerodermoid disorders. J Am Acad Dermatol 1996;35:609-14.

12. LeRoy EC, Medsger TA. Criteria for the classification of early systemic sclerosis. J Rheumtol 2001;28:1573-6.

13. Poormoghim H, Lucas M, Fertig N, Medsger TA, Jr. Systemic sclerosis sine scleroderma: demographic, clinical and serologic features and survival in forty-eight patients. Arthritis Rheum 2000;43:444-51.

14. 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;22(3 Suppl. 33):S5-13.

15. Walker JG, Pope J, Baron M, LeClercq S, Hudson M, Taillefer S, et al. The development of systemic sclerosis classification criteria. Clin Rheumatol 2007;26:1401-9.

16. Hinchcliff M, Varga J. Systemic sclerosis/scleroderma: a treatable multisystem disease. Am Fam Psysican 2008;78(8):961-8.

17. Habif TP, Campbell JL, Chapman MS, Dinulos JGH, Zug KA. Skin disease diagnosis and treatment. Philadelphia: Elsevier Mosby; 2005. p. 354-7.

18. Chifflot H, Fautrel B, Sordet C, Chatelus E, Sibilia J. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum 2008;37:223-35.

19. Mayes MD, Lacey JV Jr, Beebe-Dimmer J, Gillespie BW, Cooper B, Laining TJ, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 2003;48:2246-55.

20. Englert H, Joyner J, Bade R, Thompson M, Morris D, Chambers P, et al. Systemic scleroderma: a spatiotemporal clustering. Int Med J 2005;35:228-33.

21. Tamaki T, Mori S, Takehara K. Epidemiological study of patients with systemic sclerosis in Tokyo. Arch Dermatol Res 1991;283:366-71.

22. Alamanos Y, Tsifetaki N, Voulgari PV. Epidemiology of systemic sclerosis in Northwest Greece 1981 to 2002. Semin Arthritis Rheum 2005;34:714-20

23. Scalapino K, Arkachaisri T, Lucas M, Fertig N, Helfrich DJ, Londino AV Jr, et al. Childhood onset systemic sclerosis: classification, clinical and serologic features, and survival in comparison with adult onset disease. J Reumatol 2006;33(5):1004-13.

24. Tan FK. Systemic sclerosis: the susceptible host (genetics and environment). Rheum Dis Clin North Am 2003;29:211-37.

25. Radić M, Martinović Kaliterna D, Fabijanić D, Radić J. Sistemska skleroza-patogeneza, kliničke manifestacije i liječenje. Liječ Vjesn 2010;132:162-8.

26. Yoon JC, Elston DM. CREST syndrome treatment and management. Medscape Drug, Disease and Procedures. [updated 2015 Oct 15; cited 2015 Oct 23]. Available from: http://emedicine.medscape.com/article/1064663-treatment

27. Wollheim FA. Classification of systemic sclerosis. Visions and reality. Rheumatology 2005;44:1212-6.

28. Herrik AL, Worthington A. Genetic epidemiology: systemic sclerosis. Arthritis Res 2002;4:165-8.

29. Gladman DD, Kung TN, Siannis F, Pellett F, Farewell VT, Lee P. HLA markers for susceptibility and expression in scleroderma. J Rheumatol 2005;32(8):1481-7.

30. Del Rio APT, Sachetto Z, Sampaio-Barros PD, Marques-Neto JF, Santos Londe AC, Barros Bertolo M. HLA markers for poor prognosis in systemic sclerosis Brazilian patients. Dis Markers 2013;35(2):73-8.

31. Hartree N, Harding M, Jackson C. Systemic sclerosis (scleroderma). [cited 2015 Oct 1]. Available from: http://patient.info/doctor/systemic-sclerosis-scleroderma

32. Limited scleroderma (CREST syndrome). ). [cited 2015 Oct 1]. Available from: http://www.mayoclinic.org/diseases-conditions/crest-syndrome/basics/definition/con-20031524

33. Maitre 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;31(12):2395-401.

34. 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;77:10-6.

35. Goodfield MJD, Jones SK, Veale DJ. The connective tissue diseases. In: Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s Textbook of Dermatology. 8th ed. London: Wiley-Blackwell; 2010. p. 51.64-51.79.

36. 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;29(1):94-101.

37. Thibierge G, Weissenbach R. Concretions calcaires souscutanées et sclerodermie. Ann Dermatol Syph 1911;4:129-55.

38. Winterbauer RH. Multiple telangiectasia, Raynaud’s phenomenon, sclerodactyly, and subcutanious calcinosis: a syndrome mimicking hereditary hemorrhagic telangiectasia. Bull Johns Hopkins Hosp 1964;114:361-83.

39. Frayha RA, Scarola JA, Hulman LE. Calcinosis in scleroderma: a reevaluation of the CREST syndrome (abstract). Arthritis Rheum 1973;16:542.

40. Ensz S. Kidney (renal) involvement (main meni). International Scleroderma Network; c1998-2015 [cited 2015 Oct 1]. Available from: http://www.sclero.org/scleroderma/symptoms/renal/a-to-z.html

41. Goodfield MJ, Jones SK, Veale DJ. The connective tissue diseases. In: Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s textbook of dermatology. 8th ed. Oxford: Blackwell Publishing; 2010. p. 51.1-51.138.

42. Robertson LP, Marshall RW, Hickling P. Treatment of cutaneous calcinosis in limited systemic sclerosis with minocycline. Ann Rheum Dis Mar 2003;62(3):267-9.

43. Kawakami T, Soma Y, Mizoguchi M, Saito R. Immunohistochemical analysis of transforming growth factor-beta 3 in calcinosis in a patient with systemic sclerosis and CREST syndrome. Br J Dermatol 2000;143:1097-131.

44. Merlino G, Germano S, Carlucci S. Surgical management of digital calcinosis in CREST syndrome. Aesthetic Plast Surg 2013;37:1214-9.

45. Ngan V. Systemic sclerosis. Derm Net NZ c2003. [updated 2014 Dec 25; cited 2015 Oct 1]. Available from: http://www.dermnetnz.org/immune/systemic-sclerosis.html.

46. Limited scleroderma (CREST syndrome). [cited 2015 Oct 1]. Available from: http://www.medicalgeek.com/disease-syndromes-procedures/15910-limited-scleroderma-crest-syndrome.html.

47. Raynaud M. De l’asphyxie local de la gangrene symetrique des extremites. Paris: L. Leclerc; 1862.

48. Paravina M. Bolesti vezivnog tkiva. In: Paravina M, Spalević Lj, Stanojević M. Tiodorović J, Binić I, Jovanović D. Dermatovenerologija. Niš: Prosveta; 2006. p. 219-28.

49. Limited scleroderma (CREST syndrome). [cited 2015 Oct 1]. Available from: www.drugs.com/mcd/limited-scleroderma-crest–syndrome

50. CREST Syndrome. [cited 2015 Oct 1]. Available from: http://en.wikipedia.org/wiki/CREST-syndrome

51. Hachulla E, Coghlan JG. A new era in the management of pulmonary arterial hypertension related to scleroderma: endothelin receptor antagonism. Ann Rheum Dis 2004;63:1009-14.

52. Proudman SM, Stevens WM, Sahhar J, Celermajer D. Pulmonary arterial hypertension in systemic sclerosis: the need for early detection and treatment. Intern Med J 2007;37:485-94.

53. Wigley FM, Lima JA, Mayes M, McLain D, Chapin JL, Ward-Able C. The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the UNCOVER study). Arthritis Rheum 2005;52:2125-32.

54. Chang B, Schachna L, White B, Wigley FM, Wise RA. Natural history of mild-moderate pulmonary hypertension and the risk factors for severe pulmonary hypertension in scleroderma. J Rheumatol 2006;33: 269-74.

55. Cox SR, Walker JG, Coleman M, Rischmueller M, Proudman S, Smith MD, et al. Isolated pulmonary hypertension in scleroderma. Inter Med J 2005;35:28-33.

56. Batal I, Domsic RT, Medsger TA, Bastacky S. Scleroderma renal crisis: a pathology perspective. Int J Rheumatol 2010;2010:543704.

57. Steen VD, Medsger TA Jr. Long-term outcomes of scleroderma renal crisis. Ann Intern Med 2000;133:600-3.

58. Tarcin O, Tarcin O, Ozcivan M, Aydin H, Tiftikci A. CREST syndrome and Renal involvement. Marmara Med J 2007;20(3):186-9.

59. Sugimoto T, Sanada M, Kashiwagi A. Is scleroderma renal crisis with anti-centromere antibody-positive limited cutaneous systemic sclerosis overlooked in patients with hypertension and or renal dysfunction? Nephrology 2008;13(2): 179-80.

60. Sugimoto T, Soumura M, Soumura M. Scleroderma renal crisis in a patient with anticentromere antibody-positive limited cutaneous systemic sclerosis. Mod Rheumatol 2006;16(5):309-11.

61. Trang G, Steele R, Baron M, Hudson M. Corticosteroids and the risk of scleroderma renal crisis: a systematic review. Rheumatol Int 2012;32(3):645-53.

62. 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. Hepathol Res 2002;22:187-95.

63. Kouraklis G, Glinavou A, Karatzas G. Primary biliary cirrhosis accompanied by CREST syndrome. South Med J 2002;95(9):1058-9.

64. Mavrogeni S, Manoussakis MN, Karagiorga TS, Douskou M, Panagiotakos D, Bournia V, et al. Detection of coronary artery lesions and myocardial necrosis by magnetic resonance in systemic necrotizing vasculitides. Arthitis Rheum 2009;61:1121-9.

65. Mavrogeni S, Bratis C, Manoussakis M. Coronary artery abnormalities in crest syndrome revealed by cardiovascular magnetic resonance imaging. Can J Cardiol 2011; 27:390e5-7.

66. Tzelepis GE, Kelekis NL, Plastiras SC, Mitseas P, Economopoulos N, Campolis C, et al. Pattern and distribution of myocardial fibrosis in systemic sclerosis: a delayed-enhanced magnetic resonance imaging study. Arthritis Rheum 2007;56:3827-36.

67. Lachter J, Suissa A, Schiff E, Rosner I. Anemia in CREST syndrome. Isr Med Assoc J 2003:5:449.

68. Lauritano D, Bussolati A, Baldoni M, Leonida A. Scleroderma and CREST syndrome: a case report in dentistry. Minerva Stomatol 2011;60(9):443-65.

69. 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;6:106.

70. Hachulla E, Launay D. Diagnosis and classification of systemic sclerosis. Clin Rev Allergy Immunol 2011;40:78-83.

71. Haustein UF. Scleroderma and pseudoscleroderma: uncommon presentations. Clin Dermatol 2005;23:480-90.

72. Mayes MD, Ho KT. Understanding and managing scleroderma. Scleroderma foundation. [cited 2015 Oct 1]. Available from: http://www.scleroderma.org/site/DocServer/UandM.pdf?docID=326

73. Marangoni RG, Rocha LF, Del Rio AP, Yoshinari NH, Marquez-Neto JF, Sampaio-Barros PD. Systemic sclerosis sine scleroderma: distinct features in a large Brazilian cohort. Rheumatology 2013;52:1520-4.

74. Hachulla AL, Launay D, Gaxotte V, de Groote P, Lamblin N, Devos P, et al. Cardiac magnetic resonance imaging in systemic sclerosis: a cross-sectional observational study of 52 patients. Ann Rheum Dis 2009:68:1878-84.

75. Lyons R, Narain S, Nichols C, Satoh M, Reeves WH. Effective use of autoantibody tests in the diagnosis of systemic autoimmune disease. Ann N Y Acad Sci 2005;1050:217-28.

76. Nadashkevich O, Davis P, Fritzler MJ. A proposal of criteria for the classification of systemic sclerosis. Med Sci Monit 2004;10(11):CR615-21.

77. Van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 Classification criteria for systemic sclerosis: an American college of rheumatology / European league against rheumatism collaborative initiative. Artritis Rheumat 2013;65(11):2737-47.

78. Fransen J, Johnson SR, van den Hoogen F, Baron M, Allanore Y, Carreira PE, et al. Items for developing Revised Classification Criteria in systemic sclerosis: results of a consensus exercise. Arthritis Care Res (Hoboken) 2012;64(3):351-7.

79. Johnson SR, Fransen J, Khanna D, Baron M, van den Hogen F, Medsger TA Jr, et al. Validation of potential classification criteria for systemic sclerosis. Arthritis Care Res (Hoboken) 2012;64(3):358-67.

80. Minier T, Guiducci S, Bellando-Randone S, Bruni C, Lepri G, Czirjak L, et al. Preliminary analysis of the very early diagnosis of systemic sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign suspicion of systemic sclerosis Ann Rheum Dis 2014;73(12):2087-93.

81. Muller-Ladner U, Tyndall A, Czirjak L, Denton C, Matucci-Cerinic M, EUSTAR centres. Ten years EULAR Scleroderma Research and Trial (EUSTAR): what has been achieved? Ann Rheum Dis 2014;73(2):324-7.

82. Khanna D, Furst DE, Allanore Y, Bae S, Bodukam V, Clements PJ, et al. Twenty-two points to consider for clinical trials in systemic sclerosis, based on EULAR standards. Rheumatology 2015;54:144-51.

83. Lonzetti LS, Joyal F, Raynauld JP, Roussin A, Goulet JR, Rich E, et al. Updating The American College of Rheumatology preliminary classification criteria for systemic sclerosis: addition of severe nailfold capillaroscopy abnormalities markedly increases the sensitivity for limited scleroderma. Arthritis Rheum 2001;44(3):735-8.

84. Cutolo M, Matucci Cerinic M. Nailfold capillaroscopy and classification criteria for systemic sclerosis. Clin Exp Rheumatol 2007;25:663-5.

85. Jung P, Trautinger F. Capillaroscopy. J Dtsch Dermatol Ges 2013;11:731-6.

86. Cutolo M, Sulli A, Secchi ME, Paolino S, Pizzorni C. Nailfold capillaroscopy is useful for the diagnosis and follow-up of autoimmune rheumatic diseases. A future tool for the analysis of microvascular heart involvement? Rheumatology (Oxford) 2006;45(Suppl 4):iv43-6.

87. Baron M, Bell M, Bookman A, Buchignani M, Dunne J, Hudson M, et al. Office capillaroscopy in systemic sclerosis. Clin Rheumatol 2007;26:1268-74.

88. Hughes M, Moore T, O’Leary N, Tracey A, Ennis H, Dinsdale G, et al. A study comparing videocapillaroscopy and dermoscopy in the assessment of nailfold capillaries in patients with systemic sclerosis – spectrum disorders. Rheumatology 2015;54(8):1435-42.

89. Koenig M, Joyal F, Fritzler MJ, Roussin A, Abrahamowicz M, Boire G, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s ph enomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum 2008;58(12):3902-12.

91. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 2005;35:35-42.

92. Karp DR, Marthandan N, Marsh SG, Ahn C, Arnett FC, Deluca DS, et al. Novel sequence feature variant type analysis of the HLA genetic association in systemic sclerosis. Hum Mol Genet 2009;19(4):707-19.

93. Arnett FC, Gourh P, Shete S, Ahn CW, Honey RE, Agarwal SK, et al. Major histocompability complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls. Ann Rheum Dis 2010;69(5):822-7.

94. Loubiere LS, Lambert NC, Madeleine MM, Porter AJ, Mullarkey ME, Pang JM, et al. HLA allelic variants encoding DR11 in diffuse and limited systemic sclerosis in Caucasian women. Rheumatology 2005;44(3):318-22.

95. Fonseca C, Lindahl GE, Ponticos M, Sestini P, Renzoni EA, Holmes AM, et al. A polymorphism in the CTGF promoter region associated with systemic sclerosis. N Engl J Med 2007;357:1210-20.

96. Beretta L, Rueda B, Marchini M, Santaniello A, Simeon CP, Fonollosa V, et al. Analysis of class II human leucocyte antigens in Italian and Spanish systemic sclerosis. Rheumatology 2012;51(1):52-9.

97. Manno R, Boin F. Immunotherapy of systemic sclerosis. Immunotherapy 2010;2(6):863-78.

98. Morita A, Kobayashi K, Isomura I, Tsuji T, Krutman J. Ultraviolet A1 (340-400 nm) phototherapy for scleroderma in systemic sclerosis. J Am Acad Dermatol 2000; 43:670-4.

99. Thompson AE, Pope JE. Calcium channel blockers for primary Raynaud’s phenomenon: a meta-analysis. Rheumathology 2005;44:145-50.

100. Goundry B, Bell L, Langtree M, Moorthy A, BMJ. Diagnosis and management of Raynaud’s phenomenon. BMJ 2012;344:e 289.

101. Rybalkin SD, Yan C, Bornfeldt K, Beavo J. Cyclic phosphodiesterases and regulation of smooth muscle function. Circ Res 2003;93:280-91.

102. Gore J, Silver R. Oral sildenafil for the treatment of Raynaud’s phenomenon and digital ulcers secondary to systemic sclerosis. Ann Rheum Dis 2005;64:1387.

103. 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;92:1310-5.

104. 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;50(12):3994-4001.

105. Anderson ME, Moore TL, Hollis S, Jayson MIV, 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;41:324-8.

106. Cukierman T, Elinav E, Korem M, Chajek-Shaul T. Low dose warfarin treatment for calcinosis in patients with systemic sclerosis. Ann Rheum Dis 2004;63:1341-3.

107. Sparsa A, Lesaux N, Kessler E, Bonnetblanc JM, Blaise S, Lebrun-Ly V, et al. Treatment of cutaneous calcinosis in CREST syndrome by extracorporeal shock wave lithotripsy. J Am Acad Dermatol 2005;53:S263-5.

108. Chamberlain AJ, Walker NP. Successful palliation and significant remission of cutanous calcinosis in CREST syndrome with carbon dioxide laser. Dermatol Surg 2003;29:968-70.

109. Saddic N, Miller JJ, Miller OF 3rd, Clarke JT. Surgical debridement painful fingertip calcinosis cutis in CREST syndrome. Arch Dermatol 2009;145:212-3.

Serbian Journal of Dermatology and Venereology

The Journal of Serbian Association of Dermatovenereologists (SAD)

Journal Information

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 344 344 26
PDF Downloads 119 119 10