1. SCLERODERMA Gentleman’s Review Daniel Martingano OMSII

2. Definition Scleroderma is a clinically heterogeneous generalized disorder which affects the connective tissue of the skin and internal organs such as gastrointestinal tract, lungs, heart and kidneys. It is characterized by three pathologic processes: –skin and organ collagenous fibrosis, small vessel vasculopathy and disease specific autoantibodies.

3. SCLERODERMA Classification Schemes

4. American College of Rheumatology Several classification schemes for scleroderma have been proposed and remain in use. The American College of Rheumatology (ACR) criteria for diagnosis of scleroderma requires either 1 major criterion (proximal cutaneous scleroderma) or 2 of 3 minor criteria (sclerodactyly, digital pitting scars, bibasilar pulmonary fibrosis).

5. Major Criterion – Proximal Cutaneous Scleroderma Proximal cutaneous scleroderma is defined as symmetric thickening, tightening or induration of skin of the fingers that is proximal to metacarpophalangeal (or metatarsophalangeal) joints.

6. Minor Criterion The minor criterion includes –Sclerodactyly –digital pitting scars, and –bibasilar pulmonary fibrosis.

7. Minor Criteria Sclerodactyly. Sclerodactyly is characterized by thickening, induration, and tightening of the skin, limited to only the fingers. Digital pitting scars. As a result of ischemia, depressed areas of the fingertips or a loss of digital pad tissue occur (digital pitting scars or a loss of substance from the finger pad).

8. Bibasilar Pulmonary Fibrosis This includes a bilateral reticular pattern of linear or lineonodular densities most pronounced in basilar portions of the lungs on standard chest radiography. These densities may assume the appearance of diffuse mottling or a honeycomb lung and are not attributable to primary lung disease. Satisfaction of 1 major criterion or 2 minor criteria offers a diagnostic sensitivity of 97% and a specificity of more than 98%.

10. Clinical Spectrum of Scleroderma Scleroderma is usually divided into two forms: –Localized scleroderma (morphea) confined to the skin and subcutaneous tissues. –Systemic sclerosis (SSc) affecting both skin and internal organs. In turn systemic sclerosis is divided into two major categories: Limited cutaneous SSc (lcSSc) usually associated with mild to moderate, somewhat delayed, organ fibrosis. Diffuse cutaneous SSc (dcSSc) with corresponding more severe organ damage.

11. Clinical Spectrum of Scleroderma Visceral involvement and prognosis differ in patients with dcSSc versus lcSSc. Classifying the patient into one of these groups is useful because the degree of skin involvement predicts distinct patterns of organ involvement, disease severity and survival.

12. Limited Cutaneous SSc Raynaud phenomenon for years at presentation Skin involvement limited to hands, feet, face, and forearms (sclerodactyly), or absent Significant late incidence of pulmonary hypertension, with or without interstitial lung disease, calcinosis, and teleangiectasia

13. Limited Cutaneous SSc Dilated nailfold capillary loops, usually without capillary dropouts detected by widefield nailfold capillaroscopy A high incidence of anticentromere antibodies (ACA)

14. Diffuse Cutaneous SSc Onset of Raynaud phenomenon within one year of skin changes Skin involvement proximal to the elbows and knees (i.e., affecting the trunk, thighs and upper arms) Presence of tendon friction rubs

15. Diffuse Cutaneous SSc Significant incidence of interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease and myocardial involvement Absence of anticentromere antibodies Nailfold capillary dilatation and destruction detected by widefield nailfold capillaroscopy Presence of antitopoisomerase I (anti-Scl-70) antibodies

16. Patients with Limited SSc More than 50 % of SSc patients belong to the limited cutaneous SSc. They have a more insidious onset of illness, a long history of Raynaud phenomenon and swelling of digits, a more benign course, and a lower incidence of renal involvement and restrictive pulmonary disease with a much better prognosis. Some cases are associated with anticentromere antibodies (ACA).

17. Patients with Diffuse Cutaneous SSc Patients with diffuse cutaneous SSc have a short history. –These patients often have sclerodactyly, Raynaud phenomenon, and rapid progression of skin involvement including arms and trunk. In addition, they have a higher incidence of renal, cardiac, pulmonary disease, and tendon friction rub.

18. Patients with Diffuse Cutaneous SSc Antitopoisomerase I antibodies (anti-Scl-70) or antifibrillarin antibodies (antibodies against U3 RNA associated protein) may be present. When associated with anti-RNA polymerase, patients with diffuse SSc have the shortest survival time and worst prognosis.

19. Serum Autoantibodies Anti nuclear antibodies (ANA) have been detected in approximately 85% of SSc patients. Three main serological subgroups in SSc were described, each characterized by a distinctive pattern of clinical features: –sera containing anti-DNA-topoisomerase I antibodies (anti-Scl-70), –sera containing antibodies recognizing centromere proteins (ACA), and –sera containing antibodies to RNA-polymerase III. Each of these ANAs can be detected in roughly 20-25 % of patients, and they are generally considered to be mutually exclusive.

20. Antitopoisomerase I Antibodies (anti-Scl-70) They occur in a total of 23% of SSc patients. –They are directed against the enzyme topoisomerase which mediates the relaxation of the supercoiled DNA. Anti-Scl-70 antibodies correlate with diffuse cutaneous SSc (dSSc). Antitopoisomerase I positive patients are associated with the highest frequency of pulmonary interstitial fibrosis.

21. Anticentromer Antibodies (ACA) ACA occur nearly mutually exclusive with anti-Scl-70. –ACA interact with cell division and are closely associated with CREST-syndrome. –They occur in a total of 28% of SSc patients. The ACA group has the best prognosis of the three with the longest cumulative survival times and the lowest frequency of dcSSc, pulmonary involvement and renal disease.

22. Anti-RNA Polymerase Antibodies Anti-RNA polymerase antibodies are again of major significance, reflecting the worst prognosis. RNA polymerase represents multiple subunits of three enzymes (polymerases I, II, III), which are responsible for the protein biosynthesis by ribosomes.

23. Anti-RNA Polymerase Antibodies Patients with anti-RNA polymerase antibodies exhibit the greatest risk of dSSc, the shortest cumulative survival times, and the greatest likelihood of renal involvement compared with patients in either of the other two groups. These mutually exclusive serological subgroups of SSc may be associated with etiologically distinct disease processes or alternatively, the different antibody patterns may reflect differences in patient's vulnerability.

25. SCLERODERMA Etiology and Pathogenesis

26. Abnormal Immune Responses There is also evidence for inappropriate activation of humoral immunity, and the presence of various autoantibodies provides diagnostic and prognostic information. Virtually all patients have ANAs that react with a variety of nuclear antigens. –Two ANAs strongly associated with systemic sclerosis have been described. One of these, directed against DNA topoisomerase I (anti-Scl 70), is highly specific. –Patients who have this antibody are more likely to have pulmonary fibrosis and peripheral vascular disease

27. Abnormal Immune Responses The other, an anticentromere antibody, is found in 20% to 30% of patients, who tend to have the CREST syndrome or limited cutaneous systemic sclerosis. Only rarely does the same patient have both antibodies.

28. Vascular Damage Microvascular disease is consistently present early in the course of systemic sclerosis and may be the initial lesion. Intimal proliferation is evident in 100% of digital arteries of patients with systemic sclerosis.

29. Vascular Damage Capillary dilation with leaking, as well as destruction, is also common. Nailfold capillary loops are distorted early in the course of disease, and later they disappear. –Thus, there is unmistakable morphologic evidence of microvascular injury.

30. Vascular Damage Telltale signs of endothelial activation and injury (e.g., increased levels of von Willebrand factor) and increased platelet activation (increased percentage of circulating platelet aggregates) have also been noted. Repeated cycles of endothelial injury followed by platelet aggregation lead to release of platelet and endothelial factors (e.g., PDGF, TGF-β) that trigger perivascular fibrosis.

31. Vascular Damage Vascular smooth muscle cells also show abnormalities, such as increased expression of adrenergic receptors. Eventually, widespread narrowing of the microvasculature leads to ischemic injury and scarring.

32. Fibrosis The progressive fibrosis characteristic of the disease may be the culmination of multiple abnormalities, including –the actions of fibrogenic cytokines produced by infiltrating leukocytes, –hyperresponsiveness of fibroblasts to these cytokines, and –scarring following upon ischemic damage caused by the vascular lesions.

33. Fibrosis There is also evidence for a primary abnormality in collagen production. Consistent with this notion is the finding that a polymorphism in the gene encoding connective tissue growth factor is associated with systemic sclerosis.

35. MORPHEA

36. Definition Morphea, also known as localized scleroderma, is a disorder characterized by excessive collagen deposition leading to thickening of the dermis, subcutaneous tissues, or both. The term scleroderma includes syndromes that are confined to the skin (localized scleroderma or morphea) and syndromes that may involve skin and multiple visceral organs (systemic sclerosis).

37. Definition Physical examination of a biopsy of the involved skin may be similar or identical in both syndromes. This can lead to an impression that localized scleroderma/morphea may transition to systemic sclerosis. –However the transition from localized scleroderma/morphea to systemic sclerosis remains very rare and poorly documented.

38. MORPHEA Clinical Presentation

39. Plaque Morphea Plaque morphea is the most common subtype. Plaque morphea is characterized by one or few oval or rounded areas of induration, ranging from 1-30 cm in diameter. –These lesions are relatively superficial, primarily involving the dermis. –They usually arise on the trunk or proximal extremities.

40. Plaque Morphea The indurated plaque is usually hyperpigmented and is surrounded by an erythematous halo. Over a period that varies from lesion to lesion and from patient to patient, the induration may progress to sclerosis, which is depigmented to form an ivory-colored center. Steps of progression are erythema, nonpitting edema, and finally subcutaneous sclerosis.

42. Linear Morphea Linear morphea is a well-known variant that occurs in the extremities or scalp as single, linear, unilateral band that involves the subcutaneous or deeper tissues. En coup de sabre is a form of linear morphea that involves the frontoparietal skin, characterized by furrowing of the scalp and forehead in the form of a saber wound scar.

43. Generalized Morphea Generalized morphea is a more extensive and severe form of plaque-type disease. –Generalized morphea occurs when morphea plaques become confluent or multiply and affect a significant portion of 3 or more major anatomical regions, often involving the chest, abdomen, lower back, buttocks, and thighs. The multiple, coalescent lesions of generalized morphea often range from hyperpigmented to silvery.

44. Deep Morphea Deep morphea (subcutaneous morphea) primarily involves the subcutaneous fat and underlying structures such as fascia. Eosinophilic fasciitis is a variant of deep morphea.

45. Deep Morphea Deep morphea is characterized by ill-defined, bound-down, sclerotic plaques with a "cobblestone" or "pseudo-cellulite" appearance. The "groove sign" (a depression along the course of a vein, between muscle groups, or both) may be evident later in the course of disease. –Distribution of lesions is often symmetric

46. Laboratory Studies Eosinophilia can be seen in patients with generalized and linear scleroderma and often correlates with extent of disease. Polyclonal hypergammaglobulinemia can occur in 50% of patients with linear scleroderma.

47. Laboratory Studies: Antibodies Various circulating autoantibodies can be found in morphea, with most titers correlating with the burden of skin disease, including antinuclear antibodies (46%- 80%), anti–single-stranded DNA antibodies (50%), and antihistone antibodies (47%). The presence of rheumatoid factor (RF) (seen in 60% of cases) may predict articular involvement, and IgM RF correlates with the burden of skin disease.

48. Laboratory Studies: Antibodies Although anticentromere antibodies have been detected in up to 12% of patients with morphea, antitopoisomerase I antibodies have only been reported in a handful of cases. In contrast, antitopoisomerase IIa antibodies are frequently present in patients with morphea, found in up to 76% of patients compared with 14% of those with SSc.

49. Laboratory Studies: Antibodies Antibodies to fibrillin-1, a major component of microfibrils in the extracellular matrix, have been reported in 28% of patients with morphea. The clinical and prognostic significance of elevated autoantibodies remains unclear.

50. Morphology Early lesions are characterized by a dense inflammatory infiltrate composed of lymphocytes, macrophages, plasma cells, and occasionally, eosinophils and mast cells. The fibrotic phase follows the inflammatory stage, characterized by thickened, hyalinized collagen bundles extending from the deep reticular dermis to more superficial structures.

51. Histologic Findings The depth of involvement is important for categorization into the morphea subtypes. The sclerotic process in plaque morphea is centered in the upper and lower reticular dermis, whereas in other subtypes the process of sclerosis may extend from dermis into the subcutaneous tissue and even into the fascia and underlying muscle. –The epidermis is usually normal, but rete ridges may become flattened later in the disease course.

52. Extracutaneous Manifestations Only very few patients with extracutaneous manifestations went on to develop signs and symptoms classic for SSc. It is unlikely that they truly are part of the same disease.

53. Prognosis In terms of progression to systemic involvement, the prognosis for morphea is generally good. Lesions of morphea tend to regress spontaneously over 3 to 5 years, usually with residual pigmentary and atrophic changes.

54. SYSTEMIC SCLEROSIS

55. Definition Systemic sclerosis is divided into 2 major clinical variants: diffuse cutaneous (dcSSc) and limited cutaneous (lcSSc). They are distinguished from one another primarily based on the degree and extent of skin involvement

56. Definition In most cases, the initial complaint of lcSSc is Raynaud phenomenon patients with dcSSc often initially present with generalized swelling of the hands, skin thickening, or arthralgias with or without Raynaud.

58. SYSTEMIC SCLEROSIS Cutaneous Involvement

59. Limited Cutaenous SSc Limited cutaneous SSc is characterized on the skin by symmetric, progressive skin fibrosis of the distal extremities that is sometimes restricted to the fingers. Compared with the sclerotic plaques seen in LSc, the skin is often less sclerotic and has more prominent telangiectasias. The progression of the skin disease from the early, edematous stage to late-stage fibrosis can take between 5 and 15 years; in fact, some patients never develop significant acrosclerosis.

60. Diffuse Cutaneous SSc Diffuse cutaneous SSc patients often develop widespread, symmetrical fibrosis involving the proximal and distal extremities, trunk, and face. The time course from edematous to sclerotic phase is often shorter in diffuse SSc as compared to the limited subtype.

61. Diffuse Cutaneous SSc SSc patients are susceptible to skin ulcerations, particularly in the distal digital pulps and over bony prominences. Patients with late-stage diffuse SSc often develop calcinosis (subcutaneous or intracutaneous, calcium deposits) that can serve as a nidus for ulceration and/or infection.

62. Three Phases of Skin Thickening in Systemic Sclerosis There are three phases of skin thickening in systemic sclerosis, which follow one another, –the edematous, –indurative and –atrophic phase.

63. Edematous Phase Initially the patient complains about “puffy fingers” especially on arising in the morning. This may be a sensation only or there may be visible swelling that subsides during the day.

64. Indurative Phase Edema is gradually replaced by a thickened skin. In addition to obvious thickening, affected skin becomes shiny, taut and tightly adherent to the underlying subcutis.

65. Indurative Phase Histologically the dermis is markedly thickened but the epidermis is thinned, leading to atrophy and “choking out” of hair follicles, sweat glands and sebaceous glands. Hair loss and decreased sweating results. Skin thickening indirectly impairs mobility of muscles, tendons and joints.

66. Atrophic Phase After several years the thickened dermis softens and reverts to normal thickness or becomes thinner than normal. At this stage, the dermis is more firmly adherent to the underlying subcutaneous fat, leading to “binding down” or tethering.

67. Atrophic Phase Telangiectases increase in number and become the dominant feature. Facial changes result in a characteristic “pinched nose” appearance sometimes interpreted as an “expressionless” facies (scleroderma facies) owing to reduced mobility of eyelids, cheeks, nose and mouth during ordinary conversation.

68. Morphology: Skin Atrophy Biopsy specimens show loss of rete ridges and atrophy of skin appendages. –In the dermis there is proliferation of fibroblasts and increase of matrix tissue proteins. –There is a marked increase in compact collagen fibers in the superficial and reticular dermis that extend into the uppermost portions of the subcutis The overall impression is that excessive collagen deposition is the result of greater production rather than reduced breakdown.

69. Morphology: Vasculopathy A severe fibroproliferative vasculopathy that affects small arteries and arterioles is universally present in affected organs. Vascular disease consists of thickening of intima small arteries and arterioles, leading to narrowed lumens and obliteration of some capillaries.

70. Morphology: Vasculopathy The technique of wide-field nailfold capillaroscopy is a clinically useful method to visualize the capillary dropout characteristic of scleroderma. Inflammatory cells infiltrate of vascular walls (true vasculitis) is absent.

72. Telangiestasias Telangiectasia is a collection of dilated blood vessels. In scleroderma, telangiectasias occur on the face, upper trunk, and hands. –Telangiectasias also can occur on mucosal surfaces (e.g., lips) and throughout the gastrointestinal tract and may be symptomatic. –Mucosal telangiectasias can commonly cause gastrointestinal bleeding.

73. Calcinosis Both dcSSc and lcSSc patients have subcutaneous and intracutaneous calcium deposits (calcinosis). They occur chiefly in the digital pads and periarticular tissues but also are found in other sites of repeated trauma such as the olecranon bursae, extensor surfaces of the forearm, extensor surface of the knee and in the buttocks.

74. Calcinosis Calcium deposits vary in size from tiny punctate lesions of the fingers to large conglomerate masses. Calcinosis may be complicated by ulceration of the underlying skin, spontaneous extrusion of calcareous material (usually as “grains of sand” or as a white, toothpaste-like material) and draining sinuses with secondary bacterial infection.

75. Calcinosis Ultrastructural study of calcifications from patients with scleroderma demonstrates calcium apatite crystals. Serum calcium, phosphorus, and alkaline phosphatase typically are normal; –therefore, the calcifications are considered dystrophic.

77. SYSTEMIC SCLEROSIS Raynaud Phenomenon

78. Definition Raynaud phenomenon manifests as recurrent vasospasm of the fingers and toes and usually occurs in response to stress or cold exposure The phenomenon has also been called the “French tricolor” because it is characterized by an abrupt pallor (white), followed by cyanosis (blue-blackish) and a painful restoration of blood flow (red).

79. Pathogenesis This succession of phases is intimately linked to three mechanisms: –Vasoconstriction –ischemia and –reperfusion.

80. Pathogenesis Vasoconstriction: the fingers of the hand or feet become abruptly white and cold (“dead finger”). Ischemia: the significant reduction of blood flow and the accumulation of hypooxygenated blood cause a change in color from white to blue-black (cyanosis).

81. Pathogenesis Reperfusion: abruptly fingers become red and warm and may become extremely painful (burning fingers). –This is due to loss of vasoconstriction and rapid removal of the anoxic blood. –This phase is usually short and fades after a few minutes’ pain at which point fingers go back to their original skin color.

83. Microvascular Abnormalities Microvascular abnormalities and dysfunction are central to the pathogenesis of scleroderma- associated Raynaud phenomenon. Endothelial injury is believed to result in intimal proliferation and fibrosis, concentric narrowing of digital arteries by as much as 75-80% and occlusion by intravascular thrombi

84. Microvascular Abnormalities Resting blood flow is low in SSc patients as measured by laser Doppler flow meter. Arteries from scleroderma patients have significantly increased sensitivity to α-2-adrenoreceptor-mediated vasoconstriction. Whether this is a consequence or a cause of endothelial cell injury and dysfunction is unclear.

85. SYSTEMIC SCLEROSIS Pulmonary Involvement

86. Two main clinical manifestations of lung involvement in scleroderma are: –pulmonary fibrosis (also called fibrosing alveolitis or interstitial pulmonary fibrosis); and –pulmonary vascular disease, leading to pulmonary hypertension.

87. Pulmonary Fibrosis The earliest changes in lung biopsies are patchy lymphocyte and plasma cells infiltration of the alveolar walls, interstitial fibrosis and increased macrophages but only occasional neutrophils and lymphocytes in the alveolar spaces. –This lesional pattern is called “fibrosing alveolitis”

88. Pulmonary Fibrosis Later on during the course of disease the alveolar wall thickness increases with increased deposition of type I and type II collagen and no evidence of chronic inflammatory cells. Ultrastructural studies of lung biopsies show evidence of endothelial and epithelial injury plus edema and excess collagen deposition within the interstitium

89. Clinical Presentation Patients have progressive dyspnea and dry persistent cough, due to restrictive lung disease. –Dry rales may be the only physical finding. Patients have fibrotic changes involving the lower two thirds of the lung, with associated volume loss and honeycombing in plain chest radiograph and CT scan.

90. Functional Tests Diffusing capacity for carbon monoxide (DLCO) is sensitive for pulmonary disease, since findings are abnormal in 90% of symptomatic patients. –Marked reductions in the mean DLCO correlate highly with the extent of fibrosing alveolitis, as seen on CT. Pulmonary function tests are more sensitive to early disease. The dominant ventilatory defect is restrictive.

91. Pulmonary Fibrosis in SSc Subtypes Pulmonary fibrosis occurs in both patients with diffuse and limited cutaneous SSc. It is found more frequently (40%) in dcSSc patients, and is less common (23%) in lcSSc patients.

92. Pulmonary Fibrosis in SSc Subtypes Anticentromere antibodies (ACA) are associated with a lower prevalence of pulmonary fibrosis. –The relative protection from pulmonary fibrosis that is associated with ACA contributes to the lower prevalence of pulmonary fibrosis in patients with lcSSc. On the contrary it is the presence of antitopoisomerase antibodies that is associated with a higher prevalence of pulmonary fibrosis in patients with dcSSc.

93. Pulmonary Hypertension Pulmonary hypertension is defined as a resting mean pulmonary artery pressure above 35 mm Hg. Pulmonary hypertension is a relatively common complication, which occurs if 10-15% of patients with SSc. Pulmonary hypertension is associated with limited cutaneous SSc and with presence of anticentromere antibodies.

94. Pulmonary Hypertension Clinical symptoms occur late and are dyspnea on exertion, and signs of elevated right-sided pressures (elevated jugular venous pressure, ankle and sacral edema, ascites). Widespread endothelial cell damage in SSc is the earliest lesion in pulmonary hypertension. The end-stage lesion is microvascular luminal obliteration with medial and adventitial fibrosis and intimal proliferation.

95. SYSTEMIC SCLEROSIS Gastrointestinal Involvement

96. Histopathology This gives rise to gastroesophageal reflux and its complications including columnar metaplasia (Barrett esophagus). The hallmark of classic involvement of the gastrointestinal tract in scleroderma is progressive atrophy and collagenous fibrotic replacement of the tunica muscularis propria

97. Clinical Presentation The esophagus is the most commonly affected site of the gastrointestinal tract, or at least the one in which symptoms of involvement predominate. Fibrotic changes of the tunica muscularis lead to decreased peristalsis throughout the GI tract (gastroesophageal reflux disease, gastroparesis, constipation, pseudo-obstruction or anal sphincter incompetence).

98. Pathogenesis All the manifestations may be contributed to vascular changes. These changes in the gut are similar to these outside of the gut and include proliferation of intimal cells with luminal narrowing.

99. SYSTEMIC SCLEROSIS Renal Involvement

100. Definition Renal involvement in SSc is primarily manifested by scleroderma renal crisis. Renal crisis presents as accelerated or malignant hypertension, with headache, retinal vascular changes and vision disturbances, dyspnea, edema, oliguria and rapidly rising serum creatinine levels. –Renal crisis occurs in about 10% of all patients with systemic sclerosis

101. Histopathology Pathological changes are localized mostly in interlobular and arcuate arteries The intimal thickening leads to narrowing and even total obliteration of the lumen of interlobular arteries. Fibrinoid necrosis may be present in arterioles, associated with thrombosis of the lumen and microinfarction of the kidneys.

102. Histopathology These changes resemble those seen in malignant hypertension. –The narrowed arterial vessels are the primary cause of decreased renal perfusion, particularly cortical blood flow. The markedly elevated plasmatic levels of renin strongly support the major role of the renin-angiotensin system in mediating malignant hypertension and renal crisis.

103. Prognosis Scleroderma renal crisis that is not treated aggressively invariably leads to renal failure, requiring dialysis or renal transplantation, or even death

104. Cardiac Involvement Cardiac involvement is often present, but rarely significant clinically. – Autopsy studies have revealed myocardial fibrosis or scars and pericardial effusion in 30-80% of patients. Myocardial fibrosis may be caused by endothelial damage of small coronary arteries and repeated episodes of ischemia and reperfusion that lead to the necrosis of the myocardium and replacement by connective tissue.

105. Cardiac Involvement Pericarditis can be acute, serous or fibrinous, or alternatively present as chronic serous effusions which are not clinically significant.

106. CREST Syndrome CREST syndrome is a subset of patients with systemic sclerosis. CREST is an acronym for the cardinal clinical features of the syndrome in a given patient: –calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and telangiectases.

107. CREST Syndrome Although CREST can also occur in people with diffuse cutaneous SSc, it is most often associated with the limited cutaneous form of the disease, so much that the terms are sometimes used interchangeably.