CREST Syndrome

Background

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

Intermediate skin involvement proximal to the metacarpal phalangeal/metatarsal phalangeal joints. but do not meet the criteria for groups III and IV. . respectively. or one of these features along with one of the following: Raynaud phenomenon.edema. perivascular mononuclear cell infiltration. no telangiectasia)  Type V . heart. and (9) telangiectasias. no anticentromere antibodies.Digital sclerodactyly only (meets American College of Rheumatology minor criteria but excludes those without skin involvement)  Type IV . telangiectasia is required with one or more other acronyms. kidney). and vascular abnormalities. Fulfilling 3 or more criteria indicates definite systemic scleroderma with a sensitivity and specificity as high as 99% and 100%. which can be remembered by the abbreviation ABCDCREST. in 2005. pitting scars.Diffuse skin involvement proximal to elbows/knees. or sclerodactyly only. pulmonary fibrosis.Scleroderma sine scleroderma (capillary pattern or pitting scars and visceral involvement. distal to the elbows/knees. or visceral involvement (esophagus. The Maricq and Valter [13] proposed classification for scleroderma spectrum disease is as follows:  Type I . Also in 2004. no anticentromere antibodies. this classification system may not gain widespread acceptance in its present form. includes trunk  Type II . no skin involvement. trunk not involved  Type III .CREST.Undifferentiated connective-tissue disease with 2 of 3 of the following scleroderma features: sclerodactyly. no telangiectasia  Type VI . or scleroderma capillary pattern. however. Maricq and Valter [13] had a complex but potentially very useful proposal for classifying the scleroderma spectrum disorders. Wollheim [14] reported that without substantial independent confirmatory work. or anticentromere antibodies are required with any 2 or more acronyms Pathophysiology Three primary pathologic features are found in scleroderma and include increased collagen deposition.

and down-regulation of fibroblast collagen synthesis by collagen amino-terminal peptides is impaired. basophils. Skin fibroblasts in patients with scleroderma act as if they are persistently activated. suggesting that they are already maximally stimulated. [16] Sera from patients with systemic scleroderma contain enhanced concentrations of granulocyte macrophage colony-stimulating factor (GM- CSF). III. and proteoglycans are deposited in the interstitium and in the intima of small arteries. [15] Fibrosis is found in clinically affected and unaffected tissue. IV. suggesting that it is an early event in the pathogenesis of scleroderma. mast cells. it can also be present without fibrosis. Furthermore. and plasma levels of this cytokine are elevated in scleroderma patients (both limited and diffuse scleroderma). glycosaminoglycans. These cells secrete a variety of cytokines. Macrophages are present in higher numbers. Histologic specimens from patients with disease duration of less than 2 years show mononuclear infiltration near blood vessels and dermal appendages. 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. Transforming growth factor-beta (TGF-beta) stimulates collagen synthesis. While this inflammatory infiltrate can accompany fibrosis in tissues. CD4 lymphocytes predominate in the inflammatory infiltrate. 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. Mononuclear infiltration probably precedes fibrosis of tissues. Suppressor T cells are diminished in number. Fibroblasts from the skin of scleroderma patients express increased amounts of mRNA for TGF-beta and secrete higher levels of TGF-beta. Collagen (types I. and VII). as are eosinophils. and B cells. Incubating GM-CSF with dermal fibroblasts from systemic scleroderma patients decreases type I collagen mRNA levels and collagen synthesis while . these fibroblasts are not as sensitive as normal fibroblasts to stimulation by exogenous TGF-beta. the balance of which is important in the pathogenesis of fibrosis. fibronectin. Several cytokines have been implicated in the development of fibrosis.The pathologic hallmark of scleroderma is progressive fibrosis of tissues.

Serum tissue inhibitor of metalloproteinase-1 (TIMP-1) levels are elevated in scleroderma patients compared with normal controls. [19] Vascular abnormalities are also likely to be an early contributor to the pathogenesis of scleroderma. the smooth muscle–like mural cells of capillaries and venules. Scleroderma fibroblasts are less responsive to tumor necrosis factor-alpha. thus. Scleroderma fibroblasts secrete a higher basal level of connective tissue growth factor (CTGF) than normal fibroblasts. a potent stimulator of collagen synthesis. in the skin. Pericytes. is overexpressed in scleroderma skin. differentiation. intimal proliferation. Interleukin 4 is produced by T helper-2 (TH2) cells. elevated factor VIII-von Willebrand factor levels. PN1 plays an important role in the regulation of cell growth. The vasospastic phenomenon of Raynaud is present in most scleroderma patients. the protease nexin-1 gene (PN1) has been found to be overexpressed in systemic sclerosis fibroblasts. and IFN-gamma is produced by T helper-1 (TH1) cells. Endothelial cell injury and dysfunction.increasing the production of other extracellular matrix proteins such as fibronectin and tenascin. This may allow progressive fibrosis to result because of a relative lack of collagenase activity. and cell death by modulating proteolytic activity. which normally acts to suppress CTGF expression. [17] Interleukin 4. Other cytokine perturbations have been demonstrated. Scleroderma patients have normal or reduced levels of interferon-gamma (IFN-gamma). TIMP-1 may behave as an autocrine growth factor in the fibrotic process of scleroderma. [18]Recently. [20] Clinically. Scleroderma fibroblasts may be responding to an imbalance in these usual regulatory cytokines as a result of a predominance of TH2 cell activity. they are potential mediators of pathological changes in scleroderma. synthesize matrix components and fibroblast- activating cytokines. Pericyte density is increased in the microvasculature of the peripheral zones of active disease. thrombocytosis. microvascular changes are apparent in the nailfold capillaries as larger tufted capillaries and areas of dropout. in vitro evidence suggests it inhibits metalloproteinase activation. an inhibitor of collagen synthesis. and vasospasm are found in .

the UCD-200 chicken. because of the similarity of scleroderma to chronic graft versus host disease and the frequent onset of scleroderma in women after their childbearing years. an extracellular matrix component. as well as antinuclear antibody (ANA) production. In summary. a reasonable speculation is that vascular endothelial cell abnormalities incite mononuclear infiltration. How a defect in fibrillin. and the resulting perturbations in TH1 and/or TH2 cell and cytokine balance result in abnormal fibroblast activity and increased collagen deposition. Animal models of scleroderma may help identify abnormalities in human scleroderma. Antiendothelial cell antibodies trigger both apoptosis and increased adhesion molecule expression on endothelial cells. develops fibrosis of the skin and internal organs and the presence of ANAs. A causal linkage between microchimerism and autoimmune disorders has not been demonstrated. Microchimerism indeed occurs to a greater degree in persons with scleroderma or other autoimmune disorders than in healthy patients. The tight skin mouse model of scleroderma (Tsk1) is characterized by increased collagen deposition in the skin and some internal organs. . Nelson [23] has suggested the role of microchimerism in the pathogenesis of scleroderma. while the primary trigger for CREST syndrome is not known.scleroderma patients and result in vascular compromise. 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. may be involved in the pathogenesis of scleroderma is unclear. 22] Ischemia is an important contributor to end organ damage in scleroderma patients. These studies suggest that early pathogenetic events in scleroderma are endothelial abnormalities. [21. Affected chickens develop vascular occlusion and severe perivascular lymphocytic infiltration of the skin and internal organs. resulting in perivascular accumulation of mononuclear cells. The defect is a heterozygous mutation in the fibrillin-1 gene. Elevated levels of platelet-derived growth factor (PDGF) and increased expression of PDGF type-B receptors are found in the skin of scleroderma patients. An avian model.

however. in France it is 158 cases per million. in the United Kingdom is it 82 cases per million. but. 29. in Greece it is 154 cases per million. [11.8 patients per million per year. 28. [24] The highest prevalence has been reported in a Choctaw Native American Group in Oklahoma (660 cases per million. 32] Race Both the prevalence and incidence of systemic sclerosis is higher in blacks than in whites. systemic sclerosis occurs In 3.3 cases per million per year. in general. 24. [25] The apparent increase in both incidence and prevalence over the past 50 years is most likely an artifact of better classification.7-19.7 cases per million per year. . In Iceland. Some serum antibody studies suggest that CREST syndrome may account for 22-25% of all cases of systemic sclerosis. The prevalence of diffuse disease among black patients is nearly twice that of white patients. and improved survival.Epidemiology Frequency United States The incidence of systemic sclerosis approximates 2. earlier diagnosis. 30. The incidence in Russia is 7 cases per million adults per year. in England is 3. 31. and in New Zealand is 2. 27] International In other countries. 25. [24] Some Choctaw Native American and Thai populations are more likely to have diffuse disease. the incidence of systemic sclerosis is slightly lower than in the United States. based on 14 cases). in Greece is 11 cases per million per year. 26. a high percentage of patients in this population have limited forms of scleroderma. and in Australia it is 86-233 cases per million. while some European and white Australian groups have more limited disease. [24. The prevalence is 253-286 cases per million persons. survival for both groups is comparable. epidemiologic studies specifically looking at CREST syndrome are lacking. Disease prevalence is slightly lower in other countries compared with the United States. Survival for black patients versus nonblack patients is marginally worse during the first 12 years after diagnosis.3 new cases per million adults per year.

6:1. This difference appears greater during childbearing years. The mortality in patients with limited skin involvement results from cardiac. [11. Mayes et al [24] reported an overall female-to-male ratio of 4. 55. . while patients with sclerodactyly alone do not tend to develop any type of renal disease. and 26.4% at 15 years. The extent of skin involvement is a good predictor of survival in patients with scleroderma. Limited cutaneous disease (as defined by Medsger [33] in 1997) is associated with a better survival rate than diffuse disease. 37.1% at 10 years.Sex Females have a greater incidence of scleroderma than males.8% at 20 years. 10] Similarly. [24] the survival rate from time of diagnosis was computed to be 77. patients with sclerodactyly alone have better survival rates than patients with truncal skin involvement. and GI causes. Age The usual age of onset of scleroderma is approximately 30-65 years. [6] Renal involvement is responsible for half of all scleroderma-related deaths in patients with widespread skin changes. pulmonary.9% at 5 years. Prognosis In a large 2003 US study by Mayes et al. Black women tend to present at an earlier age.