CREST Syndrome

Updated: Aug 07, 2018
  • Author: Jeanie C Yoon, MD; Chief Editor: Dirk M Elston, MD  more...
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Overview

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. [1]

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. [2, 3] 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 [4] noted the frequent occurrence of esophageal dysmotility and suggested that the acronym CREST may be more appropriate. Velayos et al [5] 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. [6, 7, 8]

Others have shown that visceral involvement, poorer prognosis, and higher mortality are all more common in patients with diffuse disease. [9, 10, 11, 12] Several new classification systems may better categorize the wide spectrum of systemic scleroderma.

In 2004, Nadashkevich et al [13] 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 [14] had a complex but potentially very useful proposal for classifying the scleroderma spectrum disorders; however, in 2005, Wollheim [15] reported that without substantial independent confirmatory work, this classification system may not gain widespread acceptance in its present form.

The Maricq and Valter [14] 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

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Pathophysiology

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. [16] 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. [17]

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. [18]

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. [19] 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. [20]

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. [21] 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. [22, 23] 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 [24] 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.

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Etiology

The cause of limited scleroderma is yet to be determined. Studies of genetic factors show only rare occasions of multicase families. HLA associations are present but are not strong. These include HLA-DRB*01, HLADRB*11, HLA-A*30, and HLA-A*32 showing increased susceptibility to scleroderma and HLA-DRB*07, HLA-B*57, and HLA-Cw*14 being protective. [25]

The predominance of cases occurring in women after their childbearing years and the similar clinical presentation of scleroderma to graft versus host disease has suggested the importance of fetal/maternal microchimerism in the etiology of scleroderma.

Environmental factors also are likely important. Some similarities in clinical presentation occur with L-tryptophan and rapeseed oil exposure. Certain occupations have been linked to an increased risk to systemic sclerosis, including female teachers, female textile workers, and construction workers. Exposure to silica, synthetic adhesives, solvents (including chlorinated solvents, aromatic solvents, white spirit, toluene, trichloroethylene, formaldehyde, vinyl chloride, and cleaning products) have been implicated in a higher risk of developing systemic sclerosis. Interestingly, the use of vibrating tools was also found to increase the risk of systemic sclerosis. [26, 27]

The pathogenesis of calcinosis, Raynaud phenomenon, esophageal dysmotility, and sclerodactyly are described in more detail.

Calcinosis

Ultrastructural study of calcifications from patients with CREST syndrome demonstrates calcium apatite crystals. Serum calcium, phosphorus, and alkaline phosphatase levels typically are normal; therefore, the calcifications are considered dystrophic.

Elevated levels of gamma-carboxyglutamic acid (Gla), a calcium-binding amino acid found in vitamin K–dependent clotting factors, are present in the urine and the involved tissues of patients with calcinosis. Gla and other calcium-binding proteins may be deposited abnormally in soft tissues during clotting. The occurrence of calcinosis at sites of repeated trauma appears to support this idea.

Raynaud phenomenon

Microvascular abnormalities and dysfunction are central to the pathogenesis of scleroderma-associated Raynaud phenomenon.

Endothelial injury is believed to result in intimal hyperplasia and fibrosis, concentric narrowing of digital arteries by as much as 75-80%, and occlusion by intravascular thrombi.

Resting blood flow in fingers was lower in scleroderma patients compared with normal controls as measured by laser Doppler flowmeter. Arteries from scleroderma patients have significantly increased sensitivity to alpha2-adenoreceptor–mediated vasoconstriction. Whether this is a consequence or cause of endothelial cell injury and dysfunction is unclear.

Endothelin, a naturally occurring peptide, has been implicated as a pathologic mediator of vasoconstriction, fibrosis, vascular hypertrophy, and inflammation in patients with Raynaud syndrome. [28]

Esophageal dysmotility

The earliest abnormality in the involved gut of scleroderma patients is dysmotility secondary to nerve injury, perhaps resulting from arteriolar changes in the vasa nervorum or compressive nerve damage via collagen deposits. Smooth muscle atrophy occurs later (and often marks the beginning of symptoms).

The predilection for smooth muscle rather than striated muscle atrophy explains the distribution of anatomic involvement. The proximal esophagus primarily is striated muscle and remains essentially uninvolved. The esophagus typically is weakly responsive to prokinetic therapy, until, according to Sjogren, [29] the final stage of the disease (fibrotic infiltration of muscle) halts the response to medications.

The consequences of esophageal dysmotility are reflux and its complications. The reduced LES pressure in patients with scleroderma likely allows acid reflux, which is exacerbated by delayed clearance of acid from the esophagus because of abnormal distal motility. This creates an environment in which stricture, Barrett esophagus, adenocarcinoma, [30] or aspiration may supervene.

The relationship of Raynaud phenomenon to esophageal dysmotility is interesting. Cold-induced vasospasm of the hands also results in esophageal dysmotility, and reversal of this vasospasm with reserpine reverses both peripheral Raynaud phenomenon and abnormalities in esophageal motility (as reported by Sjogren [29] in 1994); however, patients with primary Raynaud phenomenon do not tend to have esophageal dysmotility. Therefore, the significance of these observations remains to be determined. [31]

Sclerodactyly

The development of sclerodactyly begins with a perivascular inflammatory infiltrate in the dermis. The trigger for this inflammatory process is not known.

The edematous phase of skin involvement results from mucopolysaccharide, glycoprotein, and collagen (types I and III) deposition in the dermis.

As collagen deposition continues, the dermis becomes more sclerotic than edematous. Meanwhile, a similar process occurs in small arteries. Mucinous deposition occurs in the intima. The adventitia is infiltrated first with inflammatory cells, and then it becomes fibrotic. This process results in narrowing of the artery and then arterial collapse or thrombosis. The tissue then becomes ischemic.

Years after the onset of skin changes, fibrosis usually subsides, leaving atrophic skin.

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Epidemiology

Frequency

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. [32] The highest prevalence has been reported in a Choctaw Native American Group in Oklahoma (660 cases per million, based on 14 cases). [33] 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. [32, 33, 34, 35]

International

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. [12, 36, 32, 37, 38, 39, 40]

Race

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. [32]

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.

Sex

Females have a greater incidence of scleroderma than males. This difference appears greater during childbearing years. Mayes et al [32] reported an overall female-to-male ratio of 4.6:1.

Age

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

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Prognosis

In a large 2003 US study by Mayes et al, [32] the survival rate from time of diagnosis was computed to be 77.9% at 5 years, 55.1% at 10 years, 37.4% at 15 years, and 26.8% at 20 years. The extent of skin involvement is a good predictor of survival in patients with scleroderma.

Limited cutaneous disease (as defined by Medsger [41] in 1997) is associated with a better survival rate than diffuse disease. [12, 11] Similarly, patients with sclerodactyly alone have better survival rates than patients with truncal skin involvement. [7] Calcinosis cutis may be problematic, even in patients with limited cutaneous disease. [42]

Renal involvement is responsible for half of all scleroderma-related deaths in patients with widespread skin changes, while patients with sclerodactyly alone do not tend to develop any type of renal disease.

The mortality in patients with limited skin involvement results from cardiac, pulmonary, and GI causes.

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