CREST Syndrome

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Original Editor - Aya Alhindi

Top Contributors - Aya Alhindi, Kim Jackson and Khloud Shreif  

Description

CREST syndrome (calcinosis and sclerodactyly)

CREST syndrome (also known as Cutaneous systemic sclerosis or limited scleroderma ) is an autoimmune disease that has been defined as a subtype of progressive systemic sclerosis (SSc) with limited skin involvement. The word "CREST " is an acronym for the clinical features that are seen in a patient with this disease:

• Calcinosis- when calcium salts are deposited into the skin and subcutaneous tissue.
• Raynaud's phenomenon.
• Esophageal dysmotility-which can cause difficulty in swallowing.
• Sclerodactyly- scleroderma in which the fingers become thin and shiny with sclerotic skin at the tip due to subcutaneous and intracutaneous calcinosis and diffused fibrosis of the collagen.
• Telangiectasia-small widened blood vessels on the skin.

Epidemiology

Wide  variation  in  prevalence of systemic sclerosis was observed, with slightly higher estimates reported in North America (13.5–44.3 per 100,000 individuals) compared to Europe (7.2–33.9 per 100,000 individuals), which may be a true reflection of epidemiological variation or an artifact of clinical data analyses. The apparent increase in both incidence and prevalence over the last 50 years is most likely due to improved classification, earlier diagnosis, and survival. CREST syndrome may account for 22-25% of all occurrences of systemic sclerosis, according to serum antibody investigations; however, epidemiologic research specifically looking at CREST syndrome are missing. SSc diagnosis was reported to occur at the ages of 33.5-59.8 years in Europe and 46.1-49.1 years in North America, and to occur more commonly in women (female:male ratio of 3.8-11.5:1 in Europe and 4.6-15:1 in North America). Women have continuously greater prevalence and incidence rates, indicating a clinically significant difference in the occurrence of SSc across genders.

Pathophysiology

The pathogenesis of SSc involves a classical triad of key mechanisms:

1. Endothelial dysfunction and apoptosis of endothelial cells.
2. Uncontrolled activation of adaptive and innate immunity (notably including M1 inflammatory and M2 pro-fibrotic macrophages).
3. Over-production of extracellular matrix (ECM) components by chronically activated myofibroblasts, resulting in the formation of a stiff and fibrotic extracellular matrix in numerous organs, interfering with their function.

Myofibroblasts are the primary contributors to ECM formation and fibrosis.In SSc, myofibroblasts are derived from a range of tissue-resident mesenchymal progenitor cell types, such as fibroblasts, pericytes, microvascular endothelial cells, and vascular preadipocytes]. In SSc, myofibroblasts undergo substantial epigenetic remodelling as well as metabolic changes such as increased glycolysis and altered NAD+ homeostasis.Furthermore, myofibroblasts in SSc exhibit apoptosis resistance as well as unregulated production of extracellular matrix (ECM) components such as collagens, tenascin C, and fibronectin. In turn, these released extracellular components can activate myofibroblasts either directly via innate immunological sensors such as TLR-4, or indirectly by mechano-sensing of increased matrix stiffness by integrins in an FAK dependent way.

Regarding limited scleroderma, although the primary cause is unknown, it is reasonable to speculate that vascular endothelial cell abnormalities induce mononuclear infiltration, and that the resulting changes in TH1 and/or TH2 cell and cytokine balance result in abnormal fibroblast activity and increased collagen deposition.

Diagnosis

In the absence of a diagnostic test proving the absence or presence of SSc, the diagnosis is based on a combination of clinical and laboratory findings. According to the latest classification scheme from 2013, SSc is confirmed by:

Major Criteria:

• skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal joints (MCP) is sufficient to classify a subject as having SSc.
• skin thickening sparing the fingers’ are classified as not having SSc.

Minor criteria:

1. Skin thickening of the fingers -Puffy fingers and Sclerodactyly of the fingers (distal to the metacarpophalangeal joints but proximal to the proximal interphalangeal joints)
2. Fingertip lesions -Digital tip ulcers and Fingertip pitting scars
3. Telangiectasia
4. Abnormal nailfold capillaries
5. Pulmonary arterial hypertension and/or interstitial lung disease
6. Raynaud’s phenomenon
7. SSc-related autoantibodies:

• Anticentromere.
• Anti–topoisomerase I [anti–Scl-70].
• Anti–RNA polymerase III.

Etiology

While the exact cause of CREST syndrome is unknown, it is thought to be the result of a complex interplay of genetic, immunological, and environmental variables.

Calcinosis

Approximately 40% of patients with limited cutaneous SSc complicating from calcinosis (or dystrophic calcification) which is the accumulation of insoluble calcified material in the soft tissues, occurring in the presence of normal calcium and phosphate metabolism. The cause of how or why these crystals form in patients with SSc is not well understood.There is some poorly understood factors have all been proposed to contribute to calcinosis including:

Chronic hypoxia

characterised by:

• Digital ulcers

• Loss of digital tip
• Abnormal capillary drop-outs seen by nailfold Capilloroscopy

Repetitive trauma

• Based on common locations of these deposits such as the fingertips and extensor surfaces of extremities.

Localised structural damage

Raynaud's phenomenon

Raynaud’s phenomenon secondary to SSc occurs in 90% of patients and is often the earliest clinical manifestation to occur.It is vasospastic disorder that characterized by frequent and sudden drops in blood flow to the fingertips, often in response to cold temperatures. Raynaud phenomenon is a symptom complex caused by impaired digital perfusion and can occur as a primary phenomenon or secondary to a wide range of underlying causes.

The etiology of SSc-associated Raynaud phenomenon includes factors such as endothelial cell injury (possibly autoantibody mediated); an imbalance between vasoconstrictor and vasodilator molecules (such as endothelin 1 and nitric oxide, respectively); structural microvascular changes from progressive microangiopathy; and intravascular events that lead to luminal occlusive disease.

Esophageal dysmotility

SSc and gastrointestinal manifestations have been proven to be associated , with more than 90% of SSc patients also having various types of gastrointestinal dysfunction, which is considered the third greatest cause of death in SSc patients . Esophageal micro-reflux, manifested as dysphagia and reflux heartburn, is the most common indication of gastrointestinal dysfunction involvement and, to some extent, exacerbates the existing interstitial lung diseases. Furthermore, Barrett's oesophagus, esophageal stenosis, and esophageal cancer induced by esophageal motility problems may worsen the prognosis of SSc patients.The etiology of esophageal motility disorders in patients with SSc is still uncertain.Many functional tests show the presence of vascular damage, fibrosis, and inflammatory illness, however these three factors may not be a complete picture and may lead to undetected etiology. Previously, some studies reporting the related pathological observations revealed esophageal muscle atrophy without evidence of vascular damage, fibrosis, or inflammatory infiltration. However, the exact mechanism of esophageal muscle atrophy is not known.

Sclerodactyly

Sclerodactyly develops from a perivascular inflammatory infiltration in the dermis.Although the cause of this inflammatory process is still unknown,it is believed that mucopolysaccharide, glycoprotein, and collagen (types I and III) deposition in the dermis causes the edematous phase of skin involvement.As collagen deposition progresses, the dermis becomes sclerotic rather than edematous. Meanwhile, in small arteries, a similar mechanism happens and in the intima, mucinous deposition occurs. The adventitia is initially invaded by inflammatory cells before becoming fibrotic. This process causes artery narrowing, followed by arterial collapse or thrombosis.As a result the tissue becomes ischemic.Fibrosis typically disappears years after the start of skin changes, leaving atrophic skin behind.

Telangiectasia

Prominent and numerous telangiectasia are a common clinical symptoms of scleroderma.The etiology of telangiectasia in general, and CREST in particular, is unknown. Models have not explained the preference for hands, face, and mucosa, as well as their proclivity to enlarge in diameter with time. Venous hypertension as a cause appears implausible given the rarity of high venous pressures in the foot.  While both Raynaud's phenomenon and telangiectasia are present in CREST, telangiectasia is not present in primary Raynaud's disease, implying that telangiectasia is not caused by recurrent vasospasm or vasoconstriction. Telangiectasia is also widespread on the face, which is unaffected by Raynaud's phenomenon.