What is CREST (Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia) syndrome?

CREST Syndrome: A Comprehensive Overview

CREST syndrome is a variant of limited cutaneous systemic sclerosis (lcSSc) characterized by five key features: Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia. 1

Definition and Classification

CREST syndrome represents a limited form of systemic sclerosis (SSc), primarily affecting the skin distal to the elbows and/or knees without truncal involvement, although skin thickening may occur on the face and neck 1. This contrasts with diffuse cutaneous SSc (dcSSc), which involves skin both distal and proximal to the knees and/or elbows and/or trunk.

Key Clinical Features

1. Calcinosis: Calcium deposits in the skin and subcutaneous tissues, particularly affecting the fingers

   • Appears to be less common in general SSc and its presence is considered a key diagnostic element of CREST syndrome 2
   • Can cause significant pain and functional impairment

2. Raynaud's phenomenon: Episodic vasospasm of digital arteries triggered by cold or emotional stress

   • Nearly all patients with SSc have Raynaud's phenomenon 1
   • Often the earliest manifestation of the disease

3. Esophageal dysmotility: Impaired esophageal function

   • Related to atrophy and fibrosis of the esophageal smooth muscle 1
   • Results in severe hypomotility and an incompetent lower esophageal sphincter

4. Sclerodactyly: Thickening and hardening of the skin of the fingers

   • Characterized by fibrosis of skin distal to the metacarpophalangeal joints

5. Telangiectasia: Dilated small blood vessels visible on the skin surface

   • Commonly affects the face, lips, and hands

Pathophysiology

The underlying pathophysiology involves three key processes:

• Vascular dysfunction
• Immune system activation
• Progressive fibrosis

CREST syndrome is associated with specific autoantibodies, particularly anti-centromere antibodies, which are present in many patients with limited cutaneous SSc 1.

Organ Involvement and Complications

Pulmonary Manifestations

• Pulmonary arterial hypertension (PAH) is a serious complication
• Occurs in up to 10% of patients with limited cutaneous SSc 1
• PAH is the cause of death in up to 50% of patients who die of scleroderma-related complications 1
• Interstitial lung disease is less common than in diffuse SSc but can occur

Gastrointestinal Involvement

• Esophageal dysfunction is a defining feature
• Results in symptoms of dysphagia and reflux
• Gastrointestinal involvement affects nearly 90% of patients with SSc 1
• The esophagus is the most commonly involved area, followed by the small bowel, colon, and anorectum

Vascular Complications

• Digital ulcers affect approximately 50% of patients 1
• Raynaud's phenomenon can lead to digital ischemia and tissue loss

Other Complications

• Cardiac involvement
• Renal disease (less common than in diffuse SSc)
• Neurological manifestations (rare)
• Intracranial aneurysms have been reported 3

Diagnosis

Diagnosis is based on clinical features and typically requires at least three of the five CREST features to be present 2. Laboratory findings may include:

• Anti-centromere antibodies
• Anti-nuclear antibodies with nucleolar pattern
• Decreased diffusing capacity of the lung for carbon monoxide (DLCO)

Management

Non-pharmacological Approaches

• Cold avoidance strategies
• Smoking cessation
• Stress management techniques 4

Pharmacological Treatment

For Raynaud's Phenomenon

1. First-line: Dihydropyridine calcium channel blockers (e.g., nifedipine)

   • Typical dosing: 10mg three times daily
   • Side effects: hypotension, peripheral edema, headaches, flushing 4

2. Second-line: Phosphodiesterase-5 inhibitors (sildenafil, tadalafil)

   • For patients who don't respond to calcium channel blockers 4

3. Severe cases: Intravenous prostacyclin analogues (iloprost)

   • For cases failing oral therapy 4

4. For digital ulcer prevention: Endothelin receptor antagonists (bosentan)

   • Particularly effective in reducing new digital ulcers in patients with systemic sclerosis 4

For Esophageal Dysmotility

• Proton pump inhibitors for reflux
• Prokinetic agents for dysmotility

For Calcinosis

• Surgical management for painful or functionally limiting calcinosis 5
• Debridement and flap reconstruction for severe cases

Monitoring and Screening

• Regular screening for pulmonary arterial hypertension is recommended 1
• Echocardiography is a key screening tool 1
• Patients with a marked decrease in DLCO (55% of predicted) have a higher risk of developing PAH 1

Prognosis

The prognosis for CREST syndrome is generally better than for diffuse cutaneous SSc, but serious complications like PAH can significantly impact survival. Early detection and treatment of complications are crucial for improving outcomes.

Therapeutic Advances

• Botulinum toxin injections have shown promise for treatment of recalcitrant Raynaud's phenomenon 6
• Minimally invasive surgical approaches can be effective for spinal calcinosis 7

Clinical Pearls

• CREST syndrome can overlap with both limited and diffuse subsets of SSc 2
• Calcinosis appears to be the most distinctive feature differentiating CREST syndrome from other forms of SSc 2
• The presence of anti-centromere antibodies is highly associated with CREST syndrome
• Regular monitoring for pulmonary hypertension is essential due to its significant impact on mortality