What are the diagnosis and treatment options for CREST (Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia) syndrome?

CREST Syndrome: Diagnosis and Treatment

Diagnostic Approach

CREST syndrome is diagnosed when at least three of the five cardinal features are present: Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia, though complete manifestation of all five features is uncommon and typically develops gradually over years. 1, 2

Initial Clinical Evaluation

• Serologic testing for anticentromere antibodies is essential, as these are present in more than 50% of CREST syndrome cases and are highly characteristic of this limited cutaneous form of systemic sclerosis 1, 2
• Antinuclear antibodies (ANA) should be obtained as part of the diagnostic workup 1
• Complete blood count is recommended to assess for anemia and inflammatory markers 3

Mandatory Screening for Life-Threatening Complications

All patients must undergo comprehensive cardiopulmonary screening at diagnosis, as pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) determine mortality. 4, 3

• Pulmonary function tests with DLCO measurement are critical, as a marked isolated decrease in DLCO is highly predictive of PAH development, with serial measurements showing linear decline years before PAH diagnosis 3
• Doppler echocardiography is essential to screen for PAH, assess right ventricular function, and evaluate for left-sided heart disease 3
• High-resolution chest CT should be performed to evaluate for ILD, though it is less common in limited versus diffuse scleroderma 3
• Patients with DLCO <55% predicted have a 35% risk of developing PAH and require annual echocardiographic screening 3

Risk Stratification

• Patients with anticentromere antibodies plus anti-U3-RNP or anti-nucleolar antibodies are at higher risk for PAH and require close monitoring 3
• Disease onset after menopause is associated with isolated PAH development 3
• Regular blood pressure monitoring is essential, especially in patients with anti-RNA polymerase III antibodies, to detect scleroderma renal crisis early 4

Treatment Algorithm by Manifestation

Raynaud's Phenomenon (First-Line Management)

Dihydropyridine calcium channel blockers, specifically nifedipine, are the initial treatment of choice for Raynaud's phenomenon. 4

• PDE-5 inhibitors should also be considered as first-line therapy 4
• For severe Raynaud's phenomenon failing oral therapy, intravenous iloprost should be administered 4
• Botulinum toxin injection (10 units per webspace, total 20 units) can be considered for recalcitrant cases, with pain improvement within one week and ulcer healing within three weeks 5

Digital Ulcers

• PDE-5 inhibitors and/or intravenous iloprost are recommended for active digital ulcers 4
• Bosentan should be used specifically for prevention of new digital ulcer formation, not for healing existing ulcers 4

Esophageal Dysmotility

• Proton pump inhibitors (PPIs) are the cornerstone of treatment for gastroesophageal reflux disease and prevention of esophageal ulcers and strictures 4
• Prokinetic drugs should be considered for symptomatic motility disturbances 4
• Aggressive nutritional support is mandatory, as malnutrition is the leading cause of mortality from gastrointestinal involvement 4

Sclerodactyly and Skin Fibrosis

Treatment is most effective within 2-5 years from onset of first non-Raynaud's features. 4

• Methotrexate, mycophenolate mofetil (MMF), or rituximab should be considered for skin fibrosis in patients with early disease and significant skin involvement 4
• Tocilizumab may be considered for early, inflammatory diffuse cutaneous disease 4

Interstitial Lung Disease (ILD)

Mycophenolate mofetil (MMF) is the first-line therapy for ILD. 4

• Cyclophosphamide or rituximab are alternatives for first-line treatment 4
• Nintedanib should be considered alone or in combination with MMF for progressive fibrotic ILD 4

Pulmonary Arterial Hypertension (PAH)

Combination therapy with PDE-5 inhibitors and endothelin receptor antagonists is first-line treatment for PAH. 4

• Intravenous epoprostenol should be used for advanced PAH (WHO functional class III and IV) 4
• Other prostacyclin analogues or riociguat can be considered 4
• Anticoagulants (warfarin) are NOT recommended for SSc-PAH, unlike idiopathic PAH 4

Calcinosis

Calcinosis has no proven effective medical therapy. 4

• For symptomatic finger calcinosis, surgical debridement is required, with simple removal adequate for minor cases 6
• Major painful cases require radical debridement with flap reconstruction, particularly for thumb involvement where the kite flap provides optimal soft tissue coverage, sensation, and functional recovery 6
• Surgical intervention typically provides complete pain resolution with full recovery of thumb motion and grip function 6

Scleroderma Renal Crisis (SRC)

ACE inhibitors must be initiated immediately at diagnosis of SRC. 4

• Patients on glucocorticoids require regular blood pressure monitoring to detect SRC early 4

Oral and Dental Management

For patients developing secondary Sjögren's syndrome:

• Saliva secretion stimulators and salivary substitutes should be used 7
• Topical fluoride in toothpastes, rinses, gels, and varnishes is essential to prevent rampant caries from xerostomia 7
• Frequent dental assessment and reinforced oral hygiene instruction are mandatory 7

Critical Pitfalls to Avoid

• Do not delay cardiopulmonary screening - PAH and ILD determine mortality, and early intervention changes natural history 4, 3
• Do not use anticoagulation routinely for SSc-PAH as you would for idiopathic PAH - evidence does not support this 4
• Do not overlook nutritional status - malnutrition from gastrointestinal involvement is a leading cause of mortality 4
• Do not pursue prolonged ineffective medical management for symptomatic calcinosis - surgical options should be considered early 4, 6
• Refer to pulmonology if DLCO <60% predicted or echocardiographic evidence of PAH 3
• Refer to cardiology for elevated pulmonary artery pressures on echocardiography (sPAP >30 mmHg) 3

Prognosis

The prognosis of CREST syndrome is relatively good with disease duration typically exceeding 10 years 2. However, pulmonary hypertension occurs in 3-14% of cases, is a very late event, and carries a severe prognosis with 50% mortality at 2 years 2.