What is the management approach for CREST (Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasias) syndrome?

Management of CREST Syndrome

CREST syndrome requires a systematic, manifestation-specific treatment approach prioritizing early screening for life-threatening complications (interstitial lung disease and pulmonary arterial hypertension), followed by targeted therapy for each component using calcium channel blockers for Raynaud's, proton pump inhibitors for esophageal symptoms, and immunosuppression for progressive skin or lung disease. 1

Mandatory Initial Screening and Risk Stratification

All patients require immediate screening for the two complications that determine mortality 1:

• Pulmonary function tests, high-resolution CT, and echocardiography to detect interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH), as ILD occurs in 40-75% of patients and PAH significantly impacts survival 1
• Regular blood pressure monitoring, particularly in patients with anti-RNA polymerase III antibodies, to detect scleroderma renal crisis before irreversible renal damage occurs 1
• Autoantibody testing including anti-centromere antibodies (characteristic of limited cutaneous disease) and antinuclear antibodies 2

Treatment Algorithm by Manifestation

Raynaud's Phenomenon (First-Line Management)

Start with dihydropyridine calcium channel blockers, specifically nifedipine, as this is the most studied and cost-effective first-line therapy with proven reduction in both frequency and severity of attacks 1, 3:

• If nifedipine is not tolerated, use alternative dihydropyridine calcium channel blockers 3
• Add or switch to PDE-5 inhibitors (sildenafil or tadalafil) if calcium channel blockers provide inadequate response 1, 3
• Escalate to intravenous iloprost for severe Raynaud's unresponsive to oral therapies 1, 3
• Botulinum toxin injections (10 units per webspace) can be considered for refractory digital symptoms, with improvement reported within one week 4

Digital Ulcers (Active Treatment and Prevention)

For active digital ulcers, use PDE-5 inhibitors and/or intravenous iloprost as these agents promote healing 1, 3:

• Bosentan specifically prevents new digital ulcer formation (not for healing existing ulcers), particularly effective in patients with multiple prior ulcers 1, 3
• PDE-5 inhibitors serve dual purpose for both healing and prevention 1, 3
• In severe cases with gangrene or osteomyelitis, amputation may be required 3

Esophageal Dysmotility

Proton pump inhibitors (PPIs) are essential to prevent gastroesophageal reflux disease complications including esophageal ulcers and strictures 1:

• Add prokinetic drugs for symptomatic motility disturbances 1
• Aggressive nutritional support is critical, as malnutrition from gastrointestinal involvement is a leading cause of mortality 1
• Monitor for dysphagia and eating difficulties that may require dietary modifications 5

Sclerodactyly and Skin Fibrosis

Treatment is most effective within 2-5 years from onset of first non-Raynaud's features 1:

• Methotrexate, mycophenolate mofetil (MMF), or rituximab for early disease with significant skin involvement 1
• Tocilizumab may be considered for early, inflammatory diffuse cutaneous disease 1
• Physical therapy to maintain range of motion and prevent contractures 3

Interstitial Lung Disease (ILD)

Mycophenolate mofetil (MMF) is first-line therapy for ILD 1:

• Cyclophosphamide or rituximab are alternatives for first-line treatment 1
• Nintedanib should be added alone or in combination with MMF for progressive fibrotic ILD 1
• Only 15-18% of patients with ILD have progressive disease, making screening essential to identify those requiring treatment 1

Pulmonary Arterial Hypertension (PAH)

Combination therapy with PDE-5 inhibitors and endothelin receptor antagonists is first-line treatment 1:

• Intravenous epoprostenol for advanced PAH (WHO functional class III and IV) 1
• Other prostacyclin analogues or riociguat as alternatives 1
• Do NOT use anticoagulants (warfarin) for SSc-PAH, as this differs from idiopathic PAH management and is not supported by evidence 1

Calcinosis

No proven medical therapy exists for calcinosis 1:

• Surgical debridement is the primary treatment for symptomatic cases, particularly when causing pain or functional impairment 1, 6
• For thumb involvement, radical debridement with kite flap reconstruction provides soft, sensate tissue with complete pain resolution and functional recovery 6
• Simple removal is adequate for minor outpatient cases, but major painful cases require radical debridement 6

Scleroderma Renal Crisis (SRC)

ACE inhibitors must be started immediately at diagnosis 1:

• Patients on glucocorticoids require more frequent blood pressure monitoring to detect SRC early 1

Telangiectasias

• Generally require no specific treatment beyond cosmetic considerations 2
• Monitor for associated oral manifestations and manage xerostomia if Sjögren's syndrome develops 5

Critical Pitfalls to Avoid

• Do not delay screening for ILD and PAH - these complications determine mortality and early intervention changes natural history 1
• Do not use anticoagulation routinely for SSc-PAH as evidence does not support this practice unlike idiopathic PAH 1
• Do not assume disease stability after initial years - many patients with diffuse disease do not improve after 4 years and may worsen later 1
• Do not overlook nutritional status - malnutrition from gastrointestinal involvement is a leading cause of mortality 1
• Do not pursue prolonged ineffective medical management for symptomatic calcinosis - consider surgical options early 1, 6
• Do not forget trigger avoidance - cold exposure, trauma, stress, smoking, and vibration injury must be addressed 3

Supportive Care Measures

• Proper warm clothing including coat, mittens, hat, and insulated footwear 3
• Physical therapy to stimulate blood flow and generate heat 3
• Topical fluoride for prevention of xerostomia-related dental complications if Sjögren's syndrome develops 5
• Frequent dental assessment and reinforcement of oral hygiene 5