Raynaud Syndrome: Diagnosis and Treatment
Diagnosis
Raynaud phenomenon is diagnosed clinically based on episodic digital vasospasm causing color changes (pallor, cyanosis, rubor) triggered by cold exposure or emotional stress, with the critical distinction being between primary (idiopathic) and secondary forms. 1, 2
Key Diagnostic Features
Primary vs. Secondary Raynaud:
- Primary Raynaud typically affects individual digits rather than the entire hand, presents with milder symptoms, and occurs without underlying disease 2, 3
- Secondary Raynaud may involve the entire hand, presents with severe painful episodes, and carries risk for digital ulcers, gangrene, or osteomyelitis 4, 2, 5
Red flags suggesting secondary disease include: 4, 2
- Older age at onset (>60 years often indicates atherosclerotic disease) 3
- Severe, painful episodes with digital ulceration 4, 2
- Asymmetric involvement 2
- Associated symptoms of connective tissue disease 6
Essential Workup for Secondary Raynaud
Laboratory evaluation should include: 4, 2
- Antinuclear antibodies (ANA), rheumatoid factor
- Anticentromere and anti-Scl-70 antibodies (for systemic sclerosis screening)
- Anticardiolipin antibodies and lupus anticoagulant
- Complete blood count with differential, erythrocyte sedimentation rate
- Anti-Sjögren syndrome A antibody if dry eyes/mouth present 2
- Prothrombotic workup (protein C, protein S, antithrombin III, Factor V Leiden, prothrombin mutations) if vascular thrombosis suspected 4, 2
Physical examination must assess for: 2
- Joint deformities, scleroderma changes, facial rosacea
- Splinter hemorrhages under nails
- Digital ulcers, tissue necrosis, or gangrene
- Nailfold capillaroscopy findings (if available)
Treatment Algorithm
Step 1: Non-Pharmacological Management (ALL Patients)
All patients with Raynaud must implement trigger avoidance and lifestyle modifications before or alongside any pharmacotherapy. 1
Mandatory interventions include: 1, 2
- Cold avoidance: Wear proper warm clothing including coat, mittens (not gloves), hat, insulated footwear, and use hand/foot warmers 1, 4
- Smoking cessation: Mandatory, as smoking directly worsens vasospasm 1, 5
- Avoid triggering medications: Beta-blockers, ergot alkaloids, bleomycin, clonidine 1, 4, 2
- Stress management techniques to reduce attack frequency 1
- Avoid vibration injury and repetitive hand trauma in occupational settings 1
- Physical therapy with exercises to generate heat and stimulate blood flow 1, 4
Step 2: First-Line Pharmacotherapy
Nifedipine (dihydropyridine-type calcium channel blocker) is the first-line pharmacotherapy for both primary and secondary Raynaud, reducing both frequency and severity of attacks with acceptable adverse effects and low cost. 1, 4, 2
Dosing and administration: 7, 3
- Extended-release nifedipine 30 mg at bedtime is the typical starting dose 8
- Swallow whole on empty stomach; do not chew, divide, or crush tablets 7
- 70-80% of patients respond with decreased severity and frequency of attacks 8
- Common adverse effects include ankle swelling, headache, flushing, and hypotension 7, 3, 6
- 20-50% develop intolerable side effects requiring alternative therapy 8
Important drug interactions: 7
- CYP3A inhibitors (ketoconazole, fluconazole, clarithromycin, erythromycin, grapefruit) increase nifedipine exposure—initiate at lowest dose 7
- Strong CYP3A inducers (rifampin, phenobarbital, phenytoin, carbamazepine, St. John's Wort) reduce efficacy—nifedipine contraindicated with rifampin 7
- Quinidine increases nifedipine Cmax by 2.3-fold and may increase heart rate 7
- Diltiazem increases nifedipine AUC by 2.2 to 3.1-fold—dose reduction necessary 7
Alternative calcium channel blockers (diltiazem) can be considered if nifedipine is poorly tolerated, though efficacy may be reduced 4, 3
Step 3: Second-Line Therapy
Phosphodiesterase-5 inhibitors (sildenafil or tadalafil) should be added or switched to when calcium channel blockers provide inadequate response, as they effectively reduce frequency, duration, and severity of Raynaud attacks. 1, 4, 2
- Effective for both attack reduction AND digital ulcer healing/prevention 1, 4
- Particularly valuable if digital ulcers are present 4
- Can be used as monotherapy or in combination with calcium channel blockers 9
Limitations: 4
- Cost and off-label use may limit utilization
- Adverse effects include headache, flushing, hypotension 6
Step 4: Third-Line Therapy for Severe Disease
Intravenous iloprost (prostacyclin analogue) should be considered for severe Raynaud unresponsive to oral therapies, with proven efficacy for reducing attack frequency/severity and healing digital ulcers. 1, 4, 2
Indications for IV iloprost: 5
- Markedly impaired quality of life despite oral therapies
- Critical digital ischemia
- Skin ulcers with risk for substantial tissue loss and amputation
- Severe, painful Raynaud unresponsive to oral medications 4
- Parenteral route of administration
- Requires hospitalization for administration 5
- Limited by lack of license in some countries 3
Management of Digital Ulcers
For prevention of new digital ulcers, particularly in systemic sclerosis patients with multiple existing ulcers, bosentan (endothelin receptor antagonist) is recommended. 1, 4, 2
Digital ulcer treatment algorithm: 1, 4, 2
Prevention:
- Bosentan is most effective for preventing new digital ulcers, especially if ≥4 ulcers present at baseline 4, 2
- Phosphodiesterase-5 inhibitors also prevent new digital ulcers 1, 4
- Note: Bosentan does NOT improve healing of existing ulcers 2, 6
Healing existing ulcers:
- Intravenous iloprost has proven efficacy for healing digital ulcers 1, 4, 2
- Phosphodiesterase-5 inhibitors improve healing of digital ulcers 4, 2
Local wound care: 2
- Soap-and-water washes with damp dressing or Silvadene cream 8
- Antibiotics only when infection is suspected 2
- Pain control is essential 2
Antiplatelet therapy:
- Low-dose aspirin is recommended for all patients with secondary Raynaud due to structural vessel damage 5
Anticoagulation:
- Consider during acute phase of digital ischemia with suspected vascular occlusive disease 5
Additional Treatment Options for Refractory Cases
For patients failing standard pharmacotherapy: 4, 9
- Topical nitroglycerin can provide ancillary benefit for acute painful episodes 4
- Digital sympathectomy can be considered for refractory cases with persistent digital ulcer healing/prevention needs 4, 9
- Botulinum toxin infiltrations or fat grafting have emerging evidence for healing and prevention of digital ulcers 4, 9
- Fluoxetine (selective serotonin reuptake inhibitor) might be considered, though evidence is limited to small studies 4, 6
Fingertip amputation: 8
- Reserved for chronic non-healing ulcers or intractable pain
- Generally heal with time and provide excellent pain relief
Critical Pitfalls to Avoid
Always evaluate for systemic sclerosis and other connective tissue diseases, as delayed diagnosis leads to digital ulcers and poor outcomes. 1, 2
Never continue triggering medications (beta-blockers, ergot alkaloids, bleomycin, clonidine), as they will undermine all treatment efforts 1, 2
Do not delay escalation in secondary Raynaud, as this leads to digital ulcers and poor outcomes—more aggressive therapy is required 1, 2
Monitor for hepatotoxicity with nifedipine: 7
- Rare elevations of alkaline phosphatase, CPK, LDH, SGOT, SGPT
- Rare instances of allergic hepatitis reported
- Cholestasis with or without jaundice can occur
Careful monitoring required in: 7
- Moderate or severe liver impairment—initiate at lowest dose
- Pre-existing chronic renal insufficiency—rare reversible BUN/creatinine elevations reported
- Patients on anticoagulation—nifedipine decreases platelet aggregation and increases bleeding time
Reassess treatment efficacy at 3-6 months and escalate therapy if inadequate response. 2