How should I evaluate and manage Raynaud’s phenomenon, including distinguishing primary from secondary causes and selecting appropriate treatment?

Evaluation and Management of Raynaud's Phenomenon

Initial Evaluation: Distinguishing Primary from Secondary Disease

Begin by assessing for red-flag features that indicate secondary Raynaud's, as this distinction fundamentally determines treatment intensity and prognosis. 1

Red-Flag Features Requiring Urgent Workup

• Severe, painful episodes with digital ulceration or tissue necrosis – present in 22.5% of systemic sclerosis patients and indicate secondary disease requiring aggressive therapy 1, 2
• Asymmetric attacks or involvement of the entire hand rather than individual digits suggests secondary Raynaud's 2, 3
• Systemic symptoms including joint pain, skin thickening, weight loss, malaise, fever, photosensitivity, dry eyes/mouth, or dysphagia point to underlying connective tissue disease 1, 2
• Abnormal or absent peripheral pulses suggest atherosclerosis or thromboangiitis obliterans (Buerger's disease) 3
• Skin changes such as thickening, telangiectasias, or calcinosis indicate systemic sclerosis 3

Laboratory and Diagnostic Testing

Order the following tests when secondary Raynaud's is suspected: 1

• Complete blood count with differential 1, 3
• Erythrocyte sedimentation rate (ESR) 1, 3
• Antinuclear antibodies (ANA) 1, 3
• Rheumatoid factor 1
• Anticentromere and anti-Scl-70 antibodies 1
• Anticardiolipin antibodies and lupus anticoagulant 1
• Nailfold capillaroscopy – critical for early diagnosis of systemic sclerosis; abnormal patterns (enlarged capillaries, hemorrhages, avascular areas) distinguish secondary from primary disease 4, 5
• Ankle-brachial index if peripheral arterial disease is suspected 1, 3

Note: Primary Raynaud's shows normal laboratory tests and normal capillaroscopy, whereas secondary disease demonstrates abnormalities in these studies 4

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Treatment Algorithm

Step 1: Non-Pharmacological Measures (All Patients)

Implement trigger avoidance and protective strategies first, as these are essential regardless of disease severity: 1

• Absolute smoking cessation – mandatory for all patients 3
• Avoid cold exposure; wear mittens, insulated footwear, hat, and coat in cold conditions 1
• Discontinue offending medications: beta-blockers, ergot alkaloids, clonidine, bleomycin 1, 2, 3
• Physical therapy to stimulate blood flow and exercises to generate heat 1
• Avoid trauma, emotional stress, and vibration injury 1

Step 2: First-Line Pharmacological Therapy

For patients requiring medication (symptoms affecting quality of life despite non-pharmacological measures), initiate nifedipine extended-release: 1

• Start nifedipine extended-release 30 mg once daily on an empty stomach 1
• Titrate over 7–14 days to target dose of 60–90 mg daily based on therapeutic response and tolerability 1
• Meta-analyses confirm nifedipine reduces frequency and severity of attacks in approximately two-thirds of patients 1
• Assess frequency, duration, and severity of attacks at each titration step 1
• Reassess in 4–6 weeks to evaluate response and tolerability 3

Critical Safety Warnings:

• Never use immediate-release nifedipine without concurrent beta-blocker therapy in acute coronary syndromes – associated with increased mortality 1
• Contraindicated in clinically significant left-ventricular dysfunction or high risk of cardiogenic shock 1

Step 3: Second-Line Therapy (Inadequate Response to Calcium Channel Blockers)

Add or switch to phosphodiesterase-5 inhibitors when calcium channel blockers provide insufficient symptom control: 1

• Sildenafil or tadalafil effectively reduce frequency, duration, and severity of attacks 1
• Particularly valuable if digital ulcers are present, as PDE5 inhibitors promote both healing and prevention 1
• Cost and off-label use may limit utilization 1

Step 4: Third-Line Therapy (Severe, Refractory Disease)

For severe Raynaud's unresponsive to oral therapies, consider intravenous prostacyclin analogues: 1

• Intravenous iloprost is the only prostacyclin analogue proven effective for Raynaud's in systemic sclerosis 1
• Particularly effective for healing digital ulcers 1
• Reserved for severe, painful Raynaud's with frequent attacks despite above treatments 1

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Management of Digital Ulcers (Systemic Sclerosis)

Digital ulcers represent a serious complication requiring aggressive intervention, occurring in 22.5% of systemic sclerosis patients: 2, 3

Prevention of New Digital Ulcers

• Bosentan (endothelin receptor antagonist) is most effective for preventing new digital ulcers, especially in patients with ≥4 digital ulcers at baseline 1
• Dosing: Start 62.5 mg twice daily for 4 weeks, then increase to 125 mg twice daily 1
• Important limitation: Bosentan prevents new ulcers but does not promote healing of existing ulcers 1

Healing of Existing Digital Ulcers

• Intravenous iloprost has proven efficacy for healing existing digital ulcers 1
• Phosphodiesterase-5 inhibitors improve healing of digital ulcers 1
• Wound care by specialized nurses/physicians, antibiotics only when infection is suspected, and pain control are essential 1

Emerging Therapies

• Topical nitroglycerin can provide ancillary benefit for acute painful episodes 1
• Digital sympathectomy can be considered for refractory cases with persistent digital ulcer healing/prevention needs 1
• Botulinum toxin infiltrations or fat grafting have emerging evidence for healing and prevention 1

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Specialist Referral

Refer to rheumatology early when secondary Raynaud's is suspected, as delays are a major cause of postponed effective treatment: 1

• Rheumatologists achieve superior outcomes: earlier diagnosis, more frequent disease-modifying therapy prescription, better prevention of joint damage, and preservation of physical function 1
• Rheumatologists possess specialized expertise in disease-activity monitoring and comprehensive knowledge of advanced therapies (PDE5 inhibitors, endothelin-receptor antagonists, prostacyclin analogues) 1
• Avoiding delays in rheumatology referral when red-flag features are present is the most significant preventable cause of poor outcomes 1

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Follow-Up Schedule

• Patients with mild, controlled symptoms: Reassess in 3–6 months 3
• Patients starting pharmacological therapy: Reassess in 4–6 weeks to assess response and tolerability 3
• Immediate reassessment required if any digital ulcers, tissue necrosis, or new systemic symptoms develop 3

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Common Pitfalls to Avoid

• Do not dismiss severe pain as typical Raynaud's – this is a red flag for secondary disease requiring urgent workup 1, 2
• Do not delay rheumatology referral when systemic symptoms or digital ulcers are present – this is the most preventable cause of poor outcomes 1
• Do not use immediate-release nifedipine inappropriately – associated with increased mortality in certain cardiac conditions 1
• Do not overlook medication-induced Raynaud's – beta-blockers, ergot alkaloids, clonidine, and bleomycin are common culprits 1, 2
• Do not forget absolute smoking cessation – particularly critical in thromboangiitis obliterans (Buerger's disease), which occurs in young tobacco smokers 1, 2