Causes of Raynaud's Syndrome
Primary vs Secondary Classification
Raynaud's syndrome is fundamentally caused by excessive vasoconstriction of digital arteries triggered by cold exposure or emotional stress, and exists in two forms: primary (idiopathic) Raynaud's without underlying disease, and secondary Raynaud's associated with connective tissue disorders, vascular diseases, medications, or occupational exposures. 1, 2
Primary Raynaud's Phenomenon
Primary Raynaud's occurs as an isolated condition without any identifiable underlying disease. 1, 2
Pathophysiologic Mechanism
- The underlying mechanism involves local abnormalities in digital arteries, specifically overexpression or hyperactivity of postsynaptic alpha-2 adrenergic receptors, leading to enhanced smooth muscle contraction 3, 4
- Cold exposure increases the sensitivity of these alpha-2 adrenergic receptors 4
- This represents pure vasospasm without endothelial abnormalities 5
Clinical Characteristics
- Typically begins at puberty and is more common in women 5
- Shows benign progression without tissue damage 5
- Laboratory tests (ESR, ANA) and capillaroscopy remain normal 5
Secondary Raynaud's Phenomenon: Autoimmune and Connective Tissue Diseases
Systemic sclerosis (scleroderma) is the single most common cause of secondary Raynaud's, occurring in 90-95% of scleroderma patients. 1, 2, 5
Major Autoimmune Associations
- Systemic lupus erythematosus is a well-established cause of secondary Raynaud's 1, 2, 5
- Rheumatoid arthritis is associated with secondary Raynaud's 1, 2
- Mixed connective tissue disease/overlap syndromes cause secondary Raynaud's, where it represents a main symptom with frequent trophic finger abnormalities 1, 5
- Sjögren syndrome can present with secondary Raynaud's 3, 5
- Polymyositis/dermatomyositis may develop secondary Raynaud's, typically with benign progression 5
Key Distinguishing Features
- Secondary Raynaud's tends to begin later in life compared to primary 5
- Involves endothelial abnormalities rather than pure vasospasm 5
- May involve the entire hand rather than just individual digits 1
- Associated with digital ulcers (22.5% in systemic sclerosis), gangrene (11% in systemic sclerosis), and potential osteomyelitis 1
Secondary Raynaud's: Vascular and Thrombotic Disorders
Arterial Diseases
- Thromboangiitis obliterans (Buerger's disease) is particularly associated with secondary Raynaud's in young tobacco smokers 1, 2
- Atherosclerosis with peripheral arterial disease causes secondary Raynaud's 1, 2
- Thromboembolic disease (both macroembolic and microembolic) is associated with secondary Raynaud's 1, 2
- Radiation-associated arteritis can cause secondary Raynaud's 1, 2
Prothrombotic and Hematologic Conditions
- Clotting system abnormalities including protein C, protein S, or antithrombin III deficiencies 1, 2
- Factor V Leiden or prothrombin mutations 1, 2
- Hyperhomocysteinemia 1, 2
- Lupus anticoagulant or anticardiolipin antibody presence 1, 2
- Prothrombotic states associated with malignancies or inflammatory bowel disease 2
Secondary Raynaud's: Drug-Induced Causes
Several medications can induce or exacerbate Raynaud's phenomenon through various vasoconstrictive mechanisms. 1, 2
Specific Causative Medications
- Ergot alkaloids can induce Raynaud's 1, 2
- Bleomycin (chemotherapy agent) can induce Raynaud's 1, 2
- Clonidine can induce Raynaud's 1, 2
- Beta-blockers may be clinically relevant in inducing Raynaud's 1, 2
- Tricyclic antidepressants, SSRIs, lithium, and dopamine antagonists have been reported to exacerbate restless leg syndrome (note: this citation appears to be from a different condition and should be disregarded for Raynaud's) 6
Secondary Raynaud's: Occupational and Environmental Causes
Physical Exposures
- Chronic cold exposure is associated with secondary Raynaud's 1, 2
- Vibration injury from occupational tools is associated with secondary Raynaud's 1, 2
Secondary Raynaud's: Other Medical Conditions
Miscellaneous Associations
- Primary biliary cirrhosis is associated with secondary Raynaud's 1, 2
- Malignancies can cause Raynaud's as a paraneoplastic phenomenon 1, 2, 5
- HIV-related conditions are associated with secondary Raynaud's 1
Red Flags Indicating Secondary Raynaud's
When evaluating a patient with Raynaud's, specific clinical features should raise immediate concern for secondary causes requiring urgent workup. 1, 2
Warning Signs
- Severe, painful episodes with digital ulceration or tissue necrosis 1, 2
- Associated systemic symptoms including joint pain, skin thickening (suggesting scleroderma), dysphagia, weight loss, malaise, or fatigue 1
- Fever is rare in primary Raynaud's; its presence suggests underlying connective tissue disease 1
- Dry eyes and dry mouth suggest Sjögren syndrome 1
- Photosensitivity and pleuritis suggest systemic lupus erythematosus 1
Clinical Pitfalls to Avoid
- Do not dismiss Raynaud's in older patients as simply age-related; onset later in life strongly suggests secondary causes and warrants thorough evaluation for connective tissue disease or malignancy 5
- In young tobacco smokers with Raynaud's, always consider Buerger's disease 1, 2
- Normal laboratory tests and capillaroscopy support primary Raynaud's, but abnormal findings (elevated ESR, positive ANA, abnormal capillaroscopy with enlarged capillaries, hemorrhages, or avascular areas) indicate secondary causes requiring further investigation 5
- Lifestyle factors including increased BMI, caffeine intake, sedentary lifestyle, and tobacco use may contribute to symptoms but are not primary causes 6