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A. Epidemiology and Classificationnavigator

  1. Common vasospastic disease (female > male) initiated with exposure to cold
  2. Raynaud's phenomenon is specifically episodic, transient digital ischemia secondary to cold
  3. Symptoms
    1. Vascular lesion causes inappropriate vasoconstriction
    2. Digits turn white, then blue, then red (Raynaud's phenomenon)
  4. Standard Classification of Raynaud's Disease
    1. Primary Raynaud's associated with no underlying conditions
    2. Secondary Raynaud's is a complex disorder with underlying disease
    3. Primary often has >10 attacks per day, precipitated by cold and emotional stress
    4. Secondary often has <5 attacks per day, precipitated mainly by cold
  5. Primary Raynaud's and Transition to Systemic Disease [3]
    1. Median time is 8-12 yrs from initial Raynaud's to diagnosis of associated disease
    2. Overall, low transition from primary Raynaud's to frank connective tissue disease
    3. Even with positive serologies, primary Raynaud's progresses ~3 per 100 patient-years
    4. When transition occurs with primary Raynaud's, systemic lupus is most common
  6. Raynaud's Phenomenon and Other Diseases
    1. Strongest association with systemic sclerosis (CREST > scleroderma)
    2. Common in mixed connective tissue disease (MCTD)
    3. Frequently found with systemic lupus erythematosus (SLE) as well
    4. Pulmonary hypertension (P-HTN) may also accompany Raynaud's

B. Pathophysiology navigator

  1. Unknown
  2. Raynaud's Phenomenon
    1. Vasoconstriction of digital arteries
    2. Precapillary arteriolar vasoconstriction
    3. Formation of cutaneous arteriovenous shunts
  3. Episodic Vasoconstriction
    1. Vasospasm leads to arterial occlusion: fingers turn white
    2. Venous collateral refill of unperfused areas: fingers turn blue
    3. Vasospasm stops: arterial opening and fresh blood, hyperemic area; fingers turn red
  4. Vasoactive Hormone Regulation
    1. Role of neuropeptide Y in vasocontrictive phase has been demonstrated
    2. Calcitonin Gene Related Peptide (CGRP) dilates vessels and may antagonize neuropeptide Y
  5. Estrogens appears to increase risk for Raynaud phenomenon 2.5 fold [4]
    1. Unopposed estrogen replacement therapy (ERT) only has this risk
    2. Progesterone + ERT does not have this risk
    3. May explain predisposition in women

C. Causes of Secondary Raynaud's Disease navigator

  1. Systemic Sclerosis
    1. Generalized (Progressive Systemic Sclerosis): ~70% have Raynaud's
    2. Localized (CREST Syndrome): >95% of CREST patients have Raynaud's
    3. Often associated with P-HTN
  2. SLE
    1. Raynaud's present in ~40% of patients with SLE
    2. Incresaed risk of P-HTN
    3. ~80% have anti-endothelial cell antibodies
  3. Other autoimmune / Rheumatologic Conditions
    1. Rheumatoid Arthritis
    2. Mixed Connective Tissue Disease (MCTD)
    3. Polymyositis / Dermatomyositis - ~35% of patients
    4. Sjogren's Syndrome
    5. Undifferentiated Connective Tissue Disease (UCTD)
    6. Systemic vasculitis
  4. Structural Arterial Disease
    1. Atheroembolic Disease / Cholesterol Emboli
    2. Takayasu's Arteritis
    3. Thromboangiitis Obliterans
    4. Thoracic Outlet Syndrome
  5. Medications
    1. Cisplatinum
    2. Bleomycin
    3. Vinblastine
    4. Vasoconstrictors - ergot alkyloids, high dose sympathomimetics
  6. Hematologic Abnormalities
    1. Leukemia
    2. Cryoglobulinemia and other Paraproteinemias
    3. Cold Agglutinin Disease (eg. with mycoplasma)
    4. Thrombocytosis
  7. Other
    1. Hypothyroidism
    2. Reflex Sympathetic Dystrophy Syndrome
    3. Arteriovenous Fistula

D. Evaluationnavigator

  1. Require at least two of the three color changes after cold exposure (episodic attacks)
  2. Nailfold capillary exam should be done (predicts secondary disease)
    1. A drop of immersion oil is placed on the nailfold
    2. An office ophthalmoscope is used to exam the capillaries
    3. Classical changes include capillary dilatation and dropout (avascularity)
    4. Often found in CREST, Scleroderma, Dermatomyositis, Polymyositis, MCTD, UCTD
    5. Less common in patients with SLE and Rheumatoid Arthritis
  3. Laboratory
    1. Standard Screening: complete blood count, antinuclear antibodies, RF, total protein
    2. Markers of systemic inflammation: ESR (erythrocyte sedimentation rate), CRP
    3. Consider anti-centromere and anti-Scl70 antibody tests
    4. Consider cryoglobulins and serum protein electrophoresis
  4. Diagnostic Criteria for Primary Raynaud's Disease
    1. Episodic attacks of acral pallor or cyanosis (especially finger tips)
    2. Strong, symmetrical peripheral pusles
    3. No digital pitting, ulcerations or gangrene
    4. No sclerodactyly
    5. Normal nailfod capillaries
    6. ANA <1:160 and ESR <20mm/hr

E. Therapy navigator

  1. Stop Vasoconstricting Agents
    1. Smoking must be stopped
    2. Decrease caffeinated beverages
    3. Very warm clothing on exposed areas
    4. Avoid ergotamines, sumatriptan, ß-blockers, clonidine, methysergide
  2. Calcium Channel Blockers
    1. Peripheral vasodilators (dihydropyridines) most effective
    2. Long acting nifedipine (long acting), amlodipine, felodipine, isradipine
    3. Diltiazem, with mild vasodilating and nodal blocking activities, may be used also
    4. Diltiazem is not as effective as dihydropyridines
    5. Verapamil is not effective
  3. Angiotensin Inhibition
    1. Angiotensin II receptor blockers may be as or more active than calcium blockers
    2. Losartan (Hyzaar®) has shown benefit in a randomized study [6]
    3. Angiotensin converting enzyme (ACE) inhibitors may also be used
  4. Nonparenteral Vasodilators
    1. Topical nitroglycerin (0.5-1.0cm 2% ointment qd) often improve blood flow
    2. Oral nitrates may also be effective
    3. Bosentan (Tracleer®) - endothelin antagonist 62.5mg po bid resolved digital ulcers in a scleroderma patient [5]
    4. alpha-adrenergic blockers may be used 3rd line - efficacy may wain over weeks
  5. Pentoxyphylline (Trental®) 400mg po tid -- data supporing efficacy sparse
  6. Sympathectomy - role in treatment of severe disease
  7. Experimental Agents
    1. Calcitonin Gene Related Peptide (CGRP): may be effective in severe disease
    2. Nitric oxide stimulation has not been effective to date
  8. Treatment of Acute Ischemia
    1. Short acting nifedipine and aspirin should be given immediately
    2. Digital or wrist block with lidocaine or bupivacaine relieves pain, blocks sympathetic neurons
    3. Epinephrine (or other vasoconstrictors) must not be used
    4. Continued ischemia can be treated with untravenous prostaglandins:
    5. Alprostadil 0.1-0.4µg/kg/min IV for 6-24 hours for 2-5 days OR
    6. Epoprostenol 0.5-6.0ng/kg/min IV for 6-24 hours for 2-5 days
    7. Iloprost is effective (not available in USA) 0.5-2.0ng/kg/min IV 6-24 hours for 2-5 days [7]
    8. Anticoagulation with heparin 48-72 hours may be added for persistent ischemia

References navigator

  1. Wigley FM. 2002. NEJM. 347(13):1001 abstract
  2. Block JA and Sequeira W. 2001. Lancet. 357(9273):2042 abstract
  3. Spencer-Green G. 1998. Arch Intern Med. 158(6):595 abstract
  4. Fraenkel L, Zhang Y, Chaisson CE, et al. 1998. Ann Intern Med. 129(3):208 abstract
  5. Snyder MJ, Jacobs MR, Grau RG, et al. 2005. Ann Intern Med. 142(9):802 abstract
  6. Dziadzio M, Denton CP, Smith R, et al. 1999. Arthritis Rheum. 42:2646 abstract
  7. Wigley FM, Wise RA, Seibold JR, et al. 1994. Ann Intern Med. 120(3):199 abstract