RAynaud's Phenomenon: AN UPDATE

Primary Raynaud’s Phenomenon (Raynaud’s Disease)

How to Make a Diagnosis?

History and Physical:

• Cold Hands: 30% of population
• Cold (or emotional stress) induced sharp demarcated pallor and/or cyanosis of the distal fingers or toes.

Prevalence: 3-5% of General population
Vasospastic attacks precipitated by cold or emotional stress:

• Symmetric attacks in both hands
• Absence of tissue necrosis or gangrene
• No history or physical findings suggestive of secondary cause
• Normal nailfold capillaries
• Normal erythrocyte sedimentation rate (ESR)
• Negative serologic findings

 

Genetic Susceptibility for PRD

• Familial aggregation of Primary RP
• 26.1% versus 5.5% first degree relative
• Studies range from 14-45%
• Family Studies:
• RP and migraine (HVR): potential locus
• Extended families: 3 potential genes located
• Case controlled study:
• No difference in allele frequencies of known polymorphisms for eNOS, BKRG, ET-1 and ETA receptor genes

 

Secondary Raynaud’s phenomenon

• Immune: Autoimmune Disease
• Trauma: Hand-Arm Vibration Syndrome
• Mechanical: Thoracic Outlet Syndrome
• Proteins: Cryoglobulins; Cyrofibrinogens
• Neurogenic: Carpal Tunnel Syndrome
• Hormones: Estrogens
• Toxins/Drugs/Vasoconstrictors: Smoking
• Vascular disease: Diabetes, Vasculitis, etc.

 

Patient Photos & Terminology

 

Cyanotic Phase:

 

Hyperemic Phase:

 

Nailfold capillaries:

 

Acrocyanosis: Persistent, painless, symmetric cyanosis of the hands and, less commonly, the feet, caused by vasospasm of the small vessels of the skin.

 

Chilblains: Localized areas of erythema, swelling, and pruritus resulting from exposure to damp cold.

 

 

Targets for Therapy

• Autonomic & Sensory Nerves
• Sympathetic Nervous system

 

 

 

Smooth Muscle

 

 

Reactive Oxidant Species —> Anti-Oxidants

 

Calcium Channel Blockers

Dihydropyridines: L-type voltage dependent

• Nifedipine                  Adalat, Procardia
• Amlodipine                Norvasc
• Nicardipine                Cardene
• Isradipine                  DynaCirc
• Felodipine                  Plendil

 

Calcium Channel Blockers in Scleroderma: Arthritis Rheum 2001

All calcium channel blockers vs. placebo:

• (6 trials): Reduction of frequency of attacks in a 2-week period of -8.31 (95% CI: -15.71, -0.91)
• (3 trials): Reduction in severity of ischemic attacks of -0.69 (95% CI: -1.21,-0.17)

Thompson et al., 2001

 

Nitrates: Topical Nitroglycerin

• Improved Skin Blood Flow compared to Placebo
• Multicenter Placebo and Weather Controlled Trial of New Topical Nitroglycerin preparation underway

 

Prostaglandins

Intravenous Prostaglandins:

• PGE1  Alprostadil
• PGI2  EpoprostenoL, Iloprost

Oral Prostaglandins

• PGE1  Misoprostol
• PGI2  Iloprost, Cisaprost, Beraprost

 

Bosentan

• Double-blind, placebo controlled trial
• 122 patients; randomized 2:1 to receive bosentan (62.5 mg po bid then to 125 mg po bid) or placebo for 16 weeks.
• Fewer new digital ulcers
• Placebo  mean  2.7 ulcers
• Bosentan  mean  1.4 ulcers
• Improved hand function

Black et al., 2003

 

Fluoxetine

• 26 patients with primary and 27 patients with secondary RP
• 6 week treatment of fluoxetine (20mg daily) versus nifedipine (40 mg daily)
• Cross-over design
• Reduction in frequency and severity of RP statistically significant for fluoxetine group (p=0.003 and 0.0002)

Coleiro et al., 2003

 

Summary of Agents

Nitric oxide:  Nitrates

Phosphodiesterase inhibitors:

• Cilostazol  Pentoxifylline
• Sildenafil  Tadalafil

Selective Serotonin Reuptake inhibitors:  Fluoxetine

Angiotensin receptor inhibitor: Lorsartan

Endothelin-1 inhibitor:  Bosentan

Antioxidants:  Statins

Specific receptor inhibitors:  Alpha2C

Rho-Kinase inhibitor:  Fasudil

Other:  Botulium toxin A

 

Other Medical Options

Digital block

• 2% Lidocaine
• 0.5% Bupivacaine
• 1% Mepivacaine

Continuous Regional Anesthesia

• O.2% ropivacaine

Greengrass et al 2003

 

Anti-platelet Therapy

• Aspirin 81 mg daily
• Vasodilator therapy
• Calcium Channel blockers
• Prostaglandins
• Other Options
• Ticlopidine, Clopidogrel
• Cilostazol, Pentoxifylline

 

Surgical Options

• Sympathectomy
• Microsurgical revascularization
• Digital arterial reconstruction
• Wound Care