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Raynaud’s Phenomenon
Jorge Mera, MD
Presbyterian Hospital Dallas
May 19, 2005
Clinical Case

A 26 YOHF with a 6 year Hx of SLE
complicated with lupus nephritis on chronic
hemodialysis, presented with severe
Raynaud’s Phenomenon (RP) involving
mainly her upper extremities. Despite
standard treatment for 3 weeks she
worsened, being aggravated by severe pain
and ischemic ulcers of her fingertips, and
the need to posture her hands downward to
decrease the pain
Clinical Case
Questions
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What is Raynaud's Phenomenon (RP)?
What is the incidence of RP?
What is the pathogenesis of RP?
What is the difference between primary and
secondary RP?
What are the most frequent causes of secondary RP
Why doesn't every patient with RP develop critical
ischemia
What lab test should you order in a patient with RP?
How do you treat RP?
How do you treat critical ischemia?
RAYNAUDS PHENOMENON
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Definition:
– It is an exaggerated vascular response
to cold temperature or emotional stress
History:
– Raynaud's Syndrome was described in 1862 by
Maurice Raynaud. He thought it was a
vasculopathy was related to an exaggerated
response of the CNS.
– In 1930 Sr. Thomas Lewis proposed RP was
due to a “local fault” since it did not get cured
with sympathectomy.
RAYNAUDS PHENOMENON

More common
– In women
– Younger age groups
– Family members of patients with RP
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Affected areas
–
–
–
–
–
–
Hands are the most common
Toes
Ears
Face
Knees
nipples
Incidence
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Incidence:
– The incidence of RP varies according to the type of center
reporting. Populations studies show an incidence of 4 - 9 % in
women and 3 – 6 % in men.
– In population studies, most cases (90 %) are due to Raynaud's
Disease or Primary Raynaud's Phenomenon
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The only prospective study to determine the incidence and
natural history of RP in a community- based cohort study was
reported by Suter et al. using the Framingham Heart Study
Offspring Cohort;
They Followed 641 men and 717 women during a 7 year
period
Incidence, persistence and
remission of RP in women and men
Women
Men
P
Baseline prevalent RP
78/717
(10.9)
50/641
(7.8)
0.05
Incident RP
14/639
(2.2)
28/78
(35.9)
50/78
(64.1)
9/591
(1.5)
18/50
(36.0)
32/50
(64)
0.4
Persistent RP
Remitted RP
Suter et al. Arthritis and Rheumatism 2005:52(4);1259-63
0.2
0.1
Clinical Manifestations
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Most commonly affects the hands
Typical symptom
– Distinct, episodic, sudden and reversible onset of
cold fingers (or toes) with sharply demarcated
color changes of
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Skin pallor (White attack) and / or
Cyanotic skin (blue attack)
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Blushing of the skin upon recovery
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Erythema of reperfusion (RECOVERY PHASE)
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– With or without pain
ISCHEMIC PHASE
Lasts 15 – 20’
Clinical Manifestations
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Begins in a single finger and spreads to
other digits symmetrically in both hands.
The most frequently involved digits are
– Index finger
– Middle finger
– Ring finger
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The Thumb is often spared
Clinical Manifestations
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Cyanosis occurs when blood flow is delayed in the capillary
vessels and the stagnant blood becomes deoxygenated.
Although it may be associated with numbness and
dysesthesias it is not associated with ischemic events. The
lack of pain and the ability to demonstrate a healthy capillary
refill on pressure is evidence that nutritional flow is till
present.
Skin pallor with sharp demarcation, especially if accompanied
by pain suggests complete closure of the digital arteries and
coetaneous vessels.
Severe critical ischemia include
– Numbness and intense pain of the whole digit, hand or distal
limb
– Posturing of the involve hand downward
Active Raynaud's Phenomenon
Wigley, F. M. N Engl J Med 2002;347:1001-1008
Raynaud’s phenomenon,
blanching of hands
Raynaud’s phenomenon: hands
Scleroderma: Raynaud’s
phenomenon, cyanosis
of the hands
Triggers
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Cold exposure
Temperature shift
Body chill
Stimulation of the sympathetic nervous
system
– Emotional stress
PATHOGENESIS
CUTANEOUS CIRCULATION
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Cutaneous circulation is critical for
thermoregulation
– Blood flow can vary from 250 ml/min at
room temperature to 6000 ml/min during
exercise (60% of Cardiac Output)
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Regulated
– Sympathetic system
– Local factors
CUTANEOUS CIRCULATION
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Most of the skin has
– Sympathetic
vasoconstriction fiber
– Sympathetic
vasodilatation fibers
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The palms, soles and
lips only have
– Sympathetic
vasoconstriction fiber
CUTANEOUS CIRCULATION
NO
Sympathetic
Local Temperature
(+)
Vasodilator
Sensory afferent
(+)
(+)
?
CGRP, NKA, SP
Internal Temperature
Skin Temperature
Cutaneous arteriole
NE, NPY
Sympathetic
Vasoconstrictor
(-)
(-)
CUTANEOUS CIRCULATION
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The skin is generally in a vasoconstriction
“mode”. And the vasodilatation is only
stimulated during exercise or intense heat
The vasoconstriction occurs by stimulation
of Alfa-2 adrenergic receptors
The receptors can be subdivided in Alpha
2A, 2B or 2C
Vasoconstriction Secondary to Cold
Norepinephrine
Alfa-2C adrenergic
receptor
Alfa-2A,2B
adrenergic
receptor
Alfa2A,B
Alfa-2C adrenergic
receptor
Cold Temperature
Smooth Muscle Cell
Contraction in an Arteriole
Vasoconstriction Secondary to Stress
Alpha-2 (A,B,)
Vascular Response to Cold
tttttttttt
tttttttttt
ttt
Why do Some Patients Develop
Critical Ischemia?
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Thermoregulatory flow.
Corresponds to 80 – 90 %
of flow. Sympathetic
regulation of A-V shunts
Nutritional flow
(constitutive), ischemia
occurs when it is
compromised
THE TWO COMPONENTS OF DIGITAL BLOOD FLOW
PATHOGENESIS OF RAYNAUDS
IN SYSTEMIC SCLEROSIS
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Vascular injury
– Microcirculation
– Small and medium blood vessels
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Genetic Factors
– Familial aggregation documented but studies in
monozygotic twins are needed
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Altered angiogenesis
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Diminished expression of AlphavB3 integrin (receptor
associated with VEGF mediated angiogenesis)
Immune mediated
– Cytokines (Increased Il-13 that correlates with
microvascular injury)
– Lymphocytes transendothelial migration (Increased CD3+,
CD4+ activated T cell migration)
Pathogenesis of Digital Ischemia in
RP Secondary to Scleroderma
Intimal Proliferation and fibrosis
Narrow arteriole lumen (75%)
Anti endothelial Ab
CD4 Lymphocytes
Ischemia
Endothelial Insult
Hypoxia
Infection
Prostacyclin
Platelet Activation
Nitiric Oxide
VASODILATATION
Tromboxane
Serotonin
VASOCONSTRICTION
Reperfusion
PATHOGENESIS: Summary
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In primary RP, abnormal vasoconstriction of digital arteries
and cutaneous arterioles due to a local defect in normal
vascular responses is thought to underlie the primary form of
this disorder, evidence suggests the defect is an increase in
alpha-2 adrenergic responses in the digital and cutaneous
vessels. This increased response could be due to
– Increased sympathetic activity
– Increased sensitivity to adrenergic stimuli
– Increased number of alpha-receptors in the vessel wall
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In secondary RP, the defect may vary depending upon the
underlying insult to the normal physiology of the digital and
cutaneous arteries.
Classification
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Primary: (Raynaud's disease)
Secondary or associated to other
medical disorders
Undefined
– Non specific symptoms
– Non definite lab abnormalities
RAYNAUDS
PHENOMENON
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It is manifested
clinically by sharply
demarcated color
changes of the skin
of the digits.
Rarely causes
ischemia lesions on
Primary Disease
Ischemic lesions in
Secondary
Raynaud's is not
uncommon
Causes of secondary Raynaud’s
phenomenon
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Connective tissue diseases
– Scleroderma, systemic lupus erythematosus, MCTD,
undifferentiated CTD, Sjogren’s syndrome,
dermatomyositis
Occlusive arterial disease
– Atherosclerosis, anti-phospholipid antibody syndrome,
Buerger’s disease
Vascular injury
– Frostbite, vibratory trauma
Drugs and toxins
– Beta blockers, vinyl chloride, bleomycin, ergot,
amphetamines, cocaine
Hyperviscosity/cold-reacting proteins
– Paraproteinemia, polycythemia, cryoglobulinemia,
cryofibrinogenemia, cold agglutinins
Diagnosis
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History of a characteristic attack
Or 3 out of the 4 following symptoms
– Unusual cold sensitivity
– Unusual digital color changes
– Positive response for blanching in comparison
with a color chart and in response to the
question “What is the palest your fingers ever
get?”
– A positive response for blanching in comparison
with actual photographs displaying digital
blanching
Diagnostic Criteria
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Definite RP:
Repeated episodes of biphasic
color changes upon exposure to
cold
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Possible RP:
Uniphasic color changes plus
numbness or paresthesia upon
exposure to cold
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No RP:
No color changes upon exposure to
cold
Brennan et al. Br J Rheumatol 1993;32:357
Differential Diagnosis
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Normal response to cold. Skin
mottling may be present but
– The recovery phase is immediate
– There is no sharp demarcation of color
changes in skin
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Acrocyanosis
– Permanent bluish discoloration in hands
nose and ears
Criteria for Primary Raynaud's
Phenomenon (Raynaud's Disease)
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Symmetric episodic vasospastic attacks
precipitated by cold or emotional stress
Absence of tissue necrosis or gangrene
No history or physical findings suggestive or
secondary RP
Normal ESR and serologic findings (ANA)
Normal nail fold capillaroscopy
Wigley, F. M. N Engl J Med 2002;347:1001-1008
Nail-Fold Capillaries in a Patient with the CREST Syndrome (Calcinosis Cutis, Raynaud's
Phenomenon, Esophageal Dysfunction, Sclerodactyly, and Telangiectasia), or Limited
Scleroderma
Wigley, F. M. N Engl J Med 2002;347:1001-1008
Clues for the Diagnosis of
Secondary RP
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Age of Onset > 40
Male gender
Signs of tissue ischemia (ulcers)
Asymmetric attacks
RP associated with signs or symptoms
of another disease
Abnormal laboratory parameters
Progression to CTD
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Primary
13 % CTD (The
majority evolve to CREST or Systemic
Sclerosis)
+ ANA is a predictor for evolving from
RP to CTD
Scleroderma: digital
pitting scars
CREST syndrome:
calcinosis cutis, fingers
Scleroderma: calcinosis,
hands
CREST Syndrome
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Calcinosis
Raynaud’s
Esophageal
dysfunction
Telangiectasias
Evaluation
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Negative Hx, Physical Exam and Nail
capillaroscopy: No need for further testing
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If above is abnormal
–
–
–
–
–
–
ANA
Anti-centromere
Complement
Cryoglobulins
Anti-Phospholipids antibodies
TSH
TREATMENT
Treatment
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Multiple treatment modalities appear
effective
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10 - 40 % respond to placebo
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Measure
– Frequency
– Severity
– Digital ulcer healing or appearance
Treatment
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General Measures
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–
–
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Eliminate unfounded misconceptions
Manage anxiety
Avoid sudden cold exposure
Keep the whole body warm (remember chills can precipitate an attack even
if the hands are warm)
– Avoid smoking
– Avoid medications that cause vasoconstriction
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B-blockers
Nasal decongestants
Caffeine ?
Herbs containing ephedra
Amphetamines
Cocaine
Behavioral therapy ?
Pharmacologic Treatment of Raynaud's Phenomenon
Treatment
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Oral Prostaglandins
–
–
–
–
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Misoprostol (oral PGE1) (+-)
Cisaprost (prostacyclin analog) (+)
Beraprost (prostacyclin analog) (+-)
Iloprost (–)
Anticoagulation
– ASA ?
– Heparin in critical ischemia (+-)
– If associated with APLS
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Sympathetic block
Management of Raynaud's Phenomenon
Education/Prevention
Avoid cold exposure
Avoid vasoconstrictor meds
Good skin care
Aspirin 81 mg
Asses Severity of
Raynaud's Phenomenon
Mild:
Few attacks occurring
only during cold exposure
Moderate:
Severe:
Multiple symptomatic
Episodes of RP occurring wo
critical ischemia
X episodes of recurrent
ischemia or digital gangrene
Monitor Clinically
Consider VD therapy in
Winter months
Critical ischemia with evidence
of macro vascular disease
Initiate Vasodilator therapy:
Ca Channel blockers
YES
NO
Hospitalization
Pain Control
High Dose VD therapy
Consider Sympathetic Block
Prostacyclin Infusion
Treat infection
Pain control
Local wound care
Maximize VD therapy
Approach to the Diagnosis of Raynaud's Phenomenon
Clinical Case
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LABS:
–
–
–
–
–
–
–
–
–
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dSDNA: 1:1280 (ref. negative)
C3: 46.7 mg/dl (ref: 86.0-185.0)
C4: < 10 mg/dL(ref.20.0-59.0).
Lupus Anticoagulant: Negative
Cryoglobulins: Negative.
HIV: Negative
RPR: Negative
Hep C ab: Negative
AFLA: Negative
Chest radiograph:
– Mild Pulmonary congestion
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TEE: Within normal limits
HOSPITAL COURSE:
Second day
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Working diagnoses:
– Refractory Severe Raynaud's Phenomenon
secondary to SLE with digital ischemia
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Rescue treatment:
– Epoprostenol 0.5 ng/kg/min IV via central line;
subsequently increased to 2 ng/kg/min.
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Results:
– Significant improvement after three days of
infusion with documented regression of the
ischemic changes in her digits.
60 minutes after
Epoprostenol infusion
Double Blind Randomized Study: Margaritas vs Placebo
for RDS (Resident Depression Syndrome)
Who’s on the Placebo Arm?