Jorge Mera, MD

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Raynauds Phenomenon

• Jorge Mera, MD
• Presbyterian Hospital Dallas
• May 19, 2005

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Clinical Case

• A 26 YOHF with a 6 year Hx of SLE complicated
  with lupus nephritis on chronic hemodialysis,
  presented with severe Raynauds 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

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Clinical Case
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Questions

• 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?

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RAYNAUDS PHENOMENON

• 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.

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RAYNAUDS PHENOMENON

• More common
• In women
• Younger age groups
• Family members of patients with RP
• Affected areas
• Hands are the most common
• Toes
• Ears
• Face
• Knees
• nipples

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Incidence

• 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
• 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

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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) 9/591 (1.5) 0.4
Persistent RP 28/78 (35.9) 18/50 (36.0) 0.2
Remitted RP 50/78 (64.1) 32/50 (64) 0.1
Suter et al. Arthritis and Rheumatism
200552(4)1259-63
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Clinical Manifestations

• Most commonly affects the hands
• Typical symptom
• Distinct, episodic, sudden and reversible onset
  of cold fingers (or toes) with sharply demarcated
  color changes of
• Skin pallor (White attack) and / or
• Cyanotic skin (blue attack)
• Blushing of the skin upon recovery
• Erythema of reperfusion (RECOVERY PHASE)
• With or without pain

ISCHEMIC PHASE Lasts 15 20
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Clinical Manifestations

• 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
• The Thumb is often spared

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Clinical Manifestations

• 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

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Active Raynaud's Phenomenon
Wigley, F. M. N Engl J Med 20023471001-1008
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Raynauds phenomenon, blanching of hands
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Raynauds phenomenon hands
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Scleroderma Raynauds phenomenon, cyanosis of
the hands
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Triggers

• Cold exposure
• Temperature shift
• Body chill
• Stimulation of the sympathetic nervous system
• Emotional stress

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PATHOGENESIS
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CUTANEOUS CIRCULATION

• 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)
• Regulated
• Sympathetic system
• Local factors

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CUTANEOUS CIRCULATION

• Most of the skin has
• Sympathetic vasoconstriction fiber
• Sympathetic vasodilatation fibers
• The palms, soles and lips only have
• Sympathetic vasoconstriction fiber

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CUTANEOUS CIRCULATION
Sympathetic
Vasodilator
Sensory afferent
()
()
?
CGRP, NKA, SP
()
Local Temperature
Internal Temperature Skin Temperature
NO
Cutaneous arteriole
NE, NPY
(-)
(-)
Sympathetic
Vasoconstrictor
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CUTANEOUS CIRCULATION

• 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

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Vasoconstriction Secondary to Cold
Alfa-2C adrenergic receptor
Norepinephrine
Alfa-2A,2B adrenergic receptor
Alfa2A,B
Cold Temperature
Alfa-2C adrenergic receptor
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Smooth Muscle Cell Contraction in an Arteriole
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Vasoconstriction Secondary to Stress
Alpha-2 (A,B,)
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Vascular Response to Cold
ttttttttttttttttttttttt
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Why do Some Patients Develop Critical Ischemia?

• 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
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PATHOGENESIS OF RAYNAUDS IN SYSTEMIC SCLEROSIS

• Vascular injury
• Microcirculation
• Small and medium blood vessels
• Genetic Factors
• Familial aggregation documented but studies in
  monozygotic twins are needed
• Altered angiogenesis
• 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)

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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 Nitiric Oxide
Platelet Activation
Tromboxane Serotonin
Reperfusion
VASOCONSTRICTION
VASODILATATION
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PATHOGENESIS Summary

• 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
• In secondary RP, the defect may vary depending
  upon the underlying insult to the normal
  physiology of the digital and cutaneous arteries.

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Classification

• Primary (Raynaud's disease)
• Secondary or associated to other medical
  disorders
• Undefined
• Non specific symptoms
• Non definite lab abnormalities

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RAYNAUDS PHENOMENON

• 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

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Causes of secondary Raynauds phenomenon

• Connective tissue diseases
• Scleroderma, systemic lupus erythematosus, MCTD,
  undifferentiated CTD, Sjogrens syndrome,
  dermatomyositis
• Occlusive arterial disease
• Atherosclerosis, anti-phospholipid antibody
  syndrome, Buergers 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

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Diagnosis

• 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

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Diagnostic Criteria

• Definite RP Repeated episodes of biphasic
  color changes upon exposure to
  cold
• Possible RP Uniphasic color changes plus
  numbness or paresthesia upon
  exposure to cold
• No RP No color changes upon exposure to
  cold

Brennan et al. Br J Rheumatol 199332357
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Differential Diagnosis

• 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
• Acrocyanosis
• Permanent bluish discoloration in hands nose and
  ears

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Criteria for Primary Raynaud's Phenomenon
(Raynaud's Disease)

• 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 20023471001-1008
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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 20023471001-1008
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Clues for the Diagnosis of Secondary RP

• Age of Onset gt 40
• Male gender
• Signs of tissue ischemia (ulcers)
• Asymmetric attacks
• RP associated with signs or symptoms of another
  disease
• Abnormal laboratory parameters

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Progression to CTD

• Primary 13 CTD (The majority
  evolve to CREST or Systemic Sclerosis)
• ANA is a predictor for evolving from RP to CTD

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Scleroderma digital pitting scars
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CREST syndrome calcinosis cutis, fingers
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Scleroderma calcinosis, hands
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CREST Syndrome

• Calcinosis
• Raynauds
• Esophageal dysfunction
• Telangiectasias

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Evaluation

• Negative Hx, Physical Exam and Nail
  capillaroscopy No need for further testing
• If above is abnormal
• ANA
• Anti-centromere
• Complement
• Cryoglobulins
• Anti-Phospholipids antibodies
• TSH

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TREATMENT
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Treatment

• Multiple treatment modalities appear effective
• 10 - 40 respond to placebo
• Measure
• Frequency
• Severity
• Digital ulcer healing or appearance

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Treatment

• General Measures
• 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
• B-blockers
• Nasal decongestants
• Caffeine ?
• Herbs containing ephedra
• Amphetamines
• Cocaine
• Behavioral therapy ?

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Pharmacologic Treatment of Raynaud's Phenomenon
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Treatment

• Oral Prostaglandins
• Misoprostol (oral PGE1) (-)
• Cisaprost (prostacyclin analog) ()
• Beraprost (prostacyclin analog) (-)
• Iloprost ()
• Anticoagulation
• ASA ?
• Heparin in critical ischemia (-)
• If associated with APLS
• Sympathetic block

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Management of Raynaud's Phenomenon
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Approach to the Diagnosis of Raynaud's Phenomenon
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Clinical Case

• LABS
• dSDNA 11280 (ref. negative)
• C3 46.7 mg/dl (ref 86.0-185.0)
• C4 lt 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
• TEE Within normal limits

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HOSPITAL COURSE Second day

• Working diagnoses
• Refractory Severe Raynaud's Phenomenon secondary
  to SLE with digital ischemia
• Rescue treatment
• Epoprostenol 0.5 ng/kg/min IV via central line
  subsequently increased to 2 ng/kg/min.
• Results
• Significant improvement after three days of
  infusion with documented regression of the
  ischemic changes in her digits.

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60 minutes after Epoprostenol infusion
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CONCLUSION

• Raynauds Phenomenon is a frequent disorder
• Understanding the pathogenesis and epidemiology
  is essential to the appropriate categorization of
  patients and judicious use of treatment options

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Double Blind Randomized Study Margaritas vs
Placebo for RDS (Resident Depression
Syndrome) Whos on the Placebo Arm?