From the HSS Manual of Rheumatology and Outpatient Orthopedic Disorders


Kyriakos A. Kirou, MD, DSc, FACP

Kyriakos A. Kirou, MD, DSc, FACP

Director, Lupus Nephritis Program, Hospital for Special Surgery
Clinical Co-Director, Mary Kirkland Center for Lupus Care, Hospital for Special Surgery
Assistant Attending Physician, Hospital for Special Surgery
Assistant Scientist, Hospital for Special Surgery
Assistant Attending Physician, NewYork-Presbyterian Hospital/Weil Cornell
Assistant Clinical Member, Memorial Sloan-Kettering Cancer Center
Assistant Professor of Clinical Medicine, Weill Cornell Medical College

KEY POINTS

Raynaud phenomenon (RP) is characterized by episodic vasospasm and occlusion of the digital arteries resulting in a well demarcated ischemic blanching of the involved digits. This may be followed sequentially by cyanosis and rubor. Tingling may occur during the reactive hyperemia phase (rubor).

  1. Exposure to cold or emotional stress is the typical inducer of RP. The duration of an attack may vary from several minutes to hours (usually 10-30 minutes). Upper extremities are most frequently involved, but 40% of patients have symptoms in their lower extremities.

  2. Primary RP (PRP) is the RP that occurs in otherwise healthy individuals while secondary RP (SRP) is observed in association with other disorders.

    1. Proposed criteria for diagnosing PRP include:

      1. appearance of symptoms with exposure to cold or emotional upset;

      2. bilateral symmetric involvement of hands; 

      3. normal pulses; 

      4. absence of, or only superficial, digital gangrene; 

      5. absence of an underlying disorder commonly associated with the symptom complex; and 

      6. symptoms present for longer than 2 years without the appearance of an underlying cause.

    2. In 1992, a stricter definition of primary RP was developed that would exclude all patients with: evidence of digital pitting, ulcerations, or gangrene; abnormal nailfold capillaries; a positive antinuclear antibody test; or an abnormal erythrocyte sedimentation rate upon presentation.

    3. The main characteristics of primary and secondary RP are summarized in Table 17-1.

Table 17-1: Characteristics of Primary and Secondary RP

ETIOPATHOGENESIS

  1. Primary RP is caused by vasospasm of the digital arteries and cutaneous arterioles. Its familial predisposition may be due to shared genetic or environmental factors.

  2. Vascular tone is determined by the balance of vasoconstrictor and vasodilatory mediators that act on the smooth muscle vascular cells.

    1. Vasodilatory neuromediators from sensory (i.e., calcitonin gene-related peptide) and parasympathetic terminals (acetylcholine) as well as vasoconstrictor mediators from sympathetic fibers (i.e., norepinephrine) act on vascular smooth muscle cells to modulate vascular tone.

    2. The endothelium plays a central role in mediating the effects of several neurotransmitters (i.e., acetylcholine, neurokinin A), circulating factors (i.e., thrombin, histamine), as well as mechanical shear stress on smooth muscle cells, by producing relaxing (i.e., nitric oxide, prostacyclin or PGI2) or constricting (i.e., endothelin-1) products.

    3. Exposure to cold activates vasoconstriction of cutaneous blood vessels by amplifying the effect of norepinephrine on the alpha2C-adrenoreceptors (AR) of the vascular smooth muscle cells.

    4. The excessive vasoconstrictive response to cold in RP may be due to increased alpha2C -AR sensitivity to cold. Other factors likely include the loss of vasodilatory sensory fibers, or an overactivity of vasoconstrictive neuromediators. Interestingly, residence in cold climates may predispose to primary RP.

  3. The etiopathogenesis of Secondary RP varies according to the specific associated disorder (Table 17-2).

    1. In systemic sclerosis (SSc) or scleroderma the RP is due to a vasculopathy that mainly affects the cutaneous arterioles/capillaries and the proper digital arteries but often also larger vessels such as the ulnar artery and the superficial palmar arch.

      1. Endothelial cell damage or dysfunction is a prominent and early characteristic of this vasculopathy. Reactive oxygen species (ROS) generated during the reperfusion injury from repeated ischemic attacks, as well as anti-endothelial antibodies have been implicated.

      2. Histologically, intimal hyperplasia and fibrosis that may be accompanied by thrombosis occurs. Adventitial fibrosis and telangiectasias of the vasa vasorum are also common and the former has been implicated in digital ischemia by virtue of external compression. 

      3. SRP due to mixed connective tissue disease (MCTD), and other scleroderma-overlap syndromes shares the same pathogenesis.

    2. The SRP associated with systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjogren syndrome, and polymyositis is usually benign and vasospastic in nature. However, when due to vasculitis or thrombosis in the context of the antiphospholipid syndrome it can lead to tissue damage and gangrene.

    3. In systemic vasculitis, the inflammatory occlusion of vessels usually leads to severe digital ischemia and gangrene.

    4. The hand-arm vibration syndrome (HAVS) or vibration-induced white finger (VWF) occurs in workers who use vibratory tools such as pneumatic hammers and chain saws.

    5. Occlusive arterial disease can occur in advanced atherosclerosis (i.e., in patients with diabetes mellitus) with asymmetric involvement of medium-sized vessels, in thromboangiitis obliterans (Buerger Disease) where smoking plays a key pathogenetic role, and in thromboembolic disease due to proximal cardiovascular clotting, thrombophilia or trauma (hypothenar hammer syndrome).

    6. Nerve compression. Compression (i.e., by a cervical rib or a pectoralis minor tendon) of brachial plexus sympathetic fibers and the subclavian artery has been implicated in the RP of the thoracic outlet syndrome (TOS). A similar mechanism may explain the RP seen in patients with the carpal tunnel syndrome.

    7. Drugs and chemicals. Ergot alkaloids have a direct vasoconstrictive action on blood vessels. Methysergide may cause intimal fibrosis. Exposure to vinyl chloride and bleomycin can cause a scleroderma-like illness with RP. Beta-blockers, sympathomimetics, cocaine, cyclosporine, interferon-alpha, vinblastine and cisplatin have been all implicated in development of RP.

    8. Hematologic abnormalities. RP has been reported in cryoglobulinemia, cold agglutinin disease, polycythemia, and macroglobulinemia. Blood hyperviscosity is the presumed mechanism.

    9. Malignancy should be suspected in RP of abrupt and rapid progression to severe digital ischemia.

    10. Other disorders associated with RP include malignancy, complex regional pain syndrome (CRPS) type 1, and hypothyroidism.

Table 17-2. Causes of Secondary Raynaud Phenomenon:

Connective Tissue Diseases

Systemic Sclerosis (SSc)
Mixed connective tissue disease (MCTD)
Polymyositis (PM) and Dermatomyositis (DM)
Systemic Lupus erythematosus (SLE)
Sjogren’s syndrome (SS)
Rheumatoid Arthritis (RA)

Systemic Vasculitis

Polyarteritis nodosa (PAN)
Takayasu’s arteritis
Giant cell arteritis (GCA)
Wegener’s granulomatosis
Microscopic polyangiitis (mPA)

Traumatic Vasospastic/Occupational

Hand arm vibration syndrome (HAVS)
After frostbites

Occlusive/Structural Arterial diseases

Atherosclerosis
Atheroemboli
Hypothenar hammer syndrome
Thromboangiitis Obliterans (Buerger’s Disease)
Nerve compression

Thoracic outlet syndrome (TOS)
Carpal Tunnel Syndrome (CTS)

Hematologic disease

Cryoglobulinemia
Cold agglutinin disease
Polycythemia Vera
Waldenstrom’s macroglobulinemia

Drugs and chemicals

Ergot alkaloids
Methysergide
Vinyl Chloride
Chemotherapy agents (bleomycin, vinblastin, cisplatin)
B-blockers
Sympathomimetics
Anticholinergics
Cyclosporine A
Interferon-a
Other disorders
Hypothyroidism
Complex regional pain syndrome (CRPS) type 1
Paraneoplastic

PREVALENCE

Population-based studies estimate a prevalence of primary RP of 3-16 % among women and 1-6 % among men, the highest noted in the coldest geographic regions assayed. PRP is much more common than secondary RP, and usually presents in teens. The prevalence of SRP in SSc or scleroderma-overlap disorders is >90%, whereas in other CTD is about 20-30%. SRP usually occurs at older ages, often over the age of 40 and a male preponderance can be seen according to the etiology.

CLINICAL MANIFESTATIONS

  1. Primary RP (PRP) is characterized by brief episodes of digital ischemia upon exposure to cold or emotional stimuli.

    1. A history of the classic triad of sequential digital pallor, cyanosis, and rubor is diagnostic. However, white alone, white and blue/purple, or white and red color changes are frequently seen.

    2. Reduced digital blood flow can be triggered by either a whole body cold exposure (through a sympathetic reflex mechanism), or local digital cooling.

  2. Clinical features suggestive of SRP are shown in Table 17-1.

    1. Persistent digital ischemia independent of vasospastic episodes, indicate structural occlusive vascular lesions, as it can be seen in scleroderma, and occlusive arterial disease (see above).

    2. The asymmetric involvement of hands and/or feet should suggest atherosclerosis, or thromboembolic disease.

    3. In systemic sclerosis (SSc), RP is often the presenting feature and it can be a major cause of morbidity. Cold-induced vasospasm in the heart (angina) and other internal organs has been noted in SSc and is called systemic or visceral RP.

    4. Occupational history of use of vibratory tools will suggest SRP due to HAVS. RP in this condition is triggered by exposure to vibration as well as the cold and it often involves the non-exposed hand as well. 

    5. A detailed drug/toxic-exposure history should always be obtained. Medications could be the cause or an aggravating factor for existing RP, such as when beta blockers are used in patients with RP in the setting of autoimmune disorders.

PHYSICAL EXAMINATION

  1. Examination of patients with primary RP (PRP) between attacks is unrevealing. Nevertheless the clinician should look for clues of an underlying disease.

  2. Asymmetric peripheral pulses should raise suspicion of an occlusive arterial disease.

  3. Puffy hands, sclerodactyly, tendon friction rubs and telangiectasias, are features of the scleroderma-like disorders. Presence of severe ischemic pain, in association with digital coolness and cyanosis, as well as digital pitting, ulcers, and gangrene indicate a compromised resting digital blood flow that occurs with a fixed arterial obstruction.

  4. The Allen test should be done to exclude radial or ulnar artery involvement. Ulnar artery involvement is not uncommon in SSc and leads to worsened digital ischemia. 

  5. Maneuvers to detect thoracic outlet compression or carpal tunnel syndrome should be undertaken.

  6. Nail fold capillaroscopy can be very helpful in differentiating primary from secondary RP. An early nailfold videocapillaroscopic pattern consisting of a few enlarged and giant capillaries, as well as hemorrhages, is very specific for SSc, although with some variation this finding can also be observed in dermatomyositis, MCTD, and SLE. Later in the disease process of SSc, loss of capillaries, ramified capillaries and vascular architectural disorganization are seen.
     This examination can be done either with application of mineral oil on the nailfold and visualization of the capillaries by ophthalmoscopy, or direct visualization with a dermoscope.

DIAGNOSTIC INVESTIGATIONS

  1. Laboratory tests

    1. Laboratory investigations are performed as dictated by the history and physical examination findings. Accordingly they may include a complete blood count with differential, serum electrolytes, glucose, and creatinine, urinalysis, liver function tests, TSH, erythrocyte sedimentation rate, antinuclear antibody, rheumatoid factor, serum protein electrophoresis and cryoglobulin levels.

    2. In ANA positive cases where the probability for SSc is higher, testing for the anticentromere and antitopoisomerase antibodies is indicated. For other diagnostic tests used in SSc, please refer to the specific chapter.

    3. Antiphospholipid antibodies should be tested for when the clinical suspicion for spontaneous thromboembolic disease exists. 

    4. Electromyograms or nerve conduction studies should be performed when nerve compression is a possibility.

    5. Echocardiography is indicated when cardiac emboli are suspected.

    6. Vascular laboratory studies can assess disease at the microvascular, macrovascular, or both levels. They are not necessary for the diagnosis of PRP, but they may help in the assessment of the several forms of SRP, i.e. in defining the extent and severity of arterial disease.

      1. Doppler studies of the palmar arch and proximal larger arteries are indicated when such involvement is suspected clinically (i.e. occlusive arterial disease). 

      2. Finger photoplethysmography (PPG) and finger systolic blood pressure determination (i.e., by a pneumatic cuff around the proximal phalanx and a photoplethysmograph placed over the distal phalanx) performed in a warm ambient temperature to avoid vasoconstriction may prove very useful. Abnormal PPG waveforms and brachial-finger pressure gradients of more than 20mm Hg indicate fixed arterial obstruction somewhere in the vascular pathway supplying the terminal phalanx. 

      3. Laser Doppler Imaging (LDI) and thermography are additional research techniques for the assessment of the microvascular integrity. 

      4. Cold provocation tests (in association with PPG, LDI, etc) have been used in research studies but are not necessary for the diagnosis RP.

  2. Radiological Studies

    1. A chest and neck x-ray might reveal a bony cervical rib in the case of TOS.

    2. Angiography (or magnetic resonance angiography) is necessary only when a proximal arterial embolic source is suspected, the proximal extent of vascular compromise needs to be defined or a microsurgical arterial reconstruction of the palmar arch is contemplated. If dye is to be injected into an artery, a sympathetic block should be done proximally to avoid reflex vasospasm.

DIFFERENTIAL DIAGNOSIS

RP must be differentiated from processes characterized by persistent vasospastic ischemia. In the following disorders vasoconstriction is probably limited to arterioles and not the digital arteries.


  1. Acrocyanosis, like RP, is exacerbated by low temperatures and emotional stress. However, cyanosis is not confined to the digits but extends diffusely to the hands or feet. The idiopathic form is a benign disorder. 

  2. Livedo reticularis, characterized by a persistent purple or blue mottling of the skin, predominantly involves the extremities; it is usually a benign condition but can be a prominent feature of cutaneous vasculitis syndromes (livedo reticularis with ulceration or atrophie blanche), due to the antiphospholipid syndrome or secondary to a systemic disorder such as systemic lupus.

TREATMENT

  1. General measures are adequate for patients with mild-moderate primary RP, but necessary for all RP. They include the following:

    1. Avoidance of a cold environment and the use of warm clothing, mittens or gloves with Thinsulate, and even electrically heated gloves. 

    2. Tobacco smoking should be discontinued. Beta-blocker drugs, if used, should be appropriately substituted. The newer vasodilatory Beta-blocker drugs may be better tolerated and potentially beneficial.

    3. In cases of PRP reassurance about the good prognosis of the disorder should be offered.

  2. Therapy of secondary RP should be aimed at correction of the underlying disorder. For example: vasculitis will require corticosteroids and or immunosuppressive therapy; antiphospholipid syndrome, other thrombophilic disorders, and thromboembolic events need appropriate anticoagulation therapy; Buerger’s disease will usually respond to smoking cessation;  severe involvement of large vessels (i.e., secondary to trauma, atherosclerosis or vasculitis) will require vascular surgery.

  3. Pharmacologic Therapy

    1. For severe PRP or SRP pharmacologic therapy with vasodilators is often required in addition to the general measures. Goals for SRP include the reduction of frequency of attacks and prevention of digital ulcer formation.

    2. Calcium channel blockers are the best studied agents in RP and thus often the first drug choice in managing vasospasm. They have been shown to have moderate effects in decreasing the frequency and severity of RP. However, if a significant occlusive component is present, as in advanced SSc, the benefit may be minimal. At times, a “steal phenomenon” can exist with worsening of the ischemia because blood flow may preferentially be directed to normal vessels, not the abnormal ones. They might aggravate esophageal reflux or constipation and they should be avoided during pregnancy. 

      1. Nifedipine can decrease the number and severity of episodes of RP. Side effects are common and include headache, tachycardia, flushing, light-headedness and edema. Initial dosage is 10 mg three times a day with upward adjustment to the maximum tolerated dose. The slow release preparations (30 or 60 mg once daily) are thought to have fewer side effects. 

      2. Amlodipine in a dose of 5-10 mg daily, and diltiazem (30 mg three or four times a day) may be used as well. 

    3. Alpha-blockers

        1. Prazosin, an alpha-1 receptor blocker, has been found beneficial in PRP but the clinical improvement may not be sustained with prolonged treatment. Syncope may occur with the first dose but can be prevented by giving the drug at bedtime and limiting the dose to 1 mg. Subsequent doses are better tolerated. Most patients can be managed on 1-2 mg three times daily.

        2. A selective a2C-AR antagonist improved digital skin perfusion during recovery from cooling in a recent small study of SSc patients. Further studies are needed to establish its usefulness in RP.

    4. Nitrates. Topical 2% ointment and sustained-release transdermal glyceryl trinitrate patches can reduce the number and severity of attacks in both primary and secondary RP, but their use is limited by the high incidence of headaches.

    5. Prostaglandins besides being potent vasodilators and platelet aggregation inhibitors, they probably have additional biologic functions of longer lasting benefits to microcirculation. Although beneficial when given intravenously, there is not yet sufficient evidence for the clinical usefulness of available oral prostaglandin preparations. They are mainly used at the early stages of severe digital ischemia in SSc. Side effects are common during infusion and include headaches, nausea, and jaw, thigh or chest pains. They should be avoided in patients with coronary disease or strokes.

      1. Iloprost is a chemically stable prostacyclin analog. Recent controlled studies have shown that Iloprost intravenous infusions promote healing of digital ischemic ulcerations and may reduce the frequency and severity of RP attacks in patients with SSc. Improvement in microcirculation after intravenous infusion of Iloprost at rate of 0.5-2 ng/kg/min for 6 hours daily for 5 days can last for 2-4 weeks and repeated monthly one-day infusions may maintain these effects. It is currently not available in the United States.

      2. Epoprostenol or Prostacyclin (PGI2) has also been effective in RP secondary to SSc. It is currently approved for use in primary pulmonary hypertension where it is given continuously (via a portable infusion pump linked to a central vein) at a starting dose of 2 ng/kg/min.

      3. Alprostadil or prostaglandin E1 (PGE1) requires a central intravenous line and has been given in infusions of 6-10 ng/kg/min over a 72 hour period. It is available in the United States for maintaining the patency of the ductus arteriosus. More stable analogs of PGE1 have also been used with success.

    6. Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI). Losartan has been shown to be superior to nifedipine in one study. Notably, in SSc, ACEI (and less so the ARB) have a special role in the management of scleroderma renal crisis.

    7. Antiplatelet agents such as 81mg of aspirin have been advocated for use in RP with ulcer formation where some degree of thrombosis might have occurred. Heparin is reserved for more severe cases.

    8. Pentoxifylline at doses of 400 mg PO three times daily is a rheologic agent that has been advocated by some, but there is little supporting evidence for their use in RP.

    9. Phosphodiesterase-5 inhibitors have been anecdotally used with success in refractory RP cases.

    10. Ketanserin, an antagonist of the S2 serotonin receptors on vascular smooth muscle and platelets, may be effective in primary and secondary (to connective tissue disease) RP. This medicine is no longer available in the U.S.

    11. Selective serotonin reuptake inhibitors (SSRI) have been used with success in RP in some studies. More data are needed to establish their role in RP.

    12. The endothelin-antagonist Bosentan has been shown to prevent new digital ulcer formation in SSc patients and may have a role in the management in RP of such patients.

    13. Antioxidant drugs such as intravenous infusion of N-acetylcysteine are presumed to have a beneficial effect by ameliorating reactive oxidant species-induced damage.

    14. Narcotic analgesics are often needed for severe ischemic pain.

  4. Surgery is indicated in refractory cases of RP with severe ischemia (“finger at risk”) and non-healing digital ulcers despite medical therapy.

    1. Cervical sympathectomy is not recommended for upper extremity RP as it does not offer long term benefits, and may have significant long-term adverse effects. However, peripheral or proximal sympathetic blocks may have a place in the acute management of severe digital ischemia (digit at imminent risk for tissue loss) in connective tissue disease and often will stabilize the condition enough to allow maintenance medical therapy. For lower extremity RP, lumbar sympathectomy is usually effective.

    2. Digital sympathectomy (adventitial stripping) can be digit saving often with immediate restoration of blood flow. The technique, in experienced hands, is a relatively safe procedure and achieves not only interruption of the vessel sympathetic innervation but also a mechanical release of arterial constriction by the adventitial and periadventitial fibrosis (“decompression arteriolysis”).

    3. Microsurgical revascularization can be effectively employed for occlusive lesions affecting the ulnar artery at the wrist and the superficial palmar arch, as may be seen in SSc.

    4. Amputations will occasionally be required for ulcers associated with distal phalanx osteomyelitis and/or DIP sepsis, or severe pain due to gangrene. However, autoamputations of mummified tissue are preferable, as they allow for the maximum possible tissue salvage. The use of oral or parenteral antibiotics for active infections in the site of ischemic finger ulcers can avoid rapid tissue breakdown.

  5. “The Finger at Risk”: At times, patients with limited scleroderma or CREST syndrome will develop the rather sudden onset of severe pains in one finger, along with marked ischemia manifested by a totally white finger. This is an emergency because prolonged ischemia will likely result in tissue loss and secondary infection. The treatment regimen that is employed in this setting is the following:

    1. Avoidance of trauma and removal from a cold environment.

    2. The use of anticoagulants, usually aspirin, at times heparin, to avoid local clotting and a low flow state.

    3. The institution of vasodilator medications, as noted above.

    4. Consultation with an anesthesiologist for an immediate sympathetic block either in the neck or the hand. Often, this “breaks” the ischemic event. It should be noted that digital arteries may be totally encased by fibrous tissue in the vessel adventitia and no amount of sympathetic block can help.

    5. If ischemia persists, adventitial stripping should be considered, especially if a hand, vascular, or plastic surgeon who is skilled at this microsurgery, is available.

    6. Stripping is usually quite effective but patients may still have some pain after the procedure. In this case, one should consider anticoagulation to avoid microthrombi due to the low flow state.

  6. Local care of existing ulcers with wet to dry dressings and antibiotic ointments is crucial to prevent local infectious complications.

PROGNOSIS

  1. Primary RP, as diagnosed by using the more strict criteria (excluding those patients with digital pitting/ulcerations/gangrene, positive ANA, high ESR, and abnormal nailfold capillaries), has an excellent prognosis, and in only up to 10% of patients will evolve into an autoimmune disorder.

  2. Secondary RP

    1. Possible SRP consists of those RP patients that do not qualify as PRP with the strict definition and do not clearly fulfill the criteria for any of the secondary diagnoses. These patients often have an isolated positive ANA test, or nonspecific nailfold capillary abnormalities. Their prognosis is also very good in that only 10-30% will develop a CTD. 

    2. The prognosis of secondary RP depends on the underlying disease. Fixed-obstruction arterial lesions upon vascular laboratory evaluation (see laboratory studies above) have been strongly correlated with digital ulcerations (half of the patients) and amputations (10-20% of the patients).

Posted: 7/25/2006

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