Raynaud’s Phenomenon

Epidemiology and Etiology

Epidemiology

• Primary Raynaud’s phenomenon (PRP):
  • Idiopathic Idiopathic Dermatomyositis, with no identifiable cause
  • Much more common than secondary RP (SRP)
  • Highly prevalent in the general population: 3%–21% depending on the climate (higher prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency in colder climates)
  • 9 times more common in women than men
  • 25% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship have a positive family history Family History Adult Health Maintenance of the condition
  • Typically begins around 15–25 years of age; unusual over the age of 40 years, but can occur at any age, even in infants
  • Migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache and variant (Prinzmetal’s) angina are overrepresented in this population.
  • Studies estimate that 13% of primary RP patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship eventually developed an autoimmune rheumatic disease.
• Secondary Raynaud’s phenomenon (SRP):
  • Refers to the presence of the phenomenon in association with an underlying illness:
    • Disease (autoimmune, endocrine, hematologic, infectious)
    • Drug use (particularly drugs that cause vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure)
    • Occupational exposure
  • More rare than PRP, but more common when presenting in older patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
  • Trophic changes in skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and subcutaneous tissue Subcutaneous tissue Loose connective tissue lying under the dermis, which binds skin loosely to subjacent tissues. It may contain a pad of adipocytes, which vary in number according to the area of the body and vary in size according to the nutritional state. Soft Tissue Abscess may be seen in SRP (but not in PRP)

Etiology

The causes of secondary Raynaud’s phenomenon are outlined in the table below.

Mnemonic for secondary Raynaud’s phenomenon: I, COLD HAND Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand: Anatomy

• Infections
• Cold agglutinins/Cryoglobulinemia/Cryofibrinogenemia
• Occupational
• Lupus erythematosus, other autoimmune/ connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue: Histology diseases
• Diabetes mellitus, other endocrinologic diseases
• Hematologic disorders
• Arterial occlusive diseases 
• Neurologic disorders 
• Drugs

Pathophysiology

Three basic pathophysiologic mechanisms have been proposed:

1. Vascular
   • Seen in both PRP and SRP 
   • High levels of vasoconstrictors (e.g., endothelin-1) plus low levels of vasodilators Vasodilators Drugs used to cause dilation of the blood vessels. Thromboangiitis Obliterans (Buerger’s Disease) (e.g., nitric oxide Nitric Oxide A free radical gas produced endogenously by a variety of mammalian cells, synthesized from arginine by nitric oxide synthase. Nitric oxide is one of the endothelium-dependent relaxing factors released by the vascular endothelium and mediates vasodilation. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic gmp. Pulmonary Hypertension Drugs) cause  vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure of digital arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries: Histology and cutaneous arterioles Arterioles The smallest divisions of the arteries located between the muscular arteries and the capillaries. Arteries: Histology.
2. Neurohormonal
   • Diminished calcitonin-secreting neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology in both primary and secondary disease ( calcitonin Calcitonin A peptide hormone that lowers calcium concentration in the blood. In humans, it is released by thyroid cells and acts to decrease the formation and absorptive activity of osteoclasts. Its role in regulating plasma calcium is much greater in children and in certain diseases than in normal adults. Other Antiresorptive Drugs is a potent vasodilator)
   • Increased contractile response as a result of increased protein tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase activity in PRP
   • Increased neuropeptide-Y, a potent vasoconstrictor, in SRP secondary to systemic sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor
3. Intravascular
   • Increased platelet aggregation Platelet aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Hemostasis and increased thromboxane A2 Thromboxane A2 An unstable intermediate between the prostaglandin endoperoxides and thromboxane B2. The compound has a bicyclic oxaneoxetane structure. It is a potent inducer of platelet aggregation and causes vasoconstriction. It is the principal component of rabbit aorta contracting substance (RCS). Arterial Pressure Regulation secretion Secretion Coagulation Studies in PRP and in SRP secondary to systemic sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor
   • Fibrotic proliferation in systemic sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor

Clinical Presentation

Clinical features seen in both primary and secondary Raynaud’s phenomenon

• Ischemic phase: 
  • Arterial vasospasm in the digits (much less commonly, tip of the nose Nose The nose is the human body’s primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Nose Anatomy (External & Internal), tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy, ear lobes, and genitals)
  • Occurs with exposure to cold or emotional stress 
  • Distal blanching Blanching Dermatologic Examination and, usually, transient numbness
• Hypoxic phase: 
  • Dilation of capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries: Histology and venules Venules The minute vessels that collect blood from the capillary plexuses and join together to form veins. Veins: Histology containing deoxygenated blood 
  • Causes subsequent cyanosis Cyanosis A bluish or purplish discoloration of the skin and mucous membranes due to an increase in the amount of deoxygenated hemoglobin in the blood or a structural defect in the hemoglobin molecule. Pulmonary Examination and blue discoloration of the affected skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions
• Hyperemic phase: 
  • With rewarming and resolution of vasospasm, oxygenated blood flows into the dilated capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries: Histology and venules Venules The minute vessels that collect blood from the capillary plexuses and join together to form veins. Veins: Histology
  • Hyperemia and erythema Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion
  • May be accompanied by painful pulsating sensation

Features of PRP

• Mild and reversible benign Benign Fibroadenoma condition, symmetric, usually lasting less than 20 minutes
• Often goes into remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches
• Nailfold capillary microscopy: normal (no enlarged, distorted, or absent capillary loops) (note: Nailfold capillaroscopy is the procedure most commonly used in clinical practice to differentiate PRP from SRP)
• No trophic changes (no skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions or subcutaneous changes, ulcers or gangrene Gangrene Death and putrefaction of tissue usually due to a loss of blood supply. Small Bowel Obstruction); if present, workup needed to exclude SRP
• Migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache headaches and variant (Prinzmetal) angina have higher prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency in PRP, but it is not known if they share a common pathogenetic mechanism.

Features of SRP

• More severe form than PRP, so trophic changes in digits can occur, including sclerodactyly Sclerodactyly Scleroderma (puffy fingers with skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions tightening), pitting scars, and ulcers; rarely, gangrene Gangrene Death and putrefaction of tissue usually due to a loss of blood supply. Small Bowel Obstruction occurs.
• Remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches is rare.
• If absent pulses and/or asymmetrical presentation, suspect non-reversible vascular occlusion, which may be primary or superimposed on SRP
• May also show ischemic changes in the more proximal segments of the limb
• Nailfold capillary microscopy:
  • Often abnormal
  • Enlarged, distorted, or absent capillary loops suggest an autoimmune rheumatic disease (loss of loops suggests scleroderma Scleroderma Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma).

Diagnostics

Features warranting further investigation for SRP include:

• Older age at onset
• Male patient
• More severe symptoms or fixed, irreversible lesions
• Asymmetric involvement
• Systemic signs
• Abnormal capillary microscopy
• Abnormal laboratory findings

Laboratory workup for secondary causes is directed by history and physical examination and may include:

• Autoantibody investigations:
  • Antinuclear antibody (ANA)
  • Cyclic citrullinated peptide antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions/immunoglobulin G ( IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis)
  • Scleroderma-related autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques, including: 
    • Anticentromere (anti-CENP-B)
    • Anti-Th/To
    • Anti-topoisomerase I (Scl-70)
    • Anti-RNA polymerase III Anti-RNA polymerase III Scleroderma 
• CBC
• Erythrocyte sedimentation rate Erythrocyte Sedimentation Rate Soft Tissue Abscess
• C-reactive protein

Management

Mild cases

• Reassurance Reassurance Clinician–Patient Relationship
• Cessation of tobacco smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases
• Keeping warm by avoiding cold exposure and wearing proper clothes, not only for hands and feet but the whole body, to prevent cold-induced reflex vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure
• Avoiding or managing emotional stress
• Avoiding vasoconstrictive drugs ( nasal decongestants Nasal decongestants Drugs designed to treat inflammation of the nasal passages, generally the result of an infection (more often than not the common cold) or an allergy related condition, e.g., hay fever. The inflammation involves swelling of the mucous membrane that lines the nasal passages and results in inordinate mucus production. The primary class of nasal decongestants are vasoconstrictor agents. Rhinovirus, amphetamines Amphetamines Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopressin, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. Stimulants, methylphenidate Methylphenidate A central nervous system stimulant used most commonly in the treatment of attention deficit disorder in children and for narcolepsy. Its mechanisms appear to be similar to those of dextroamphetamine. Stimulants sumatriptan Sumatriptan A serotonin agonist that acts selectively at 5ht1 receptors. It is used in the treatment of migraine disorders. Triptans and Ergot Alkaloids, herbal drugs with ephedra)

Severe cases

• Dihydropyridine Dihydropyridine Pyridine moieties which are partially saturated by the addition of two hydrogen atoms in any position. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers) calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channel blockers ( CCBs CCBs Calcium channel blockers (CCBS) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBS: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers)) such as oral nifedipine Nifedipine A potent vasodilator agent with calcium antagonistic action. It is a useful anti-anginal agent that also lowers blood pressure. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers) and amlodipine Amlodipine A long-acting dihydropyridine calcium channel blocker. It is effective in the treatment of angina pectoris and hypertension. Hypertension Drugs ( non-dihydropyridine Non-Dihydropyridine Pulmonary Hypertension Drugs CCBs CCBs Calcium channel blockers (CCBS) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBS: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers) such as diltiazem Diltiazem A benzothiazepine derivative with vasodilating action due to its antagonism of the actions of calcium ion on membrane functions. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers) are less effective). If CCBs CCBs Calcium channel blockers (CCBS) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBS: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers) not tolerated or contraindicated, then one or more of the following can be prescribed:
  • Alpha-1 adrenergic antagonists such as prazosin Prazosin A selective adrenergic alpha-1 antagonist used in the treatment of heart failure; hypertension; pheochromocytoma; raynaud disease; prostatic hypertrophy; and urinary retention. Antiadrenergic Drugs, doxazosin Doxazosin A prazosin-related compound that is a selective alpha-1-adrenergic blocker. Antiadrenergic Drugs, and terazosin Terazosin Antiadrenergic Drugs
  • Phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil Sildenafil A phosphodiesterase type-5 inhibitor; vasodilator agent and urological agent that is used in the treatment of erectile dysfunction and primary pulmonary hypertension. Phosphodiesterase Inhibitors, tadalafil Tadalafil A carboline derivative and phosphodiesterase 5 inhibitor that is used primarily to treat erectile dysfunction; benign prostatic hyperplasia and primary pulmonary hypertension. Phosphodiesterase Inhibitors, and vardenafil Vardenafil A piperazine derivative, phosphodiesterase 5 inhibitor and vasodilator agent that is used as a urological agent in the treatment of erectile dysfunction. Phosphodiesterase Inhibitors
  • Topical nitrates Nitrates Nitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand. Nitrates (not in conjunction with PDE5 inhibitors because of the risk of severe hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension)
  • Angiotensin II Angiotensin II An octapeptide that is a potent but labile vasoconstrictor. It is produced from angiotensin I after the removal of two amino acids at the c-terminal by angiotensin converting enzyme. The amino acid in position 5 varies in different species. To block vasoconstriction and hypertension effect of angiotensin II, patients are often treated with ace inhibitors or with angiotensin II type 1 receptor blockers. Renal Sodium and Water Regulation receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors blockers
  • Selective serotonin reuptake inhibitors Selective Serotonin Reuptake Inhibitors Serotonin Reuptake Inhibitors and Similar Antidepressants
• If severe acute ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage threatening digital loss:
  • Start anticoagulation Anticoagulation Pulmonary Hypertension Drugs therapy, and continue it until a thrombotic cause is excluded.
  • Then start a CCB, followed by IV prostaglandin ( prostacyclin Prostacyclin A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension. Eicosanoids/ PGI PGI An aldose-ketose isomerase that catalyzes the reversible interconversion of glucose 6-phosphate and fructose 6-phosphate. In prokaryotic and eukaryotic organisms it plays an essential role in glycolytic and gluconeogenic pathways. In mammalian systems the enzyme is found in the cytoplasm and as a secreted protein. This secreted form of glucose-6-phosphate isomerase has been referred to as autocrine motility factor or neuroleukin, and acts as a cytokine which binds to the autocrine motility factor receptor. Deficiency of the enzyme in humans is an autosomal recessive trait, which results in congenital nonspherocytic hemolytic anemia. Glycolysis₂ preferred) 
  • If no response to CCB, then local or regional block if IV prostaglandin unavailable or there is insufficient response.

Cases refractory to medical therapy and lifestyle modifications

• Digital sympathectomy 
• Local injection of botulinum toxin Botulinum toxin Toxic proteins produced from the species Clostridium botulinum. The toxins are synthesized as a single peptide chain which is processed into a mature protein consisting of a heavy chain and light chain joined via a disulfide bond. The botulinum toxin light chain is a zinc-dependent protease which is released from the heavy chain upon endocytosis into presynaptic nerve endings. Once inside the cell the botulinum toxin light chain cleaves specific snare proteins which are essential for secretion of acetylcholine by synaptic vesicles. This inhibition of acetylcholine release results in muscular paralysis. Botulism may be effective but not in all patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.