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A. Characteristics

  1. Blanchable, erythematous, edematous, papules or plaques ("Hives")
  2. Usually pruritic
  3. Size usually ~2mm to 20mm ± serpiginous borders
  4. Transient, usually lasting a few hours (<24 hours)
  5. Angioedema
    1. Occurs in ~50% of urticaria cases
    2. Well demarcated swelling, dermal layers
    3. Prediliction for palms, soles, periorbital/oral
    4. Lip swelling less concerning than tongue swelling
  6. Incidence
    1. ~15% of population, F>M
    2. ~50% have urticaria with angioedema, 40% only urticaria, 10% only angioedema
    3. Acute (<6 weeks) versus chronic
  7. Etiology of Urticaria
    1. Usually idiopathic
    2. Systemic Lupus Erythematosus
    3. Urticarial Vasculitis
    4. Hepatitis (including Hepatitis B or C Virus)
    5. Serum Sickness
    6. Plasma cell dyscrasia (associated paraprotein)
    7. Familial Cold Urticaria
    8. Physical urticaria and hives due to dermatographism
  8. Serum Sickness
    1. Urticaria, fever, angioedema
    2. Arthralgias, myalgias, and palpable purpura
    3. Immune complex mediated with necrotizing cutaneous venulitis
    4. Common following heterologous serum or allergic drug reaction
    5. C3 and C4 levels usually decreased; risk for developing renal disease fairly high
  9. Mastocytosis - may cause chronic urticarial-like illness
  10. May be associated with Hashimoto's Thyroiditis

B. Histology

  1. Acute: Dermal edema, sparse perivascular infiltrate
  2. Eosinophils
    1. Often present with drug allergy
    2. Positive staining for eosinophil major basic protein (MBP) is common
    3. Variable numbers in other urticarias
  3. Chronic urticaria - CD4+ lymphocytes and increased cutaneous mast cells
  4. Edema
    1. Urticaria - post-capillary venule leak in superficial dermis
    2. Angioedema - post-capillary deep dermis and cutis edema
  5. Mast cell activation

C. Types of Urticarial Syndromes

  1. IgE Mediated
    1. Usually atopic individuals (Type I Hypersensitivity)
    2. Foods, drugs, bee stings
    3. Foods include shellfish, peanuts, eggs, wheat and milk
    4. Drugs include PCN, sulfonamides
    5. Animal danders common
  2. Complement Mediated
    1. Serum Sickness
    2. Systemic Syndromes - Hepatitis B infection, systemic lupus (SLE)
  3. Hereditary Angioedema
  4. Anaphylactoid Reactions
    1. Direct Mast cell activation
    2. Radiocontrast dyes, opiates, polyanionic antibiotics
    3. Hyperosmolar solutions (mannitol, dextran)
    4. Amphetamines
  5. Abnormal Arachidonate Metabolism
    1. Aspirin reactions such as triad asthma
    2. Other NSAID allergy
  6. Chronic Urticaria - see below
  7. Physical Urticarias [3]
    1. Exercise induced
    2. Cold induced (~2% of urticaria in clinical practice; may have angioedema)
    3. Pressure urticaria (dermatographism) - lesions typically last 0.5-2 hours
    4. Solar urticaria
  8. Familial Cold Urticaria [5]
    1. Rare autosomal dominant disorder
    2. Mutations in CIAS1 gene on chr 1q44
    3. CIAS1 is a pyrin domain protein with likely role in inflammation
    4. Symptoms develop by age 1 year
    5. Cold air causes delayed, nonpruritic nonurticarial maculopapular rash
    6. Rash may be accompanied by chills, fever, arthralgias, conjunctivitis
    7. Myalgias, headache and fatigue can occur
    8. Amyloidosis develops in some patients
    9. Muckle-Wells Syndrome is related to familial cold urticaria but not triggered by cold
    10. Muckle-Wells also associated with progressive sensorineural deafness
  9. Cholinergic Urticaria - exercise or hot shower elicits pruritic eruption

D. Chronic Idiopathic Urticaria [4]

  1. Majority of chronic cases
    1. Lasts at least 6 weeks, mainly affects adults
    2. Women 2:1 to men
    3. Up to 50% of cases also have angioedema
  2. Characteristics
    1. Wheals are smooth, edematous, pink/red, surrounded by bright red flare
    2. Wheals last <24 hours, usually ~12 hours
    3. Clearing of central portion
    4. Typically worse at night
    5. May be accompanied by angioedema (nonpruritic subcutaneous, submucous swelling)
    6. Abnormal thyroid function occurs in ~20% of patients
    7. Thyroid autoantibodies typical of Hashimoto's Disease in ~25%
  3. Pathogenesis
    1. Most likely an autoimmune disease
    2. 35% of patients with IgG anti-IgE receptor (alpha subunit) autoantibodies
    3. Anti-IgE receptor Abs may stimulate mast cell and basophil histamine release [3]
    4. ~5% of patients with autoantibodies against IgE itself also described
    5. Anti-IgE Abs cross-link IgE and can activate mast cell and basophil degranulation
    6. Low molecular weight histamine releasing factor has been identified in some patients
    7. Lesions show perivascular inflatration with CD4+ lymphocytes, some monocytes
    8. Variable numbers of neutrophils and eosinophils
  4. Diagnosis
    1. May coexist with dermatographism, pressure urticaria, or urticarial vasculitis
    2. Rule out ingestion, drugs, cold induced, detergents
    3. Serum electrolytes, urinalysis, routine blood counts usually normal
    4. Rule out vasculitis - skin biopsy must be considered
    5. Other vasculitis evaluation: ESR, ANA, RF, cryoglobulin screen
    6. Complement levels for vasculitis evaluation or in angioedema without hives
    7. Erythrocyte sedimentation rate (ESR) and CRP usually normal unless vasculitis
    8. Consider culture for ova and parasites and/or dental/sinus films
  5. Treatment (see below)
    1. Avoidence of exacerbating factors including aspirin, NSAIDs, narcotics, acid juices
    2. Nonsedating antihistamine H-1 Blockers are mainstay of therapy
    3. Sedating antihistamines may be used but cause CNS and anticholinergic (mainly dry mouth, constipation) effects
    4. Ciproheptadine 4mg per dose may be added to hydroxyzine with added efficacy
    5. Leukotriene antagonists (zafirlukast, montelukast) may improve control
    6. Doxepin, 25mg po qd to tid may be effective
    7. Addition of H-2 Antagonists may provide some additional relief
    8. Glucocorticoids only for resistant (severe) cases and urticarial vasculitis
    9. Inhaled or systemic ß2 agonists may be helpful with airway compromise (see below)
    10. Plasmapheresis may be effective in severe cases

E. Therapy for Urticaria

  1. Treat or Avoid underlying causes - see evaluation above for chronic urticaria
  2. Nonsedating antihistamines recommended first line therapy [6]
    1. Few adverse CNS or anticholinergic effects
    2. Fexofenadine (Allegra®) 60-120mg po bid
    3. Loraditine (Claritin®) 10-20mg po bid
    4. Certirizine (Zyrtec®) 10-20mg po qd (about as effective as 30mg hydroxyzine)
    5. Levocetirizine (L-cetirizine, Xyzal®): 5mg qd; active cetirizine enantiomer [8]
    6. Fexofenadine appears to be most effective and safe at recommended doses overall []
    7. Fexofenadine free of sedation, even at high doses; loratadine nonsedating at standard doses; cetirizine more sedating than other second generation agents [8]
  3. First Generation Antihistamines [6]
    1. May cause somnolence, slowed cognition and reaction time, reduced work efficacy
    2. Also, urinary retention, dry mouth and tachycardia; prolonged QTc very uncommon
    3. Examples: Diphenhydramine (Benadryl®), Chlorpheniramine (Chlor-Trimeton®)
    4. Triprolidine (Actifed®), hydroxyzine (Atarax®, Vistaril®)
  4. Doxepin
    1. Tricyclic with anti-histaminergic and anti-cholinergic properties
    2. Often effective when antihistamines insufficient
    3. Doses 25mg qd - tid sedating but
    4. Doxepin 5% cream applied tid-qid approved for itching in eczema [7]
  5. Glucocorticoids
    1. For patients who fail above medications
    2. For any patients with moderate or severe airway obstruction
    3. Require 4-6 hours for onset of action
    4. Doses prednisone 0.25-0.5mg/d po for mild/moderate symptoms
    5. For severe disease, 1-2mg/kg IV methylprednisolone qd (may be divided) should be used
  6. Airway Compromise
    1. ß-agonists - nebulized
    2. Intravenous antihistamines (such as diphenhydramine 50mg IV)
    3. Epinephrine - 0.3cc SC 1:1000; if fails, 0.5cc IV 1:10,000 (NOTE CONCENTRATIONS)
    4. Glucocorticoids - eg. 125mg iv methylprednisolone (SoluMedrol®)
  7. NSAIDs and aspirin tend to exacerbate skin lesions
  8. Plasmapheresis may be considered in severe cases
  9. Immunosuppression if needed
    1. Cyclophosphamide is often used
    2. Mycophenolate may be considered
    3. Methotrexate may be glucocorticoid sparing
  10. Experimental Agents
    1. Substance P antagonists
    2. Dapsone
    3. Hydroxychloroquine
    4. Sulfasalazine
    5. Intravenous immune globulin (IVIg)

F. Other Syndromes

  1. Atopic Dermatitis (Eczematous)
  2. Contact Dermatitis

References

  1. Kay AB. 2001. NEJM. 344(2):109 abstract
  2. Greaves M. 2000. J Allergy Clin Immunol. 105(4):664 abstract
  3. Hide M, Francis DM, Grattan CEH, et al. 1993. NEJM. 328:1599 abstract
  4. Kaplan AP. 2002. NEJM. 346(3):175 abstract
  5. Drenth JPH and van der Meer JWM. 2001. NEJM. 345(24):1748 abstract
  6. Antihistamines. 1996. Med Let. 38(970):21 abstract
  7. Doxepin Cream. 1994. Med Let. 36(934):99 abstract
  8. Levocetirizine. 2007. Med Let. 49(1275):97 abstract