1. Urticaria and Angioedema 101
Scot Laurie, MD
Allergy and Asthma Center at NorthPark
Assistant professor, University of Texas Southwestern Medical Center

2. Case Presentation
Jim S. is a 45 y/o who presented for evaluation of his urticaria. He has been suffering with hives for the past 4 months. He is unable to tell what triggers his hives.
His hives are generalized and an individual hive will last a few hours; he has had several episodes of lip swelling as well.
He might have had a similar episode 10 years ago and his doctor told him he was allergic to penicillin

3. Case presentation
He has visited his primary care physician who suggested he take Claritin
He returned when his hives persisted and the doctor told him that he was allergic to something and suggested an allergy evaluation.

4. Case presentation Past medical history Medications Review of systems
Hypothyroidism
Medications
levothyroxine
Ibuprofen prn
Review of systems
Occasional headaches; otherwise negative
Physical exam

6. Case presentation How would his hives be classified?
What is causing his hives?
Are his medical conditions or medications contributing to his hives?
What tests should be done to evaluate his hives?
How are his hives best treated?

7. URTICARIA & ANGIOEDEMA
DESCRIPTION
Urticaria
Raised, erythematous, blanching
Pruritic
Lesions well-circumscribed; typically coalesce
Angioedema
Subcutaneous swelling
Predilection to areas of loose connective tissue, such as the face or mucus membranes involving the lips or the tongue

9. Urticaria or “Hives” Urticaria or “Hives”
Urticaria consists of raised, erythematous skin lesions that are markedly pruritic, tend to be evanescent in any one location, and generally are worsened by scratching. Angioedema is frequently associated with urticaria except that it occurs in deeper tissues and is clinically characterized by asymmetric swelling of tissue.
Metzger WJ. Urticaria, angioedema, and hereditary angioedema. In: Patterson, et al, eds. Allergic Diseases: Diagnosis and Management. 4th ed. Philadelphia, Pa: JB Lippincott Co; 1993:

11. Urticaria and Angioedema
Clinical features: Urticaria
Repeated occurrence of short-lived cutaneous wheals accompanied by erythema and pruritus
Wheals range in size from a few millimeters to several centimeters
Wheals may coalesce to form larger lesions
Individual wheals typically last less than 24 hours
Urticaria may occur anywhere on the skin
Mucus membrane involvement is rare
Lesions should resolve without any residual marking

12. Urticaria and Angioedema
Clinical features: Angioedema
Approximately 50% of patients with chronic urticaria have angioedema as well
Episodes of short-lived deep dermal and subcutaneous or submucosal edema
Like urticaria, symptoms generally last less than 24 hours
Larger swellings may take longer to resolve
Pruritus does not consistently accompany angioedema, and may not occur at all.

13. Mediators of hives and swelling
Source
Factor
Mast cells (cutaneous)
Histamine
Prostaglandin D2
Leukotrienes C and D
Platelet Activating Factor
Complement system
Anaphylatoxins C3a, C4a, C5a: histamine
Hageman factor- dependent pathway
Bradykinin
Mononuclear cells
Histamine-releasing factors, chemokines

14. Urticaria and Angioedema
Classification
Acute: < 6 weeks
Allergic
Infectious
Idiopathic
Recurrent acute
Chronic: > 6 weeks
Autoimmune
Physical

15. URTICARIA CLASSIFICATION
Acute: < 6 weeks
Affects as many as 10-20% of the population at some point in their lives
Etiology frequently identified
Food allergy
Drug allergy
Stings/venoms
Infection
Viral infection leading cause of urticaria in children

16. Urticaria Classification
Recurrent acute (intermittent)
Episodes of urticaria lasting days or weeks with intervals of days, weeks, or months in between episodes
Chronic: > 6 weeks
Idiopathic
Physical urticarias

17. URTICARIA ETIOLOGIES Common Idiopathic Medications Stings Foods
Infection
Physical urticarias
Rare Causes
Neoplasms
Collagen vascular disease
Endocrine
Urticarial vasculitis

18. Urticaria etiologies
Urticaria is rarely, if ever the presenting or sole symptom of an underlying disease
A complete Review of Systems will suggest or identify any systemic disease in which the urticaria occurs

19. URTICARIA ETIOLOGIES Medications
Any drug has the potential to elicit an allergic reaction
Antibiotics in general, and penicillins specifically, are most often indicated
Aspirin/NSAID’s
Considered second most common cause of acute drug allergic reactions
Frequently exacerbate chronic urticaria and angioedema

20. URTICARIA ETIOLOGIES Foods Infection
Important cause of acute urticaria
Primary allergens are peanuts, tree nuts, shellfish, fish, eggs, milk
Chronic urticaria typically unrelated to food allergy
Infection
Common cause of acute urticaria
Viral infection most common cause in children
Episodes are self-limited
Rare cause of chronic urticaria

21. INSECT BITES & STINGS Generalized urticaria/angioedema
Indicates systemic reaction
Requires allergist evaluation for possible immunotherapy
Urticaria in children does not require immunotherapy
Hymenoptera
bees, wasps, yellow jackets, hornets
Fire ants

22. URTICARIA ETIOLOGIES Aeroallergens Contact Urticaria
Rarely, if ever, cause urticaria
Animals may cause contact urticaria
Inhaled latex may result in systemic allergic reaction
? seasonal pollens
Contact Urticaria
Nonimmunologic
cinnamic acid, benzoic acid
Diagnosed by open patch test
Immunologic (Allergic)
Latex, fruits, vegetables
Diagnosed by applying material to eczematous or scratched skin

23. Urticaria etiologies Endocrine/autoimmune Thyroid disease
Urticaria and angioedema has been associated with hypo- and hyperthyroidism
Possible association with the presence of thyroid autoantibodies (antithyroid peroxidase and antithyroglobulin)
Thyroid autoimmunity has been demonstrated in % of subjects with chronic urticaria
Thyroid autoimmunity occurs in 3-6% of the population

24. URTICARIA ETIOLOGIES Chronic urticaria
Most common etiology is idiopathic
30-60% of patients exhibit a wheal-and-flare with autologous serum skin testing
Thought to be due to a complement-activating, histamine-releasing autoantibody (IgG) against the α-chain of the high-affinity IgE receptor (FcεRI)
These autoantibodies are able to trigger mast cell or basophil histamine release through direct crosslinking of adjacent receptors
Can cause histamine release in healthy subjects
Treatment implications: urticaria may be more difficult to control

25. Plasma of patients with chronic urticaria shows signs of thrombin generation, and its intradermal injection causes wheal-and-flare reactions more frequently than autologous serum
J Allergy Clin Immunol 2006;117:

26. Chronic urticaria: etiologies
51/96 (53%) patients had positive ASST
61/71 (86%) patients had positive APST
Prothrombin fragment F(1+2) (marker of thrombin generation) was higher in patients than in controls
Levels directly related to severity of urticaria

27. Chronic urticaria: etiologies
Conclusions
Suggests role of the activation of the extrinsic coagulation pathway with thrombin generation in chronic urticaria
Thrombin increases vascular permeability (edema)
May trigger mast cell degranulation
Possible therapeutic use of anticoagulants (heparin/warfarin)

28. Natural history: Chronic Urticaria
Up to 50% patients resolve within 3-12 months
Another 20% of patients resolve in months or months
Up to 1.5% of patients persist for 20+ years
50% of patients with chronic urticaria will have recurrences
Physical urticarias tend to last longer, as do more severe forms of chronic urticaria

29. PHYSICAL URTICARIAS Symptomatic dermographism Cholinergic
Delayed pressure
Cold
Aquagenic
Solar
Vibratory
adrenergic

30. PHYSICAL URTICARIAS Dermographism
Very common- affects 2-5% of population
Small fraction of these patients will seek treatment
Stroking of the skin results in linear wheals which may persist as long as 30 minutes
patients may complain of generalized pruritus or “skin crawling”

32. PHYSICAL URTICARIAS Cholinergic urticaria
Likely the most common of the physical urticarias- 30% of the physical urticarias
Occurs primarily in teenagers and young adults
Pruritic, small macules and papules occur in response to heat, exercise, or emotional stress
May occur with wheezing
May occur without visible skin lesions (cholinergic pruritus)

34. Physical urticarias Cold urticaria
Characterized by the rapid onset of pruritus, erythema, and swelling after exposure to a cold stimulus
Holding cold objects: hand swelling
Eating cold items: lip swelling/ oropharyngeal edema
Swimming, with total body immersion, can result in massive mediator release, resulting in hypotension
Risk factor: oral symptoms with ingestion of cold items

37. URTICARIA EVALUATION Acute urticaria and angioedema
History to ascertain for possible triggers: food, drug, sting, infection
Exam to confirm diagnosis
May refer to board-certified allergist for select skin testing/challenge tests to suspected agents

38. Urticaria evaluation Chronic urticaria History and physical exam
Confirm diagnosis of urticaria/angioedema
Laboratory studies
Usually none required
No relationship has been found between the number of identified diagnoses and the number of laboratory tests performed
Consider thyroid evaluation (TSH, thyroid autoantibodies) in patients who fail initial therapy
If urticarial vasculitis suspected:
ANA, complement levels
Referral for skin biopsy

39. Skin biopsy Indications
Individual urticarial lesion persists for >48 hours
Urticaria are less than moderately pruritic
Lack of significant response to “maximum” doses of antihistamines

40. URTICARIA MANAGEMENT Goals control symptoms & keep patient comfortable
search for and treat underlying etiologies
exclude serious diseases
Avoidance
causative factor if identified
NSAID’s & ASA
excessive heat
Supportive therapy
Reassurance
Patient education is most important

41. Urticaria management Chronic idiopathic urticaria
Because there is no one specific causative agent that can be withdrawn, the hives cannot be “cured”.
Treatment is considered palliative, until the condition resolves on its own
Goal is to maintain a patient’s quality of life, despite condition

42. INITIAL URTICARIA PHARMACOTHERAPY
Antihistamines: H1 receptor antagonists
Second generation (“Non-sedating”)
equal in efficacy to first generation without as many side effects
cetirizine, levocetirizine, desloratadine, fexofenadine, loratadine
First generation
Generally administered on a daily basis for preventative therapy
hydroxyzine, diphenhydramine, chlorpheniramine, etc.
dose at qhs initially to reduce daytime somnolence
May be used on a prn basis

43. SECONDARY URTICARIA PHARMACOTHERAPY
H2 antagonists
15% of histamine receptors in the skin are H2
May use in combination with H1 antagonists
Inhibits metabolism of hydroxyzine, resulting in higher plasma concentration of hydroxyzine
Doxepin
Very potent H1 antagonist
H2 antagonist as well
May be very sedating- generally use at night
Leukotriene antagonists
Zafirlukast and montelukast superior to placebo in the treatment of chronic urticaria

44. Urticaria management Antihistamine “cocktail”
Begin with 2nd generation antihistamine once a day; if response unsatisfactory,
Double the dose (either split-dose twice daily, or full dose once daily); if response unsatisfactory, ADD
Doxepin qhs (titrate over time to reduce sedation)
Levocetirizine/cetirizine>fexofenadine>desloratadine/
loratadine

45. SECONDARY URTICARIA PHARMACOTHERAPY
Oral corticosteroids
Role of systemic steroids in the treatment of chronic urticaria is limited
Short-term use in special situations (e.g. control of symptoms prior to an important event.)
Prolonged treatment complicated by severe side effects along with worsening of urticaria upon withdrawal

46. Alternative agents for refractory chronic urticaria
Drug Level of evidence
Leukotriene modifiers Ib
Dapsone IIb
Sulfasalazine III
Hydroxychloroquine Ib
Colchicine III
Calcineurin inhibitors Ib
Mycophenolate IIb
Omalizumab III

47. SECONDARY URTICARIA PHARMACOTHERAPY
Immunomodulatory agents
Limited studies demonstrate efficacy of cyclosporine in improving urticaria along with decreasing dependence on prednisone.
Suppressive effect on basophil and mast cell activation
Requires monitoring of a patient’s blood pressure and renal function

48. Cyclosporine
Patients with chronic, severe urticaria with positive autologous skin test
3-month course of treatment resulted in 80% totally or almost clearing their symptoms
Upon medication withdrawal at 3 months:
1/3 remained clear
1/3 relapsed mildly
1/3 relapsed to baseline
Br J Dermatol 2000;143:368.

49. Urticaria and angioedema
Pearls
Urticaria and angioedema frequently is not an allergic condition
Urticaria does not respond to topical treatment
Urticaria in the setting of antibiotics use might be due to the infection, rather than the antibiotic
Almost all urticaria is responsive to antihistamines; if your initial dose does not work, use more
When all else fails, refer to your favorite fellowship-trained allergy and immunology specialist
Treatment references: N Engl J Med 2002;346:175-9
or Allergy and Asthma Proc 2004;25:

50. I Need an Allergist!!