Urticaria: A Diagnostic and Therapeutic Approach American College of Physicians (ACP) October 10, 2008

1. Urticaria: A Diagnostic and Therapeutic ApproachAmerican College of Physicians (ACP)October 10, 2008 Jill A. Poole, MD, FAAAAI, FACAAI Assistant Professor Pulmonary, Critical Care, Sleep & Allergy Section University of Nebraska Medical Center 402-559-4087 japoole@unmc.edu

2. Objectives • To recognize the causes of acute urticaria and angioedema • To recognize the causes of chronic urticaria and angioedema • To recognize the provocative challenges for physical urticarias • To discuss the treatment of urticaria and angioedema

3. Urticaria (aka Hives) • Common problem! • Affects up to 20% of the population • Pruritic (itch!) • Blanche with pressure • Fleeting (“Leaves no trace”) -No scarring

4. Angioedema (Swelling) • Edema of the deep layers of the dermis and subcutaneous tissue. • Non-pitting edema • Skin is not hot • Non-dependent areas It is not: “pre-tibial pitting edema”

5. Pruritus • Chronic Itch without Rash • Differential diagnosis is different (not chronic urticaria) • Uremia • Cholestasis • Malignancy • Non-Hodgkins Lymphoma • Polycythemia vera • Thyrotoxicosis • Multiple sclerosis • Iron Deficiency Anemia • Diabetes (Autonomic dysfunction) • Medications • Psychiatric Illness

6. Case: 35 year old man with hives for the past 4 days. Skin lesions are described as VERY itchy. Diphenhydramine helps, but does not last long, and he is taking 5-6 tablets a day. Hives began when he was eating dinner Friday night, shrimp entree. However, he has not had any shrimp since Friday night and the hives are still occurring. Plus, he has never had hives with shrimp before.No swelling, shortness of breath, throat closing, nausea, vomiting, or diarrhea. Diagnosis?

7. Definition: Hives lasting less than 6 weeks Common triggers: Foods *Shellfish, peanut, wheat, egg, fresh fruits, milk Infections More common in children Animal dander Pollens DrugsAspirin, NSAIDS, antibiotics Occupational Stinging Insects Acute Urticaria Kaplan, A. P. N Engl J Med 2002;346:175-179

8. What do you tell the patient? • It may take several weeks for the hives to go away completely. • Strict avoidance of shrimp. • Treatment with long-acting, non-sedating anti-histamines. • Initiate a laboratory work up to include complete blood count, complete metabolic panel, thyroid testing, urinalysis. • All of the above, except #4. • It may take several weeks for the hives to go away completely. • Strict avoidance of shrimp. • Treatment with long-acting, non-sedating anti-histamines. • Initiate a laboratory work up to include complete blood count, complete metabolic panel, thyroid testing, urinalysis. • All of the above, except #4.

9. Case: 18 year-old man with almost daily hives for the past 2-3 months. Hives appear after scratching the skin and last for 30-60 minutes. Sometimes hives occur along his waist when he exercises. Review of systems is otherwise negative. Diagnosis?

10. DermatographismA Physical Urticaria Scratching skin results in hives lasting 30 mins to 2 hours Kaplan, A. P. N Engl J Med 2002;346:175-179

11. Physical Urticarias • Reproducible by environmental factors • Physical stimuli • Most frequently in young adults • Episodic and often limited to areas of inciting stimulus • Usually, unresponsive to corticosteroids • Overall, treatment with non-sedating antihistamines

12. Examples of Physical Urticarias 1. If you stroke the skin, and a hive occurs? Answer: Dermatographism 2. If you place an ice cube on the forearm, and after removal of ice cube, hive occurs? Answer: Cold-induced urticaria 3. If hives occur when the patient sweats or exposure to heat? Answer: Cholinergic urticaria or localized heat urticaria

13. More Examples of Physical Urticaria 4. If shoulder swells (angioedema) 4-6 hours after carrying a heavy shoulder bag? Answer: Delayed pressure-induced urticaria & angioedema Note: may require cortiosteroids 5. If patient develops hives only while mowing the lawn? Answer: Vibratory-induced urticaria

14. Case:8 year old boy with numerous pruritic small lesions on arms and legs. A flea collar was placed on Fluffy, the cat, yesterday. • Papular urticaria • A hypersensitivity reaction to the bites of mosquitoes, fleas, bedbugs, and other insects causes papular urticaria. Diagnosis? Treatment: Treat the cat

15. Case: 34 year-old woman with almost daily hives for the past five to six months. She occasionally has associated right upper lip swelling, but denies dyspnea or throat swelling/closing. She states hives occur randomly. She takes 5-6 tablets of diphenhydramine a day. Review of systems is otherwise negative. Diagnosis? Etiology?

16. Chronic Urticaria & Angioedema • Definition: Hives occurring greater than 6 weeks • Hives and angioedema (40%) • Hives alone (40%) • Angioedema alone (20%) Etiology: • Difficult to determine, cause rarely found • Common in 3rd and 4th decade of life • Usually not foods, drugs, pollens, infections, “dyes” • Bad News: May last years….

17. Chronic Urticaria & Angioedema Thyroid Disease Association Thyroid function tests Thyroid autoantibodies Hives: 4 to 36 hours? Autoimmune Autoantibodies to the high affinity IgE receptor (40%) Hives: 4 to 36 hours Idiopathic* Hives: 4 to 36 hours Urticarial Vasculitis Systemic or isolated Hives: > 24 hours Faint hyperpigmentation Kaplan, A. P. N Engl J Med 2002;346:175-179

18. Chronic Urticaria Diagnostic Evaluation • History & Physical Exam • Diary • Relationship of hives with menstrual cycle? • Provocative tests for physical causes • Laboratory tests: (Not proven to be cost effective) • CBC with diff, ESR, CRP, UA, LFTs • Thyroid function, anti-thyroid antibodies • Skin tests • Autologus serum skin test • Complements

19. Chronic Urticaria Diagnostic Evaluation • Skin biopsy? • Generally, not helpful • Indications: • Lesions lasting more than 24 to 48 hours • Atypical? • Scarring • Red blood cell extravasation • Cutaneous vasculitis • Urticaria pigmentosa • Refractoriness to therapy

20. Chronic Autoimmune Urticaria • Functional antibody (IgG) to the alpha subunit of the high affinity IgE receptor (30%) • Functional anti-IgE antibody (5-10%) • Diagnosis • Immunoblotting has been unsuccessful • Autologous serum skin testing (ASST) • Intradermal injection of subject’s serum • Wheal and flare reaction after 30 minutes • Basophil CD203c Expression Greaves, JACI 2000; Kaplan, NEJM 2002

21. Management of Chronic Urticaria/Angioedema • Avoidance or treatment of underlying cause • Avoidance of potentiating factors • Alcohol • Non-steroidal anti-inflammatory drugs • Main therapy • H1 anti-histamines • Non-sedating, long-acting antihistamines • Combination of therapies • Triple drug therapy: H1 & H2 antagonists plus leukotriene blockers • Tricyclic antidepressants • Immunomodulators (e.g. steroids, cyclosporine) • Tried with “?” benefit: Hydroxychloroquine, dapsone, calcium channel blockers, methotrexate, colchicine, pentoxyfilline, cyclophosphamide

22. Urticarial Vasculitis (Rare) • Inflammatory injury of capillaries and postcapillary venules in the skin. • Etiology: Manifestation of systemic disease • Clinically: • Hives persisting > 24 hours •  pruritic • Painful, stinging, burning sensation • “Leaves a trace” • Faint residual hyperpigmentation, indicating red blood cell extravasation

23. Conclusions • Hives • Very common • Acute Urticaria (Hives < 6 weeks) • History is key • Non-sedating anti-histamines • Physical Urticarias • History and provocative challenges • Non-sedating histamines • Chronic Urticaria (Hives > 6 weeks) • Etiology: Rarely determined • Therapy: Difficult