Hives – Is that itch really allergic? Vinay Gowda, MD Palo Alto Medical Foundation Santa Cruz, CA

Disclosures Financial Disclosures: None Off Label Use of Medications: Montelukast in the treatment of urticaria is an off label use as it is only FDA approved for asthma and allergic rhinitis. H2 Blockers, Pepcid/Zantac/Tagamet/Axid are off label in the treatment of urticaria and are FDA approved for GERD.

Urticaria Urticaria are described as: -Slightly raised -Well circumscribed -Erythematous welts -Mobile -Typically associated with angioedema

Pathophysiology of Urticaria Dilatation of small venules and capillaries in dermis Minimal perivascular lymphocytic infiltrate Swelling of collagen fibers Baxi S, Dinakar C. Immunol Allergy Clin N Am. 2005;25(2): Greaves MW. N Engl J Med. 1995;332(26): Copyright ©1995 Massachusetts Medical Society. All rights reserved.

Chronic Urticaria Can Impact Patients’ Lives Discomfort and reduced mobility Sleep disturbance Emotional factors –Anxiety and depression –Concern over physical appearance –Negative impact on self-image Productivity losses –Missed work days –Deterioration of work performance 1 O’Donnell BF, et al. Br J Dermatol. 1997;136(2): ; 2 Baiardini I, et al. Allergy 2003;58(7):

Acute or Chronic Acute hives: Less than 6 weeks. Chronic hives: More than 6 weeks.

Why does time frame matter? Acute hives can be allergic. They typically are due to allergic causes and non allergic causes. Allergic causes include bites/stings, medications, contactants, latex, food, viral infections or the development of chronic hives.

Medications ACE Inhibitors Angiotensin Blockers (ARBs) Aspirin/NSAIDs

Bugs Stinging Insects (Bees, wasps, hornets, yellow jackets, fire ants) Bed Bugs (Triatoma) Triatoma=Kissing Bug

Why does the time frame matter? It matters as chronic urticaria (i.e. hives less than 6 weeks) is NOT thought to be allergic. It is actually thought to be autoimmune in most cases. There is an IgG autoantibody against the Fc portion of the IgE receptor on mast cells. This results in release of mediators such as histamine, leukotrienes and prostaglandins.

Pathophysiology of Urticaria Reproduced from Hennino A, et al. Clin Rev Allergy Immunol. 2006;30(1):3-11. Non-Immunological ActivationImmunological Activation Edema Degranulation Immediate Phase Cytokines Chemokines Late Phase Prostaglandins Leukotrienes Leukocyte infiltration CD48 CD88 TLR Ca++ STAT6

Epidemiology of Chronic Urticaria Prevalence of chronic urticaria (CU) –Affects 0.1%–3% of the population –30%–50% of cases have an autoimmune component 50% are likely to remit within 1 year Over 50% of patients will experience at least one recurrence of CU 1 Negro-Alvarez JM, Miralled-Lopez JC. Allergol Immunopathol (Madr). 2001;29(4): ; 2 Greaves MW. Curr Opin Allergy Clin Immunol. 2003;3(5): ; 3 Krishnaswamy G, Youngberg G. Postgrad Med. 2001;109(2): , , ; 4 Beltrani VS. In ACP Medicine Online: Immunology/Allergy, 2007.

Chronic Urticaria Thus, chronic urticaria is thought NOT to be allergic in most cases.

Chronic Urticaria European dermatologic societies do not recommend a work up. The U.S. allergy societies (AAAAI, ACAAI) do not recommend an allergy workup. Some advocate to check for underlying disease with a CBC, LFTs, ESR and appropriate testing based on the history and physical.

What else to check? There are anecdotal reports of associated thyroid disease, H. Pylori infection. Thus, some with check a TSH level and/or Helicobacter Pylori urea breath test.

What else to check? However, since chronic urticaria can be autoimmune in the majority of cases, one can check a CU Index or a Histamine Release Assay to check for autoimmunity against the mast cell.

Differential Diagnosis of Chronic Urticaria Diseases or syndromes with classic urticarial lesions –Cryporin-mediated autoinflammatory disorders Familial cold autoinflammatory syndrome Muckle-Wells syndrome Chronic infantile neurologic cutaneous articular syndrome –Schnitzler syndrome Diseases with fixed atypical urticarial lesions –Cutaneous lupus erythematosus –Urticarial vasculitis –Cutaneous mastocytosis, urticaria pigmentosa –Fixed drug eruption –Bullous pemphigoid Reproduced with permission of American College of Allergy, Asthma & Immunology, from Brodell LA, Beck LA. Ann Allergy Asthma Immunol. 2008;100: ; permission conveyed through Copyright Clearance Center, Inc.

Differential Diagnosis. Urticarial Vasculitis. Mast Cell Activation Syndromes

Urticarial Vasculitis These are hives that are atypical. They are tender, can be associated with bruising and leave residual hyperpigmentation. A skin biopsy can help diagnose this condition. Typically immunosuppressants are required such as prednisone, cyclosporine.

Mast cell activation syndrome Systemic mastocytosis. There will be a high burden of mast cells in the bone marrow. Patients can present with hives and syncope. A tryptase is typically elevated. Bone marrow biopsy is indicated for diagnosis.

Treatment Antihistamines: They are 1 st line treatment. H1 antihistamines block histamine at the receptor. 1 st generation antihistamines are sedating and short acting. Although some are useful when used at night (i.e. hydroxyzine).

H1 Blockers 2 nd generation antihistamines. These are once daily antihistamines used to help relieve hives. Last 24 hours. Non sedating (Allegra, Claritin, Clarinex) Partially sedating (Zyrtec, Xyzal)

H2 Blockers 10-15% of histamine receptors are type II histamine type. Thus, H2 blockers such as Pepcid, Zantac, Axid and Tagamet can potentially help with hives. This is an off label use in the treatment of hives, flushing.

Anti-leukotrienes Anti-leukotrienes are released by mast cells when their IgE receptor is cross linked. One study showed efficacy with Singulair (montelukast) when combined with desloratadine in the treatment of hives (Nettis E et al.: Desloratadine in combination with montelukast in the treatment of chronic urticaria: a randomized, double-blind, placebo-controlled study. Clin Exp Allergy 2004, 34(9): ). This is an off label use of montelukast as it is FDA indicated for asthma, allergic rhinitis.

Treatment Xolair is a monoclonal antibody against free IgE and IgE bound to the mast cell. Its initial approval was for allergic asthma. In 2014, it received a FDA approval for chronic urticaria.

Xolair (omalizumab) Although its true mechanism of action is poorly understood. It seems that when this monoclonal antibody binds to free IgE, it decreases the amount the autoreactive IgG antibody bound to the mast cell; hence decreasing mediator release. 40% of patients will respond to antihistamines; however, an additional 40% will respond to Xolair.

Summary Hives: Is that itch really allergic? For acute urticaria, hives can be allergic. In chronic urticaria, hives are uncommonly allergic and are typically autoimmune. 40% of patients will respond to antihistamines. If no response then consider referral to a skin specialist as another 40% will respond to Xolair.