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Getting Hives Just Thinking About It! Approach to the Work up and Management of Urticaria

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Getting Hives Just Thinking About It! Approach to the Work up and Management of Urticaria Getting Hives Just Thinking About It! Approach to the work up and management of urticaria Sarina B. Elmariah, MD, PhD Director, MGH Itch and Neurocutaneous Disorders Clinic Massachusetts General Hospital Harvard Medical School Disclosures I have the following relevant financial relationship with a commercial interest to disclose: • Sanofi/Regeneron • RAPT Therapeutics • Menlo Therapeutics • Trevi Therapeutics PART I: OVERVIEW OF URTICARIA What Are Urticaria? • Aka hives or wheals • Evanescent, pruritic, pink edematous papules or plaques that typically have a peripheral flare of pallor • Lesions last < 24 hrs • If >24 hours, consider other urticarial dermatoses or vasculitis • Round, annular or serpiginous • Affect any part of the body • Can be associated with angioedema (deep swellings) Images from Bolognia, J, Schaffer JV, and Cerroni L. Dermatology 4th Ed. 2018 Clinical Subtypes Spontaneous Inducible • Mechanical urticaria • Acute: < 6 weeks – Dermatographism • Chronic: > 6 weeks, – Delayed pressure most days • Contact urticaria – – Autoimmune urticaria Chemical contact – Cold contact • Episodic: recurrent but – Heat contact <2 days per week • Solar urticaria • Vibratory urticaria • Aquagenic urticaria • Cholinergic urticaria • Adrenergic urticaria Epidemiology • Acute urticaria affects up to ~20-25% population overall • Chronic urticaria has a lifetime prevalence of 1.8% – ~80% spontaneous or idiopathic urticaria (prevalence 1% in US, similar in other countries) • 30-60% of these are considered autoimmune – ~20% are inducible or physical urticarias – 40% CU associated with angioedema • 2:1 predominance in women • Affects all ages, peaks between 3rd to 5th decades PART II: PATHOPHYSIOLOGY AND DIAGNOSTIC WORK UP OF URTICARIA Pathophysiology Beck LA, et al., Acta Derm Venereol. 2017 Feb 8;97(2):149-158. Porebski G, et al. Front Immunol. 2018 Dec 20;9:3027 Immediate symptoms of itch, Influx of inflammatory cells, pro- burning, edema and erythema inflammatory cytokine release and due to vasodilation and neural increased vasodilation activation Forsythe P., Trends Neurosci. 2019 Jan;42(1):43-55. Clinical Subtypes Zuberbier T et al., Allergy 2009: 64: 1417-1426. Autoimmune Urticaria • Common • Estimated to account for ~30-50% cases of chronic spontaneous urticaria • Round, annular, or serpiginous edematous papules and plaques develop spontaneous, resolve within 24 hours Image from AsthmaAllergyNetwork.org • Extracutaneous symptoms include headaches, fatigue, joint pain, wheezing, n/v, diarrhea, other GI sx • Often associated with co-morbid autoimmune thyroid disease, SLE, RA, Sjogren’s, celiac. Emerging data suggesting increases odds of atopic diseases, vitiligo, Henoch Schonlein Purpura, and IBD. Kolkhir P, et al. Autoimmun Rev. 2017 Dec;16(12):1196-1208 Autoimmune Urticaria • Diagnostic test: screen for 2 basic mechanisms • Type I (IgE-autoantibodies to autoantigens, e.g., thyroperoxidase (TPO)) • Type II (IgG-autoantibodies to IgE or FcεRI) identified on autologous serum skin test (ASST) or immunoassays • The autoantibodies anti-IgE and IgG anti-FceRI were found in sera from ~45–55% of patients with CU. Table from Confino-Cohen R et al, JACI. 2012 May;129(5):1307-13 Pressure Urticaria Dermatographism Delayed Pressure Urticaria • Deep, pruritic and painful swellings after • Affects ~5% of people sustained pressure • Develops within 30 min to 12 hours • Develops within seconds to minutes after skin stroke after onset of pressure, can last days • Commonly affects shoulders (F), waist, • Diagnostic test: scratch skin with soles, genitalia broken tongue depressor ▪ Diagnostic test: apply 2.5kg weight to Images from Bolognia J. Dermatology 4th Ed. 2018 thigh/back for 20min, monitor for 8 hrs Contact Urticaria • Common, often arises due to occupational exposure • Environmental (plants, animals), food, cosmetics, preservatives • Wheals develop within ~30 min following external exposure with triggering substance, typically resolve within few hours • Extracutaneous symptoms include wheezing, rhinitis, lip or throat swelling, n/v/d, anaphylaxis From DermNetNZ.org Contact Urticaria • Diagnostic test: • Open and scratch tests: substance is applied, gently rubbed or occluded for 15 min on skin • Prick testing: intradermal injection of substance • RAST testing: serum IgE • At risk occupations • Agricultural, dairy workers: cow dander, grains and feeds • Food workers: cheese, egg, milk, shellfish, fruit, flour and wheat • Bakers: ammonia persulfate, flour, a-amylase • Dental workers: latex, acrylate, epoxy, toothpaste • Medical/veterinary: latex • Electronic workers: acrylate, latex • Hairdressers: ammonia persulfate, latex Images from Giménez-Arnau A.. Rev Environ Health. 2014;29(3):207-15.; DermNetNZ.org Cold Contact Urticaria • Primary: 95% of cold urticarias – Affects 0.05% general population, typically young to middle-aged adults – Usually idiopathic, but may be associated with viral infections or following URIs – Develop 2–5 minutes after exposure and last for 1–2 hours – ~ 25-30% patients report resolution after 5-10 years – Associated with flushing, HA, syncope, abdominal pain, hypotension, anaphylaxis • Secondary cold contact urticaria – Lasts >24 hours – Associated with cryoglobulinemia, Cryofibrinogenemia, cold agglutinins, hemolysins – Check Hep B/C, EBV, evaluate for Lymphoproliferative disorders • Familial cold urticaria: rare – Burning itching plaques last up to 48 hours – Mutation in NLRP3, cryopyrin gene (same as Muckle-Wells syndrome) – Associated with fever, HA, leukocytosis Images from Bolognia, J, Schaffer JV, and Cerroni L. Dermatology 4th Ed. 2018 Cold Contact Urticaria • Diagnostic test: apply an ice cube against the skin of the forearm for 1-5 minutes, monitor for development of hive within 10 minutes Images from Huissoon A, Krishna MT. N Engl J Med. 2008 Feb 21;358(8):e9 ‘Neurovascular’ Subtypes Cholinergic urticaria Adrenergic Urticaria ▪ Common (est up to 20%) in young adults, • Very rare unusual in elderly • Multiple 1-3mm red or pink papules with ▪ Numerous pinpoint to 3mm edematous papules blanched or pale, vasoconstricted halo with pronounced flare, stinging and pain > itch • Triggers include trauma, emotional upset, ▪ Arise within 15 min of rise in core body temp coffee, chocolate, and ginger ▪ May have systemic symptoms (faint, wheezing), but also associated with cold urticaria, • May have associated with wheezing, dermatographism, and aquagenic urticaria palpitations, parasthesias and malaise ▪ Diagnostic test: exercise to induce sweating or • Diagnostic test: ID injection of 5-15 ng of Epi partial immersion in hot bath 42C for 10 min or 3-10 ng of NE in 0.02 mL of saline Images from Fukunaga A et al., Clin Auton Res. 2018 Feb;28(1):103-113., Bolognia et al. Dermatology 4th Ed. 2018 Aquagenic Urticaria ▪ Very rare, < 100 cases reported ▪ Predominantly affects women, onset in puberty ▪ 1-3 mm folliculocentric wheals with surrounding 1-3 cm erythematous flares ▪ Develop 20-30 mins following contact with water, sweat or tears, and typically resolve after 60 mins ▪ Associated with pruritus, burning and prickling or stinging. ▪ Rarely associated with wheezing or SOB ▪ Associations reported with cystic fibrosis, HIV, and occult thyroid papillary carcinoma Images from Robles-Tenorio A, et al., Clin Case Rep. 2020 Sep 24;8(11):2121-2124. Bolognia et al. Dermatology 4th Ed. 2018 Aquagenic Urticaria • Diagnostic test: apply a cloth soaked in room temperature water to the patient’s skin for 20 minutes monitor for development of hive within 30 minutes Images from Robles-Tenorio A, et al., Clin Case Rep. 2020 Sep 24;8(11):2121-2124. Solar Urticaria • Uncommon, represents < 0.5% of all urticaria cases and 7% of all photodermatoses • Predominately affects women, onset in young adults (median age 35 years) • Erythema, edematous papules occurs within minutes of sunlight, lasts < 60 mins • May occur on sun-exposed areas or those covered with thin, white clothing • May be associated with nausea, headache, syncope, wheezing or dyspnea • Diagnostic test: Photo provocation testing to UVA, UVB and visible light. Need to assess every 10 minutes for an hour. Images from Bolognia, J, Schaffer JV, and Cerroni L. Dermatology 4th Ed. 2018 Diagnostic Evaluation • History • Examination – Helpful in some cases of inducible urticaria • Diagnostic testing – Allergy provocation testing – Autoimmune profiles – Infectious disease evaluation Key Elements of History Zuberbier T et al., Allergy. 2018;73:1393–1414. Inducible vs Autoimmune Saini SS, Kaplan AP. J Allergy Clin Immunol Pract. 2018 Jul-Aug;6(4):1097-1106. Key Elements of Examination • In general, exact etiology cannot be determined by physical examination. • However, occasional features may help distinguish subtypes: • Generalized vs localized • Large plaques vs small papules • Erythematous flare vs pale vasoconstriction Zuberbier T et al., Allergy. 2018;73:1393–1414. ASST = autologous serum skin test (wheal/flare develops at site of patient’s own intradermally injected serum) largely replaced by immunoassays for the auto-antibodies Radonjic-Hoesli S et al. Clin Rev Allergy Immunol. 2018 Feb;54(1):88-101. Evaluating Patients with Chronic Urticaria • Routine: CBC w/ diff, ESR, CRP, TSH • As indicated by HPI, PE or ROS: ANA, RF, cryoglobulins, anti-TPO antibodies, anti-IgE and anti-FcεRI antibodies, Hep B/C serologies, stool O + P • Skin biopsies are usually NOT helpful unless vasculitis is expected (e.g. ‘painful’ urticaria which last >24-72 hours) Bolognia, J, Schaffer JV, and Cerroni
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