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Home , Aquagenic urticaria, Hives, Ligelizumab, Vitiligo

Getting Just Thinking About It! Approach to the work up and management of urticaria

Sarina B. Elmariah, MD, PhD Director, MGH 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 or plaques that typically have a peripheral flare of pallor • last < 24 hrs • If >24 hours, consider other urticarial dermatoses or • Round, annular or serpiginous • Affect any part of the body • Can be associated with (deep swellings)

Images from Bolognia, J, Schaffer JV, and Cerroni L. 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 • • • 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, and inflammatory 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., 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 disease, SLE, RA, Sjogren’s, celiac. Emerging data suggesting increases odds of atopic diseases, , 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 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

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, , preservatives • Wheals develop within ~30 min following external exposure with triggering substance, typically resolve within few hours • Extracutaneous symptoms include wheezing, , lip or throat swelling, n/v/d,

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 • 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 . 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, , cold agglutinins, hemolysins – Check Hep B/C, EBV, evaluate for Lymphoproliferative disorders

• Familial : 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.

• 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-

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 are usually NOT helpful unless vasculitis is expected (e.g. ‘painful’ urticaria which last >24-72 hours)

Bolognia, J, Schaffer JV, and Cerroni L. Dermatology 4th Ed. 2018 Diagnostic Evaluation of CU: Practice Guidelines

Beck LA et al. Acta Derm Venereol. 2017 Feb 8;97(2):149-158. Tests to confirm inducible CU: Practice Guidelines

Beck LA et al. Acta Derm Venereol. 2017 Feb 8;97(2):149-158. PART III: MANAGEMENT OF URTICARIA US Guidelines on CU Treatment

Beck LA et al. Acta Derm Venereol. 2017 Feb 8;97(2):149-158.

Bolognia, J, Schaffer JV, and Cerroni L. Dermatology 4th Ed. 2018 Antihistamines

• 40-50% of CU patients at tertiary clinics will clear/almost clear at licensed doses of anti-

• For refractory cases: • Increase to 4-6x recommended dose • Combine antihistamines (non-sedating /long-acting with sedating at night) • If adding H2 antihistamines, is preferable. interferes with hepatic drug metabolism and binds androgen receptors.

• Special considerations • For cold urticaria, try cyproheptadine (anti-cholinergic) • For adrenergic urticaria, add propranolol to regimen • In pregnancy, and thought to be safest • Avoid chlorpheniramine close to delivery and during breastfeeding • In patients > 65 yo, avoid chlorpheniramine, and due to more potent anti-cholinergic and neuropsychiatric effects. The AGS Beers Criteria panel advises 2nd generation H1-antihistamines (cetirizine or loratadine). Leukotriene Antagonists

• Rationale: Cysteinyl leukotriene injection causes a wheal and flare response • Efficacy: Few small RCTs demonstrating mixed results for efficacy • 3 showed benefit over placebo (Erbagzi 2002, Pacor 2001, Bagenstose 2004) • No benefit compared with placebo (Reimers 2002) • Less benefit than 2nd gen. antihistamines (Di Lorenzo 2004) • SEs: headache, GI infections, sedation in trials, real world data suggesting possible neuropsychiatric SEs • Tips: Might be worth a 2-4 weeks trial, but if unhelpful would discontinue. Anti-Inflammatory Agents

Hydroxychloroquine Dapsone • Rationale: Disrupts T- receptor • Rationale: Sulfone antimicrobial with cross-linking dependent calcium antineutrophilic effects signaling and Ag processing • Efficacy: 2 RCTs showing benefit • Efficacy: 1 RCT showing benefit (Engin, 2008, Morgan, 2015) (Reeves 2004) • SEs: dose-related hemolysis, • SEs: GI upset; retinopathy after 5 yrs methemoglobinemia, peripheral neuropathy, GI distress, • hepatotoxicity, agranulocytosis, Tips: DRESS – Consider when co-morbid • – Takes at least 3-6 months to Tips: work – Use this occasionally – Need baseline and annual – Requires G6PD screening at ophtho exam baseline and Hgb and LFT monitoring Anti-inflammatory Agents

Methotrexate Colchicine • Rationale: MOA unclear but may include • Rationale: antineutrophilic effects increased adenosine levels, apoptosis in activated CD4 T cells, and decreased • Efficacy: Case series and negative RCT neutrophil chemotaxis (Pho 2011; Lawlor 1989) • Efficacy: anecdotal success in my patients; case series and negative RCTs • (Perez 2009; Sharma 2014; Leducq 2020) SEs: dose-related GI distress and diarrhea • SEs: potential for GI sx, stomatitis, h/a, fatigue, hematologic abnormalities; • Tips: rarely, hepatoxicity, pulmonary toxicity, – Rarely helpful in my patients, limited and myelosuppression evidence • Tips: – Infrequent lab monitoring – Consider when co-morbid autoimmune disease – Takes at least 1-2 months to work – Need frequent lab monitoring Cyclosporine

• Rationale: Inhibits calcineurin and suppresses function; inhibits IgE-induced release from and MCs

• Efficacy: 2 dbRCTs, numerous observational and prospective studies (Grattan 2000, Vena 2006)

• SEs: Nephrotoxicity, hypertension, infection, (malignancy at higher doses), hirsutism, h/a, paresthesia, n/v, abdominal pain

• Tips: – Use for more rapid control, but will transition over to alternative agents after 6 months – Requires frequent monitoring of BP and q4-8 week labs including CSA levels, BUN/Cr, Magnesium Immunosuppressants

Tacrolimus Mycophenolate • Rationale: Calcineurin inhibitor, • Rationale: Inhibits inosine-50- inhibits IgE-mediated MC and monophosphate dehydrogenase, degranulation depletes activated lymphocytes

• Efficacy: No RCTs, 1 retrospective • Efficacy: Case series and open label study (Kessel, 2005) study (Zimmerman 2012, Shahar 2006)

• SEs: nephrotoxicity, infection, • SEs: GI distress and diarrhea, infection, malignancy, h/a, GI upset h/a

• Tips: •Tips: – Requires frequent BP and –Useful in my patients, but limited laboratory monitoring (renal evidence function, hepatic function, –Frequent lab monitoring (q2-3 electrolytes, glucose) months) Biologics

Kolkhir P, et al. Ann Allergy Immunol. 2020 Jan;124(1):2-12.

• Rationale: Monoclonal directed against IgE

• Efficacy: Multiple RCTs demonstrating efficacy (Maurer 2013; Saini 2015; Kaplan 2013; Maurer 2018)

• SEs: well-tolerated overall, but h/a, nasopharyngitis, arthralgia, viral URI, nausea, sinusitis, and cough

• Tips: – Generally safe and well-tolerated, but expensive – Requires in-office administration with 25 min monitoring afterwards, epi-pen • N = 323 • Omalizumab q4weeks at 75 mg, 150 mg, and 300 mg doses (x3) or placebo • 16 week observation period • Both the 150 mg and the 300 mg groups showed significant improvement in itch and hive scores compared with placebo • Complete resolution 44% at 300 mg and 22% at 150 mg • No long-term effect in remission

Maurer M et al., N Engl J Med 2013; 368:924-935 • Open label phase: omalizumab q4weeks at 300 mg (x6) • N = 205

• Subsequent 24 week double blinded phase with investigator-assessed clinical worsening → transitioned to open label omalizumab treatment and continued through week 48 • N = 134 • CIU relapse: 60% placebo vs 21% omalizumab • DLQI worsening: 66% placebo vs 20% omalizumab

Maurer M, et al, JACI. 2018 Mar;141(3):1138-1139.e7 Alternatives

• Limited to case reports or small case series ▪ TNF inhibitors (etanercept, , ) ▪ B cell targeted therapies (rituximab) ▪ Anti-IL-1 therapies (anakinra) ▪ IVIG (has case reports and small OLS) ▪ Many immunomodulatory activities including modulation of adhesion, complement function, cytokine levels, and autoantibodies ▪ Limited known efficacy, but generally well-tolerated ▪ In phase III trials ▪ Ligelizumab ▪ Ph IIb trial Ligelizumab with placebo and omalizumab comparators ▪ Complete clearance: 51% ligelizumab 72 mg SC q4 weeks vs 26% omalizumab 300 mg q4 weeks vs 0% placebo

Maurer M. et al., N Engl J Med. 2019 Oct 3;381(14):1321-1332. Treatment Considerations

• Combination therapy may be required

• Optimal duration of therapy is unknown

• Treat until patient has achieved 3-6 symptom-free months

• Then, attempt to taper with clinical monitoring for CU recurrence • Taper anti-inflammatory and immunosuppressive agents every 3-6 weeks • Taper omalizumab frequency to q6-8 weeks or as tolerated Agent Typical Dose Improvement Efficacy Risk Labs Cost

LTRA 10 mg QD 2-4 wk Low Minimal None $$ (B) HCQ 200 mg BID Up to 12 wk Moderate Low Baseline: LFT, BUN/Cr $ (C) Dapsone 100 mg QD with 1-6 wk Moderate Low-moderate Baseline: G6PD, CBC, LFT $ reduction as tolerated (C) Monthly: CBC, LFT x6 mo., then periodically SSZ 500 mg BID with <4 wk Moderate Low Baseline: CBC, LFT, BUN/Cr $ increase to 1 g BID (C) Monthly: CBC, LFT, BUN/Cr x3 mo., then q3mo. MTX 10-15 mg weekly 1-6 mo Moderate Moderate-high Baseline: CBC, LFT, BUN/Cr, CXR $ (X) Every 2-4wk: CBC, LFT, BUN/Cr Colchicine 0.6 mg BID Unclear Low- Low Baseline: LFT, BUN/Cr $$$ moderate (C) CSA (LD) 1-2 mg/kg/d <4 wk Moderate- Low-moderate Baseline: CBC, LFT, BUN/Cr, K, Lipids $$$ high (C) CSA (HD) 3-5 mg/kg/d 1-7 d High Moderate-high Every 2-4 wk: BUN/Cr, K, CSA $$$ (C) Periodic: Lipids, Glucose 1 mg BID, increasing PRN 1-2 wk High Moderate-high SAA except checking tacrolimus levels $$$ to 2-3 mg BID (C) MMF 1000 mg BID, increasing 1-9 wk Moderate Moderate-high Baseline: CBC, LFT, BUNM/Cr; Weekly CBC $$$ PRN to 4-6 g/d (D) x1 mo, then every 2 wk x2-3 mo., then monthly XOLAIR 150-300 mg q4weeks 1-2 wk High Low-moderate None $$$$ (B) IVIG 150-400 mg/kg q4weeks HD: 2 wk Moderate Low-moderate Baseline: BUN/Cr, CBC $$$$ or daily x5d LD: 4-5 mo. (C) Periodic monitoring of BUN/Cr, CBC A nasty case of hives

Thank you!