key: cord-0747120-8pqbstrr
authors: Goodman, Brian; Jariwala, Sunit
title: Dupilumab As a Novel Therapy To Treat Adrenergic Urticaria
date: 2020-07-01
journal: Ann Allergy Asthma Immunol
DOI: 10.1016/j.anai.2020.06.034
sha: 4dbe154dd008f31dac0b23217ef647937a7901b0
doc_id: 747120
cord_uid: 8pqbstrr

nan

intermittent outbreaks of stress-induced diffuse pruritic urticarial papules. First described in 2 1985 1 , there has been growing literature further elucidating the mechanism of the disease as well 3 as novel therapeutic options. A frequently occurring challenge in the diagnosis of AU is 4 differentiating it from the more common cholinergic urticaria (CU). While in AU the papules are 5 surrounded by halos of hypopigmented and vasoconstricted skin, in CU the small papules are 6 surrounded by large red flares 2 . Furthermore, the triggers for AU include trauma, emotional 7 upset, coffee, chocolate, and ginger while triggers for cholinergic urticaria are stress, exercise, 8 and diaphoresis 3 . 9

A proposed mechanism of AU is a sympathetic hyperactivity response resulting in both 10 epinephrine and norepinephrine release. The epinephrine causes vasoconstriction appearing as 11 the halo portion of the AU lesion with the norepinephrine release causes cutaneous mast cell 12 degranulation resulting in erythema, vasodilation, and edema appearing as the erythematous 13 center of the AU lesion 3 . Interestingly, AU is associated with postural orthostatic tachycardia 14 syndrome (POTS), in which there is also hyperactivity of the sympathetic nervous system 4 

Diagnosis of AU can be made by using an intradermal injection of adrenaline or 16 noradrenaline 5 , which induces the rash, or clinically by response to propanolol, which suppresses 17 the rash and reduces further exacerbations. While the rash of AU is usually improved with 18 trigger avoidance, propranolol, and antihistamines, there are few other documented treatments. 19

Such other treatments include case reports showing improvement with oral clotiazepam and 20 omalizumab injections 6, 7 . Here we present the first known case of AU responding to dupilumab was triggered by heat, stress, and exercise. Labwork was significant for elevated serum IgE to 24 134 IU/mL and both tryptase and urine 5-Hydroxyindoleacetic acid (5-HIAA) were within 25 normal limits. Skin biopsy of the papules was nondiagnostic and showed lymphohistiocytic 26 infiltrate associated with eccrine ducts in the dermis. The patient was initially treated for 27 presumed cholinergic urticaria yet he was non-responsive to high dose second-generation H1-28 antihistamines, H2-antihistamines, montelukast, dapsone, and omalizumab monthly injections. 29

Diagnosis was reconsidered given his poor response to treatment and he was subsequently 30 diagnosed with AU given the appearance of his rash and diagnosis of POTS. A potential 31 weakness to the paper is that the patient did not receive an intradermal injection of adrenaline or 32 noradrenaline for definitive diagnosis. Additionally, the patient does not fit the typical picture of 33 AU, as his triggers were more consistent with CU. However, his association with POTS and the 34 appearance of the rash make AU a more likely diagnosis. After failing several treatments and 35

given the severity of his symptoms, the patient was started on dupilumab monthly injections and 36 within 2 weeks his rash completely resolved. The patient originally had great control of his 37 symptoms with monthly dupilumab, propranolol 20mg twice daily, and an antihistamine. Diagnosis of AU can be made by using an intradermal injection of adrenaline or 16 noradrenaline 5 , which induces the rash, or clinically by response to propanolol, which suppresses 17 the rash and reduces further exacerbations. While the rash of AU is usually improved with 18 trigger avoidance, propranolol, and antihistamines, there are few other documented treatments. 19

Such other treatments include case reports showing improvement with oral clotiazepam and 20 omalizumab injections 6, 7 . Here we present the first known case of AU responding to dupilumab was triggered by heat, stress, and exercise. Labwork was significant for elevated serum IgE to 24 134 IU/mL and both tryptase and urine 5-Hydroxyindoleacetic acid (5-HIAA) were within 25 normal limits. Skin biopsy of the papules was nondiagnostic and showed lymphohistiocytic 26 infiltrate associated with eccrine ducts in the dermis. The patient was initially treated for 27 presumed cholinergic urticaria yet he was non-responsive to high dose second-generation H1-28 antihistamines, H2-antihistamines, montelukast, dapsone, and omalizumab monthly injections. 29

Diagnosis was reconsidered given his poor response to treatment and he was subsequently 30 diagnosed with AU given the appearance of his rash and diagnosis of POTS. A potential 31 weakness to the paper is that the patient did not receive an intradermal injection of adrenaline or 32 noradrenaline for definitive diagnosis. Additionally, the patient does not fit the typical picture of 33 AU, as his triggers were more consistent with CU. However, his association with POTS and the 34 appearance of the rash make AU a more likely diagnosis. After failing several treatments and 35

given the severity of his symptoms, the patient was started on dupilumab monthly injections and 36 within 2 weeks his rash completely resolved. The patient originally had great control of his 37 symptoms with monthly dupilumab, propranolol 20mg twice daily, and an antihistamine. 38

However, in the summer of 2019, the patient had a flare up of symptoms due to hot weather and 39 resuming classes so his propranolol was up-titrated to a maximum dose of 60 mg twice daily and 40 his symptoms completely resolved. During this period his POTS symptoms were not 41 exacerbated. Unfortunately, in the spring of 2020, his dupilumab injections were temporarily 42 paused due to the COVID-19 pandemic and his symptoms recurred. The patient is soon to be 43 restarted on therapy and once his symptoms resolve, the ultimate goal would be to space the dupilumab injections may be an adjuvant therapeutic option in AU. Dupilumab is a receptor 48

antagonist that binds to the alpha subunit of the IL-4 receptor and modulates signaling of both 49 the IL-4 and IL-13 pathway 8 . Therefore, a possible mechanism for dupilumab decreasing the 50 severity of the rash in AU is by preventing the progression of the IL-4 pathway, thus preventing 51 the increased expression of FceR1 on B cells, mast cells, and basophils. By decreasing the 52 production of FceR1, there is an overall reduction in their cross-linking by IgE on the mast cell's 53 surface, which decreases mast cell activation and histamine release. Although propranolol 54 partially controlled his symptoms, dupilumab was necessary for complete resolution.

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