The Leukotriene Antagonist Zafirlukast As a Therapeutic Agent for Atopic Dermatitis

THE CUTTING EDGE

SECTION EDITOR: GEORGE J. HRUZA, MD; ASSISTANT SECTION EDITORS: LYNN A. CORNELIUS, MD; JOHN STARR, MD The Leukotriene Antagonist Zafirlukast as a Therapeutic Agent for Atopic Dermatitis

John A. Carucci, MD, PhD; Kenneth Washenik, MD, PhD; Alan Weinstein, MD; Jerome Shupack, MD; David E. Cohen, MD, MPH; New York University Medical Center, New York, NY

The Cutting Edge: Challenges in Medical and Surgical Therapeutics

REPORT OF CASES CASE 4

CASE 1 A 47-year-old man presented with a history of atopic dermatitis that had been treated with numerous courses A 42-year-old man presented with a 10-year history of of prednisone during the 7 years prior to his visit to our atopic dermatitis that was refractory to treatment with department. During this period, his prednisone dosage UV light, oral antihistamines, and high-potency topical varied between 10 and 40 mg/d. His dermatitis was corticosteroids. On presentation, he denied any other uncontrollable without prednisone during that time. He medical problems and was taking no medicines. His con- had no other medical problems and was taking no other dition improved with the use of cyclosporine; however, medicines. Topical therapy consisted of 0.1% triam- this regimen was discontinued secondary to transami- cinolone acetonide ointment and 0.2% zinc pyrithione nitis due to hepatitis C infection, which was treated with applied twice daily. On physical examination, he had an interferon alfa. His atopic dermatitis flared after discon- eczematous dermatitis involving 25% of his body sur- tinuation of cyclosporine therapy. A physical examina- face area. tion showed erythroderma involving more than 70% of his body surface area approximately 2 weeks after cyclosporine therapy was discontinued. THERAPEUTIC CHALLENGE

CASE 2 Our goal was to alleviate symptoms in patients with atopic dermatitis refractory to other therapeutic modalities or A 61-year-old man presented with a lifelong history of in patients in whom the immunosuppressive effects of atopic dermatitis. His condition did not improve with the prednisone or cyclosporine contraindicated the use of use of high-potency topical corticosteroids and UV-B pho- those agents. totherapy. He had no other medical problems and was taking no medicines. On physical examination he had an erythematous dermatitis with scale involving 25% of his SOLUTION body surface area. Each patient began treatment with zafirlukast, 20 mg orally CASE 3 twice per day. Within 2 days, the erythroderma of patient 1 subsided and his atopic dermatitis is now limited A 41-year-old woman presented with a 10-year history to scattered erythematous patches involving less than 15% of atopic dermatitis and urticaria. Other medical prob- of his body surface area while continuing zafirlukast lems included asthma, for which she was using a therapy. In patient 2, the dermatitis subsided within 2 ␤-adrenergic inhaler. On physical examination, she weeks and his skin remains markedly improved 6 weeks had erythematous patches on her chest and back. Her after therapy was begun. In patient 3, no eczematous atopic dermatitis was initially controlled with the use patches remained after 2 weeks of therapy. The patient of 0.1% triamcinolone acetonide ointment applied was able to discontinue treatment with antihistamines twice daily. The dermatitis recurred despite topical and topical corticosteroids. In patient 4, the prednisone therapy and oral antihistamines, including terfena- dosage was reduced to 5 mg/d and his atopic dermatitis dine, loratadine, hydroxyzine hydrochloride, and ceti- subsided to several patches involving less than 5% of his rizine hydrochloride, and the patient’s respiratory body surface area within 2 weeks of starting treatment symptoms eventually worsened. with zafirlukast.

ARCH DERMATOL / VOL 134, JULY 1998 785

©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 COMMENT It appears that zafirlukast alleviated the symptoms of atopic dermatitis in the patients described herein. More We report 4 cases, the first thus published, in which the extensive and controlled studies of zafirlukast in indi- cysteinyl leukotriene (LT) inhibitor zafirlukast success- viduals with atopic dermatitis as well as other inflam- fully alleviated symptoms of atopic dermatitis. Za- matory skin disorders will be necessary to evaluate the firlukast is currently available in the United States as Ac- potential role of LT antagonists as therapeutic agents for colate (Zeneca Pharmaceuticals, Wilmington, Del) and cutaneous disease. is indicated in the treatment of mild to moderate asthma.1 Atopic dermatitis may be defined as a chronically REFERENCES relapsing, eczematous disorder associated with a history of asthma, a family history of atopic disease, or el- 1. Kelloway JS. Zafirlukast: the first leukotriene-receptor antagonist approved for 2 evated serum levels of IgE. While the pathogenesis of the treatment of asthma. Ann Pharmacother. 1997;31:1012-1021. atopic dermatitis is not completely understood, increas- 2. Brehler R, Hildebrand A, Luger TA. Recent developments in the treatment of atopic ing evidence supports the potential role of soluble me- eczema. J Am Acad Dermatol. 1997;36:983-994. 3,4 3. Sansom JE, Taylor GW, Dollery CT, Archer CB. Urinary leukotriene E4 levels in diators, including LTs. Leukotriene antagonists have patients with atopic dermatitis. Br J Dermatol. 1997;136:790-791. been used successfully in the treatment of asthma and 4. Ruzica T, Ring J. Enhanced releasability of prostaglandin E2 and leukotrienes allergic rhinitis.5-7 However, the potential therapeutic ben- B4 and C4 from leukocytes of patients with atopic eczema. Acta Derm Venereol. efit of these agents in inflammatory disorders of the skin 1987;67:469-475. is yet to be determined. 5. Fish JE, Kemp JP, Lockey RF, Glass M, Hanby LA, Bonucelli CM. Zafirlukast for symptomatic mild-to-moderate asthma: a 13-week multicenter study. Clin Ther. The LTs are metabolites of the arachidonic acid path- 1997;19:675-690. 8 way. Arachidonic acid, 1 of the 3 essential fatty acids, is 6. Donnelly AL, Glass M, Minkwitz MC, Casale TB. The leukotriene D4-receptor an- released from membrane phospholipids through the ac- tagonist, ICI 204,219, relieves symptoms of acute seasonal allergic rhinitis. Am J Respir Crit Care Med. 1995;151:1734-1739. tivation of phospholipase A2. Arachidonic acid metabo- 7. Spector SL, Smith LJ, Glass M. Effects of 6 weeks of therapy with oral doses of lism proceeds via 2 major pathways. The cyclooxygen- ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial ase pathway leads to synthesis of prostaglandins and asthma. Am J Respir Crit Care Med. 1994;150:618-623. thromboxane while the 5-lipoxygenase pathway leads to 8. Needleman P, Turk J, Jakschik BA, Morrison AR, Lefkowith JB. Arachidonic acid synthesis of the LTs. Leukotriene synthesis begins metabolism. Annu Rev Biochem. 1986;55:69-102. with the translocation of activated 5-lipoxygenase to 9. O’Byrne PM. Leukotrienes in the pathogenesis of asthma. Chest. 1997;111: 27S-34S. the cell membrane where it forms a complex with 5- 10. Bernstein JA, Greenberger PA, Patterson R, Glass M, Krell R, Thyrum PT. The lipoxygenase activating protein. This complex catalyzes effect of the oral leukotriene antagonist, ICI 204,219, on leukotriene D4 and his- the metabolism of arachidonic acid to 5-hydroperoxy- tamine-induced cutaneous vascular reactions in man. J Allergy Clin Immunol. eicoatetraenoic acid and subsequently to LTA4 , which 1991;87:93-98. 11. Spector SL. Management of asthma with zafirlukast: clinical experience and tol- may be converted to LTB4, or may be conjugated with erability profile. Drugs. 1996;52(suppl 6):36-46. glutathione to form LTC4 and subsequently LTD4 and LTE4. Submissions Leukotrienes mediate chemotaxis, airway constric- tion, smooth muscle contraction, and vascular permeability.9 Zafirlukast has been shown to inhibit LTD4 and Clinicians, local and regional societies, residents, and fel- histamine-mediated cutaneous vascular permeability.10 lows are invited to submit cases of challenges in man- This function indicates a potential role for zafirlukast in agement and therapeutics to this section. Cases should a number of inflammatory skin disorders. follow the established pattern. Submit 4 double-spaced copies of the manuscript with right margins nonjusti- Zafirlukast appeared to be well tolerated in previ- 11 fied and 4 sets of the illustrations. Photomicrographs and ous clinical trials for asthma. The most commonly oc- illustrations must be clear and submitted as positive color curring adverse effects included pharyngitis and head- transparencies (35-mm slides) or black-and-white prints. ache. In addition, zafirlukast has been infrequently Do not submit color prints unless accompanied by origi- associated with elevations in alanine aminotransferase val- nal transparencies. Material should be accompanied by ues, which resolved with the discontinuation of the drug. the required copyright transfer statement, as noted in “In- It is likely that zafirlukast inhibits the cytochrome P-450 structions for Authors.” Material for this section should system and has been associated with increased pro- be submitted to George J. Hruza, MD, Cutaneous Sur- thrombin time values in patients concomitantly treated gery Center, Suite 16411, 1 Barnes Hospital Plaza, St with warfarin. No adverse effects were experienced by Louis, MO 63110. Reprints are not available. our patients.

ARCH DERMATOL / VOL 134, JULY 1998 786