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Transcript
Anti-IgE: Beyond Asthma Michael S. Blaiss, MD Clinical Professor of Pediatrics and Medicine University of Tennessee Health Science Center Memphis, Tennessee Introduction Omalizumab (Xolair®) anti-IgE is approved throughout the world for the treatment of allergic asthma Obviously, IgE is involved in the pathogenesis of many other atopic conditions beyond asthma Purpose: Review studies looking at omalizumab treatment in other disorders Omalizumab-Other Conditions Allergic rhinitis Immunotherapy Mastocytosis Indolent and systemic Drug allergy Nasal polyposis/sinusitis Insulin allergy Latex allergy Idiopathic anaphylaxis Chronic urticaria/angioedema Idiopathic, autoimmune, cholinergic, cold induced Eosinophilic gastrointestinal diseases ABPA Atopic dermatitis Urticaria Courtesy of David Khan, MD Epidemiology of Urticaria Overall limited data, particularly in US Acute urticaria 20% in 1969 (Champion et al, England)1 19% in 2004 (Gaig et al, Spain)2 Chronic urticaria2 147 of 5003 (2.9%) patients reported a history of CU 0.6% prevalence (active disease) CU = chronic urticaria; GP = general practitioner. 1. Champion RH, et al. Br J Dermatol.1969;81:588-597. 2. Gaig P, et al. J Invest Allergol Clin Immunol. 2004;14:214-220. 3. Paul E, et al. Hautarzt. 1991;42:366-375. Autoimmune Theory of Chronic Urticaria 1983 History of Autoimmunity in CIU1 1986 1988 1991 1993 Functional IgG anti-FcεRlα antibodies in CIU subjects6 Histamine releasing activity (HRA) in CIU sera with anti-IgE properties5 IgG anti-IgE in CIU with ELISA4 + ASST (Autologous serum skin test) in 7/12 CIU subjects3 An association of CIU with thyroid autoimmunity2 1. Brodell LA, et al. Ann Allergy Asthma Immunol. 2008;100:291-297. 2. Leznoff A, et al. Arch Dermatol. 1983;119:636-640. 3. Grattan CE, et al. Br J Dermatol. 1986;114:583-590. 4. Gruber BL, et al. J Invest Dermatol. 1988;90:213-217. 5. Grattan CE, et al. Clin Exp Allergy. 1991;21:695-704. 6. Hide M, et al. N Engl J Med. 1993;328:1599-1604. Stepwise Approach to Chronic Urticaria Therapy Step 1 Second-generation antihistamine Step 2 Higher-dose second-generation antihistamine Step 3 Second-generation antihistamine + first-generation antihistamine (hydroxyzine or doxepin taken at bedtime up to 150 mg qhs) Step 4 Antihistamines + leukotriene-receptor antagonist Step 5 Anti-inflammatory alternative therapy (eg, dapsone, sulfasalazine, hydroxychloroquine) Step 6 Immunosuppressant alternative therapy (eg, tacrolimus, cyclosporine, mycophenolate) Step 7 Biologic therapy (eg, omalizumab) Step 8 Other alternative therapies (eg, phototherapy, anticoagulants) Chronic Autoimmune Urticaria and Omalizumab Rationale for omalizumab in CAU Omalizumab is a recombinant humanized mAb that selectively binds to IgE It inhibits the binding of IgE to the high affinity IgE receptor (FceRI) on the surface of mast cells and basophils It reduces the number of FceRI receptors on basophils It reduces free IgE in the serum May block the initial antigen presentation Reduces the additional production of IgE Reduces the numbers of inflammatory cells such as eosinophils, B lymphocytes, and T-helper and T cytotoxic lymphocytes J Allergy Clin Immunol 2008;122:569-73 Methods Twelve patients with CAU, identified by basophil histamine release assay and autologous skin test, with persistent symptoms for at least 6 weeks despite antihistamines Treated with placebo for 4 weeks followed by omalizumab (≥0.016mg/kg/IU mL-1 IgE per month) every 2 or 4 weeks for 16 weeks Urticaria Activity Score (Pruritus severity, Interference with sleep, interference with daily activity) What happens after omalizumab therapy was stopped? Kaplan et al investigated the post-treatment clinical course over the 2 years following discontinuation of omalizumab (4 month trial) Of the 7 complete responders, 5 had no recurrence, one experienced a mild exacerbation 6 months later that spontaneously resolved, and one experienced intermittent urticaria treated with as-needed hydroxyzine. What happens after omalizumab therapy was stopped? (cont) Of the 4 patients with a partial response: One had mild urticaria for 6 months which then worsened requiring prednisone and diphenhydramine for 1 year and is now treated with cetirizine Two have had continuous mild urticaria for 2 years treated with cetirizine, and hydroxyzine respectively One worsened immediately after omalizumab was stopped Required cyclosporine therapy for 1 1/2 years and is now treated with cetirizine MAINTENANCE OF REMISSION WITH LOW-DOSE OMALIZUMAB IN LONG-LASTING, REFRACTORY CHRONIC URTICARIA Italian report in Annals of Allergy, Asthma, and Immunology in January 2010 Two patients with refractory CU and highly atopic respond to omalizumab and able to decrease dose to every 28 days without relapse Quick remission in both patients in 72 hours JACI 2011 Study In this multicenter, randomized, double-blind, placebo-controlled study patients with CU (male/female, 18-70 years of age) with IgE autoantibodies against TPO who had persistent symptoms (wheals and pruritus) despite standard antihistamine therapy Randomized to receive either omalizumab (75-375 mg, dose determined by using the approved asthma dosing table) or placebo subcutaneously once every 2 or 4 weeks for 24 weeks Other Types of Urticaria At least 2 cases in solar urticaria (Waibel et al. JACI 2010) Cold-induced urticaria (Boyce JACI 2006) Cholinergic urticaria (Otto et al. Allergy Asthma Proc 2009) JACI 2011 Methods Phase IIa prospective, DB, placebo controlled dose ranging study in patients with chronic urticaria not responsive to antihistamines using single dose of omalizumab 75mg, 300 mg, and 600 mg omalizumab Change in UAS from baseline to 4 weeks Atopic Dermatitis and Omalizumab Atopic Dermatitis AD involves many different components of the immune system In the acute phase, there is emphasis of a Th2 immune response leading to the production of IL-4 and IL-13 (triggering production of IgE by B lymphocytes), IL-5 (important for recruitment and activation of eosinophils), and IL-6. Chronic AD is characterized by a switch from Th2 cells to Th1 cells with the subsequent up-regulation of interferon (IFN) and IL-5 Atopic Dermatitis Various antigen-presenting cells are also involved in this immunologic process Langerhans cells, dendritic cells, and macrophages Langerhans cells are increased in number in chronic AD lesions, express FcRII and FcRI (high affinity) IgE receptors, and have been found to be carrying IgE antibodies Dermal dendritic cells and inflammatory dendritic epidermal cells also have an affinity to anti-FcRI receptors Studies In one study by Krathen and Hsu, three patients with chronic severe lichenified AD and other atopic comorbidities who were followed for 4 months on 450 mg of omalizumab dosed every 2 weeks had no improvement at 4 months It was noted that these patient’s pretreatment serum IgE levels ranged from 5440 to 24,000 IU/mL. Krathen RA, and Hsu S. Failure of omalizumab for treatment of severe adult atopic dermatitis. J Am Acad Dermatol 53:338 –340, 2005. Studies Three nonasthmatic patients aged 10–13 years old, presented by Lane et al Their pretreatment serum IgE levels ranged from 1990 to 6120 IU/mL. This study showed clinical improvement in severity of AD with dosing of omalizumab as high as 450 mg given every 2 weeks over a 22week period Lane JE, Cheyney PA, Lane TN, et al. Treatment of recalcitrant atopic dermatitis with omalizumab. J Am Acad Dermatol 54: 68–72, 2006 Study The primary objective of this study was to examine the efficacy of omalizumab for the treatment of AD in 21 patients aged 14–64 years with IgE levels ranging from 18 to 8396 IU/mL, with the majority of patients having food allergy as the trigger for their AD Results Although improvement was noted in all three subgroups, a more profound improvement in SCORAD scores was noted in those patients with lower pretreatment serum IgE levels compared with those patients with high or very high IgE levels Clinical improvement seen as early as one month Conclusions Omalizumab has demonstrated efficacy for allergic asthma and rhinitis Data continues to accumulate of it’s benefit in two common skin conditions-chronic autoimmune urticaria and atopic dermatitis Though definitely not a first-line treatment in either condition, it gives another option in patients when these disorders are recalcitrant to other medications