Anti-IgE: Beyond Asthma Anti-IgE: Beyond Asthma

Michael S. Blaiss, MDMichael S. Blaiss, MDClinical Professor of Pediatrics and MedicineClinical Professor of Pediatrics and Medicine

University of Tennessee Health Science Center University of Tennessee Health Science Center Memphis, TennesseeMemphis, Tennessee

IntroductionIntroductionOmalizumab (Xolair®) anti-IgE is approved Omalizumab (Xolair®) anti-IgE is approved throughout the world for the treatment of throughout the world for the treatment of allergic asthmaallergic asthma

Obviously, IgE is involved in the pathogenesis Obviously, IgE is involved in the pathogenesis of many other atopic conditions beyond of many other atopic conditions beyond asthmaasthma

Purpose: Review studies looking at Purpose: Review studies looking at omalizumab treatment in other disordersomalizumab treatment in other disorders

Omalizumab-Other Omalizumab-Other ConditionsConditions

Allergic rhinitisAllergic rhinitis

ImmunotherapyImmunotherapy

Drug allergy Drug allergy

Insulin allergy Insulin allergy

Idiopathic anaphylaxisIdiopathic anaphylaxis

Eosinophilic Eosinophilic gastrointestinal gastrointestinal diseasesdiseases

ABPA ABPA

Mastocytosis Indolent Mastocytosis Indolent and systemic and systemic

Nasal Nasal polyposis/sinusitis polyposis/sinusitis

Latex allergy Latex allergy

Chronic Chronic urticaria/angioedema urticaria/angioedema Idiopathic, Idiopathic, autoimmune, autoimmune, cholinergic, cold cholinergic, cold inducedinduced

Atopic dermatitis Atopic dermatitis

UrticariaUrticaria

Courtesy of David Khan, MD

Epidemiology of UrticariaEpidemiology of UrticariaOverall limited data, particularly in USOverall limited data, particularly in US

Acute urticariaAcute urticaria

20% in 1969 (Champion et al, England)20% in 1969 (Champion et al, England)11

19% in 2004 (Gaig et al, Spain)19% in 2004 (Gaig et al, Spain)22

Chronic urticariaChronic urticaria22

147 of 5003 (2.9%) patients reported a history of CU147 of 5003 (2.9%) patients reported a history of CU

0.6% prevalence (active disease)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 UrticariaAutoimmune Theory of Chronic Urticaria

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.

1983 1986 1988 1991 1993

An association of CIU with thyroid autoimmunity2

+ ASST (Autologous serum skin test) in 7/12 CIU subjects3

IgG anti-IgE in CIU with ELISA4

Histamine releasing activity (HRA) in CIU sera with anti-IgE properties5

Functional IgG anti-FcεRlα antibodies in CIU subjects6

History of Autoimmunity in CIU1

Stepwise Approach Stepwise Approach to Chronic Urticaria Therapyto Chronic Urticaria Therapy

Step 1 Second-generation antihistamine

Step 2 Higher-dose second-generation antihistamine

Step 3Second-generation antihistamine + first-generation antihistamine (hydroxyzine or doxepin taken at bedtime up to 150 mg qhs)

Step 4 Antihistamines + leukotriene-receptor antagonist

Step 5Anti-inflammatory alternative therapy (eg, dapsone, sulfasalazine, hydroxychloroquine)

Step 6Immunosuppressant alternative therapy (eg, tacrolimus, cyclosporine, mycophenolate)

Step 7 Biologic therapy (eg, omalizumab)

Step 8Other alternative therapies (eg, phototherapy, anticoagulants)

Chronic Autoimmune Chronic Autoimmune Urticaria and OmalizumabUrticaria and Omalizumab

Rationale for omalizumab Rationale for omalizumab in CAUin CAU

Omalizumab is a recombinant humanized mAb that Omalizumab is a recombinant humanized mAb that selectively binds to IgEselectively binds to IgE

It inhibits the binding of IgE to the high affinity IgE receptor It inhibits the binding of IgE to the high affinity IgE receptor (FceRI) on the surface of mast cells and basophils (FceRI) on the surface of mast cells and basophils It reduces the number of FceRI receptors on basophilsIt reduces the number of FceRI receptors on basophilsIt reduces free IgE in the serumIt reduces free IgE in the serumMay block the initial antigen presentation May block the initial antigen presentation Reduces the additional production of IgEReduces the additional production of IgEReduces the numbers of inflammatory cells such as eosinophils, Reduces the numbers of inflammatory cells such as eosinophils, B lymphocytes, and T-helper and T cytotoxic lymphocytesB lymphocytes, and T-helper and T cytotoxic lymphocytes

J Allergy Clin Immunol 2008;122:569-73

MethodsMethodsTwelve patients with CAU, identified by Twelve patients with CAU, identified by basophil histamine release assay and basophil histamine release assay and autologous skin test, with persistent symptoms autologous skin test, with persistent symptoms for at least 6 weeks despite antihistaminesfor at least 6 weeks despite antihistamines

Treated with placebo for 4 weeks followed by Treated with placebo for 4 weeks followed by omalizumab (≥0.016mg/kg/IU mL-1 IgE per omalizumab (≥0.016mg/kg/IU mL-1 IgE per month) every 2 or 4 weeks for month) every 2 or 4 weeks for 16 weeks16 weeks

Urticaria Activity Score (Pruritus severity, Interference with sleep, interference with daily activity)

What happens after What happens after omalizumab therapy was omalizumab therapy was

stopped?stopped?Kaplan et al investigated the post-treatment Kaplan et al investigated the post-treatment clinical course over the 2 years following clinical course over the 2 years following discontinuation of omalizumab (4 month trial)discontinuation of omalizumab (4 month trial)

Of the 7 complete responders, 5 had no Of the 7 complete responders, 5 had no recurrence, one experienced a mild exacerbation recurrence, one experienced a mild exacerbation 6 months later that spontaneously resolved, and 6 months later that spontaneously resolved, and one experienced intermittent urticaria treated one experienced intermittent urticaria treated with as-needed hydroxyzine.with as-needed hydroxyzine.

What happens after omalizumab What happens after omalizumab therapy was stopped? therapy was stopped? (cont)(cont)

Of the 4 patients with a partial response:Of the 4 patients with a partial response:

One had mild urticaria for 6 months which then One had mild urticaria for 6 months which then worsened requiring prednisone and diphenhydramine worsened requiring prednisone and diphenhydramine for 1 year and is now treated with cetirizinefor 1 year and is now treated with cetirizine

Two have had continuous mild urticaria for 2 years Two have had continuous mild urticaria for 2 years treated with cetirizine, and hydroxyzine respectivelytreated with cetirizine, and hydroxyzine respectively

One worsened immediately after omalizumab was One worsened immediately after omalizumab was stoppedstopped

Required cyclosporine therapy for 1 1/2 years and is now Required cyclosporine therapy for 1 1/2 years and is now treated with cetirizinetreated with cetirizine

MAINTENANCE OF REMISSION WITH LOW-DOSEMAINTENANCE OF REMISSION WITH LOW-DOSEOMALIZUMAB IN LONG-LASTING, REFRACTORYOMALIZUMAB IN LONG-LASTING, REFRACTORY

CHRONIC URTICARIACHRONIC URTICARIA

Italian report in Annals of Allergy, Italian report in Annals of Allergy, Asthma, and Immunology in January Asthma, and Immunology in January 20102010

Two patients with refractory CU and Two patients with refractory CU and highly atopic respond to omalizumab highly atopic respond to omalizumab and able to decrease dose to every 28 and able to decrease dose to every 28 days without relapsedays without relapse

Quick remission in both patients in 72 Quick remission in both patients in 72 hourshours

JACI 2011

StudyStudyIn this multicenter, randomized, double-blind, In this multicenter, randomized, double-blind, placebo-controlled study patients with CU placebo-controlled study patients with CU (male/female, 18-70 years of age) with IgE (male/female, 18-70 years of age) with IgE autoantibodies against TPO who had persistent autoantibodies against TPO who had persistent symptoms (wheals and pruritus) despite standard symptoms (wheals and pruritus) despite standard antihistamine therapyantihistamine therapy

Randomized to receive either omalizumab (75-375 Randomized to receive either omalizumab (75-375 mg, dose determined by using the approved mg, dose determined by using the approved asthma dosing table) or placebo subcutaneously asthma dosing table) or placebo subcutaneously once every 2 or 4 weeks for 24 weeksonce every 2 or 4 weeks for 24 weeks

Other Types of UrticariaOther Types of Urticaria

At least 2 cases in solar urticaria (Waibel At least 2 cases in solar urticaria (Waibel et al. JACI 2010)et al. JACI 2010)

Cold-induced urticaria (Boyce JACI 2006)Cold-induced urticaria (Boyce JACI 2006)

Cholinergic urticaria (Otto et al. Allergy Cholinergic urticaria (Otto et al. Allergy Asthma Proc 2009)Asthma Proc 2009)

JACI 2011

MethodsMethodsPhase IIa prospective, DB, placebo Phase IIa prospective, DB, placebo controlled dose ranging study in controlled dose ranging study in patients with chronic urticaria not patients with chronic urticaria not responsive to antihistamines using responsive to antihistamines using single dose of omalizumabsingle dose of omalizumab

75mg, 300 mg, and 600 mg omalizumab75mg, 300 mg, and 600 mg omalizumab

Change in UAS from baseline to 4 weeksChange in UAS from baseline to 4 weeks

Atopic Dermatitis and Atopic Dermatitis and OmalizumabOmalizumab

Atopic DermatitisAtopic DermatitisAD involves many different components of the AD involves many different components of the immune systemimmune system

In the acute phase, there is emphasis of a Th2 In the acute phase, there is emphasis of a Th2 immune response leading to the production of IL-4 immune response leading to the production of IL-4 and IL-13 (triggering production of IgE by B and IL-13 (triggering production of IgE by B lymphocytes), IL-5 (important for recruitment and lymphocytes), IL-5 (important for recruitment and activation of eosinophils), and IL-6. activation of eosinophils), and IL-6. Chronic AD is characterized by a switch from Th2 Chronic AD is characterized by a switch from Th2 cells to Th1 cells with the subsequent up-regulation cells to Th1 cells with the subsequent up-regulation of interferon (IFN) and IL-5of interferon (IFN) and IL-5

Atopic DermatitisAtopic DermatitisVarious antigen-presenting cells are also Various antigen-presenting cells are also involved in this immunologic processinvolved in this immunologic process

Langerhans cells, dendritic cells, and macrophagesLangerhans cells, dendritic cells, and macrophagesLangerhans cells are increased in number in chronic Langerhans cells are increased in number in chronic AD lesions, express FcRII and FcRI (high affinity) IgE AD lesions, express FcRII and FcRI (high affinity) IgE receptors, and have been found to be carrying IgE receptors, and have been found to be carrying IgE antibodiesantibodiesDermal dendritic cells and inflammatory dendritic Dermal dendritic cells and inflammatory dendritic epidermal cells also have an affinity to anti-FcRI epidermal cells also have an affinity to anti-FcRI receptorsreceptors

StudiesStudiesIn one study by Krathen and Hsu, three patients In one study by Krathen and Hsu, three patients with chronic severe lichenified AD and other with chronic severe lichenified AD and other atopic comorbidities who were followed for 4 atopic comorbidities who were followed for 4 months on 450 mg of omalizumab dosed every months on 450 mg of omalizumab dosed every 2 weeks had no improvement at 4 months2 weeks had no improvement at 4 months

It was noted that these patient’s pretreatment It was noted that these patient’s pretreatment serum IgE levels ranged from 5440 to 24,000 serum IgE levels ranged from 5440 to 24,000 IU/mL. IU/mL.

Krathen RA, and Hsu S. Failure of omalizumab for treatment ofsevere adult atopic dermatitis. J Am Acad Dermatol 53:338 –340,2005.

StudiesStudiesThree nonasthmatic patients aged 10–13 years Three nonasthmatic patients aged 10–13 years old, presented by Lane old, presented by Lane et alet al

Their pretreatment serum IgE levels ranged Their pretreatment serum IgE levels ranged from 1990 to 6120 IU/mL. from 1990 to 6120 IU/mL.

This study showed clinical improvement in This study showed clinical improvement in severity of AD with dosing of omalizumab as severity of AD with dosing of omalizumab as high as 450 mg given every 2 weeks over a 22-high as 450 mg given every 2 weeks over a 22-week periodweek period

Lane JE, Cheyney PA, Lane TN, et al. Treatment of recalcitrantatopic dermatitis with omalizumab. J Am Acad Dermatol 54:68–72, 2006

StudyStudy

The primary objective of this study was The primary objective of this study was to examine the efficacy of omalizumab to examine the efficacy of omalizumab for the treatment of AD in 21 patients for the treatment of AD in 21 patients aged 14–64 years with IgE levels ranging aged 14–64 years with IgE levels ranging from 18 to 8396 IU/mL, with the majority from 18 to 8396 IU/mL, with the majority of patients having food allergy as the of patients having food allergy as the trigger for their ADtrigger for their AD

ResultsResultsAlthough improvement was noted in all Although improvement was noted in all three subgroups, a more profound three subgroups, a more profound improvement in SCORAD scores was noted improvement in SCORAD scores was noted in those patients with lower pretreatment in those patients with lower pretreatment serum IgE levels compared with those serum IgE levels compared with those patients with high or very high IgE levelspatients with high or very high IgE levels

Clinical improvement seen as early as one Clinical improvement seen as early as one monthmonth

ConclusionsConclusionsOmalizumab has demonstrated efficacy for Omalizumab has demonstrated efficacy for allergic asthma and rhinitisallergic asthma and rhinitis

Data continues to accumulate of it’s benefit Data continues to accumulate of it’s benefit in two common skin conditions-chronic in two common skin conditions-chronic autoimmune urticaria and atopic dermatitisautoimmune urticaria and atopic dermatitis

Though definitely not a first-line treatment Though definitely not a first-line treatment in either condition, it gives another option in either condition, it gives another option in patients when these disorders are in patients when these disorders are recalcitrant to other medicationsrecalcitrant to other medications