Anti-Ige) and © 2020 Kathuria PC, Et Al

Case Report *Corresponding author Pooran Chand Kathuria, Department of Pulmonology, National Allergy Centre, 1/3 East Patel Nagar (Opp. Successful Treatment by Metro pillar number 181), New Delhi, 110008, India, Email: [email protected] Submitted: 12 October 2020 Combination Therapy of Accepted: 24 November 2020 Published: 25 November 2020 Copyright Omalizumab (Anti-IgE) and © 2020 Kathuria PC, et al. House Dust Mite Allergen ISSN: 2573-1254 OPEN ACCESS Immunotherapy for Severe Keywords • Atopic Dermatitis; SCORAD (Scoring Atopic Dermatitis); Dermatophagoides Pteronyssinus (DP); Dermatophagoides Farinae (DF); House Dust Mite Refractory Steroid-Dependent (HDM); Subcutaneous Allergen Immunotherapy (SCIT); Allergen Immunotherapy; Rhinitis Control Assessment Test (RCAT); Asthma Control Test Atopic Dermatitis with Rhinitis (ACT); DLQI (Dermatology Life Quality Index); Oral Corticosteroids (OCS); Peak Expiratory Flow Rate and Asthma - A Case Report- (PEFR) Follow Up for 5 Years Pooran Chand Kathuria* and Manisha Rai Department of Pulmonology, National Allergy Centre, India

Abstract

Chronic Atopic Dermatitis (AD) is characterized by genetic predisposition, skin barrier disruption and aberrant immune response to environmental allergens as well as innate immunity dysregulation. The complex interplay among barrier deficiency and immunological mechanism contributes to the development of progression and chronicity of this disease. Most of the patients with moderate to severe AD are unable to receive systemic therapy because of adverse events with currently available immunosuppressants. Systemic corticosteroids are frequently used for severe refractory atopic dermatitis and during exacerbations but many patients also develop adverse side effects.

We report a case of severe refractory steroid-dependent Atopic Dermatitis with Rhinitis and Asthma, early onset difficult to treat, symptoms only responded to oral corticosteroids (OCS). Our patient improved in response to combined therapy by House Dust Mite Subcutaneous Allergen Immunotherapy (HDM SCIT) and Anti-IgE (Omalizumab) for three years and further maintained disease control during follow-up for two years after cessation of therapy. The combined synergistic approach with (HDM SCIT and Omalizumab) resulted in improved Quality of Life and marked decrease in severity of the disease with reasonable safety profile.

ABBREVIATIONS differentiation genes and abnormal content of extracellular lipids, which results in increased permeation to allergens, AD: Atopic Dermatitis; SCORAD: Scoring Atopic Dermatitis; irritants and microbes [3]. Approximately 20% of patients Dp: Dermatophagoides pteronyssinus; Df: Dermatophagoides with AD have moderate to severe forms of the disease and is farina; HDM: House Dust Mite; SCIT: Subcutaneous Allergen associated with important immunological markers are elevated Immunotherapy; RCAT: Rhinitis Control Assessment Test; ACT: serum immunoglobulins E (IgE) levels, Thymic stromal lympho- Asthma Control Test; DLQI: Dermatology Life Quality Index; OCS: proteins (TSLP), Thymus and activation regulated chemokine Oral Corticosteroids; PEFR: Peak Expiratory Flow Rate (TARC) and OX40 ligand (OX40L) [4]. The European Academy of INTRODUCTION disease as a SCORAD severity score of greater than 40 or BSA Dermatology and Venereology Taskforce on AD defined severe disease that affects 20%-30% of children and 7% to 10% of adults involvement is more than 10% and associated with impairment [1,2].Atopic Skin barrier Dermatitis impairment (AD) is and a commonabnormal inflammatory immune response skin of the patient’s quality of life, such as with regard to sleep quality, are both critical in the pathogenesis of the disease. The defective emotional, mental health disturbance and interference with daily epidermal barrier is caused by altered expression of keratinocyte activities [5].

Cite this article: Kathuria PC, Rai M (2020) Successful Treatment by Combination Therapy of Omalizumab (Anti-IgE) and House Dust Mite Allergen Immu- notherapy for Severe Refractory Steroid-Dependent Atopic Dermatitis with Rhinitis and Asthma - A Case Report-Follow Up for 5 Years. JSM Allergy Asthma 4(1): 1026. Kathuria PC, et al. (2020)

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House dust mites (HDMs) belong to the most potent indoor In our experience with this case of severe refractory steroid- allergen sources worldwide and are associated with allergic dependent Atopic Dermatitis with Rhinitis and Asthma with manifestations in the respiratory tract and the skin. House dust allergen sensitization to house dust mites and high level of total mite allergens display protease activity and are able to disrupt intercellular junction and activate several innate immunity receptors. Few allergens from HDMs have been extensively IgE, has a significant improvement in SCORAD score (Scoring characterized regarding their IgE binding frequencies, allergenic AssessmentAtopic Dermatitis)- Test)-10/25 75/103 to 22/25, to 10/103, ACT (Asthma DLQI Control (Dermatology Test)- activities, clinical relevance in diagnosis of HDM allergy. Der p 11 Life Quality Index)-20/30 to 28/30, RCAT (Rhinitis Control is a major allergen for patients suffering from atopic dermatitis (AD), whereas it is only a minor allergen for patients suffering 11/25 to 23/25, PEFR (Peak Expiratory Flow Rate)-350 L/mt to two500 L/mts years after even combining after cessation HDM SCIT of combined and anti-IgE therapy (Omalizumab) by House immunotherapy containing Der p 11 has shown to be effective Dustfor 3 Miteyears Subcutaneousand maintained Allergen disease Immunotherapy control during follow-up (HDM SCIT) for forfrom the respiratorytreatment of formsAD (Novak of et HDM al.,2012) allergy. [6,7]. Allergen-specific

Atopic dermatitis is frequently associated with food allergen from Greer Laboratories, Inc and Anti-IgE (Omalizumab) from sensitization and food challenge proven IgE-mediated food NovartisCASE DISCUSSION Ltd. allergy is present in up to one-third of patients with moderate- to-severe atopic dermatitis. Food allergens such as milk, egg and We report the case of a 20 years old male who has been peanut have been related to AD exacerbations especially during suffering from severe refractory steroid-dependent Atopic childhood [8,9]. years, poorly responding to conventional treatment (topical Staphylococcus aureus colonizes frequently AD skin. (18) corticosteroids,Dermatitis with Rhinitis leukotriene and Asthma, inhibitors, onset at anti-histamines, the age of 4 polyclonal enterotoxins activate T-cells have ability to release courses of cyclosporin oral and OCS). He has had history of of huge amount of IgE and other Immunoglobulin isotypes. The staphylococcal enterotoxin B strongly promotes the secretion of perirregular month). intake Symptoms of OCS, exacerbate suspected on steroid-dependency, exposure to dust, ingestion 4-8mg also could contribute to autoimmune disorders [7]. ofmethylprednisolone alcohol, peanuts and alternate eggs. Ondays physical (64 mg examination methylprednisolone we used Th17/ Th22 cytokines and switch toward Th1 and Th 17 profile Omalizumab is a recombinant DNA-derived humanized

AssessmentSCORAD score Test)-10/25, (Scoring ACTAtopic (Asthma Dermatitis)- Control 75/103, Test)-11/25, DLQI IgG monoclonal antibody that specifically binds to free human (Dermatology Life Quality Index)-20/30, RCAT (Rhinitis Control withimmunoglobulin moderate to Esevere in the AD blood [10-12]. and interstitialThis molecule fluid. binds A number specially of case series describe a beneficial effect of omalizumab in patients objectivePEFR (Peak parameters. Expiratory Flow Rate)-350 L/mt to assess severity to the third constant domain of the heavy chain of the human of the disease and Quality of Life to measure subjective and In-vivo and In-vitro test: Table 1: Total IgE->15000 IU/ml, byIgE Fc in region. the Fc Theregion, use ofthus monoclonal competing anti-bodies, with IgE specific like conventional receptors were positive for D. pteronyssinus- 6mm, D. farinae -6mm, Immunotherapy(FCeRI and low affinity has not IgE been receptor associated CD 23), with that persistent also binds disease to IgE Absolute Eosinophil Count-400 cells/Ul, Skin Prick Test (SPT) modifying effects. Novel monoclonal antibodies have potential in combination with allergen to augment the effect of conventional Cockroach-4mm,Specific IgE were Egg- 6mm,positive peanut-4mm. for D. pteronyssinus- 62.2 Kua/l, Allergen Immunotherapy. When combined with immunotherapy D. farinae- 58.0 Kua/l, Cockroach-1.76 Kua/l IU/ml. it lessens immunotherapy-associated side-effects, increasing Recommendation tolerability. This allows patients to receive higher doses faster He was given combined therapy by House Dust Mite Subcutaneous Allergen Immunotherapy (HDM SCIT Greer Immunotherapy is given to higher risk patients with asthma [13]. with AD. The European Academy of Dermatology’s recent weeks) (Table 2) with effective dose [gradual up-dosing protocol There is conflicting evidence on the use of AIT for patients guideline agree with the Joint Task Force that although AIT ofLaboratories, build-up phase Inc) toand achieve Anti-IgE Maintenance (Omalizumab dose 150mg (MD) every- 500 3-4AU subset of highly sensitized patients with house dust mite, birch orshould grass not pollen be first-line sensitization treatment with for symptom all AD patients, exacerbation there thatis a per 4 weeks] with supportive therapy for 3 years. He achieved The most recent guidelines from the American usegradual of OCS improvement, (8 mg methylprednisolone SCORAD score-10/103, per month). DLQI-28/30, RCAT-22/25, ACT-23/25, PEFR-500L/mts along with occasional tomay recommend benefit [14]. AIT use, whereas the joint Task Force suggests DISCUSSION Academy of Dermatology suggests that there is insufficient data that clinicians can consider AIT use in select patients with Our case represents an extreme spectrum of severe refractory aeroallergens sensitivities [15]. Recommendations posed by steroid-dependent Atopic Dermatitis with Rhinitis and Asthma. Ridolo et al., revolve around three considerations: a) sensitization Our patient had history of taking cyclosporins 5mg/kg/day to aeroallergens must be proven with skin prick test and/or IgE physician must choose a standardized product for AIT [16]. alternatebut found days. no significant benefit even after 3 months of therapy assay, b) exposure to aeroallergens induces AD flare-ups, c) and only responded to OCS (4 to 8 mg methylprednisolone) on

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Table 1: Clinical characteristics of the patient. 2014 2019 SCORAD

DLQI 75/103 10/103 PEFR 20/30 28/30 10/11 RCAT/ACT scoring 350 L/mtBaseline 500 L/mt Total IgE 22/23 Eosinophil % / AEC >15000 IU/ML 9236 IU/ml Serum cortisol 5.8 % / 400 cells/ul 6.2% / 440 cells/ul Specific IgE 10.1 SPT mcg/dl wheal withsize 64 Specific mg/month IgE OCS 13.63 mcg/dl with 8 mg/month OCS SPT wheal size N/A N/A 5mm 5mm Histamine Dp 62.2 kua/l 9mm 5mm Df 38.4 kua/l Cockroach 58.0 kua/l 8mm 46.2 kua/l 1.76 kua/l 3mm 2mm 1.01 kua/l

SCORAD: Scoring Atopic Dermatitis, AEC: 4mmAbsolute Eosinophil Count, Dp: Dermatophagoides pteronyssinus, Df: Dermatophagoides farinae,

Expiratory Flow Rate RCAT: Rhinitis Control Assessment Test, ACT: Asthma Control Test, DLQI: Dermatology Life Quality Index, OCS: Oral Corticosteroids, PEFR: Peak

Table 2:

Combined House dust mite extract (Dp-50%, Df-50% 500 AU per MD) for Subcutaneous Cluster doses X 7 visits X 4 months till MD Dosesachieved of HDMfor 3 years as per schedule along with Inj Omalizumab (150 mg) X 15 days before AIT followed by 300 mg0.5 every ml 2-3 weeks till MD-500AU 0.05 ml 0.05/0.1 ml 0.1/0.15 ml 0.15/0.2 ml 0.2/0.25 ml 0.5 ml 0.5 ml as MD for achieved, then 150 mg once a month for 3 years. (1 dose) (1 dose) (2doses) (2 doses) (2 doses) (2 doses) (1 dose) SCIT- 500 AU (DP-50%, DF-50%) Inj Omalizumab 150 mg 1503 years mg Cluster Dose First day 15 days 15 days 15 days 20 days 20days 20 days 300 mg 300 mg 300 mg 300 mg 300 mg 300 mg frequency 50 AU 150 AU 250 AU 500 AU 500 AU 500 AU 4-6 weeks AU: Allergy Unit, MD: Maintenance Dose (500 AU), Conc.-concentration, AIT: Allergen Immunotherapy; HDM-Hose Dust Mite; AD-Atopic Dermatitis 350 AU 450 AU

We used different scales both for the severity of the disease House Dust Mite Subcutaneous Allergen Immunotherapy (HDM ife before and after treatment combinationand the compromised to immunotherapy Quality of L with Omalizumab has been & SCIT) and Anti-IgE (Omalizumab- Novartis Ltd). with HDM SCIT and Anti-IgE (Omalizumab- Novartis Ltd). The AIT in AD. The majority of the clinical trials investigating Allergen ImmunotherapyThough there (AIT) are multiple as a potential articles treatment suggesting for the moderate efficacy toof a decrease in rescue medication use during seasonal exposure. shown to decrease symptoms score upto 48% Vs SCIT alone with severe AD with allergen sensitization only concentrate on HDM We started combined therapy by House Dust Mite AIT [17]. Subcutaneous Allergen Immunotherapy (HDM SCIT Greer and Asthma are often polysensitized towards a large number of along with concomitant therapy (moisturizing agent, topical differentPatients allergen with severe molecules refractory and thus Atopic exhibit Dermatitis extremely with complex Rhinitis steroids,Laboratories, antihistamines Inc) and Anti-IgE along with (Omalizumab- tapering dose Novartis of OCS- Ltd)

IgE sensitization profile as found in our patient and diagnosis was oral methylprednisolone). His skin inflammation settled consistentconfirmed historyby Skin ofPrick exacerbation Test-9mm of wheal symptoms size and after Specific exposure IgE: toD. (SCORAD-10/103, DLQI-28/30, RCAT-22/25, ACT-23/25, PEFR- pteronyssinus-62.2 Kua/L and D. farinae-58.0 Kua/l along with 500L/mts) after 6 months and he continued his therapy along clinically relevant allergen for AIT. Our patient has a long history with supportive therapy for 3 years. Patient had an improvement effect to OCS. We emphasize that in a patient of severe refractory ofdust. aggravation Polysensitization of AD and contributes worsening to of difficult symptoms interpretation of sneezing, of in Quality of Life and severity of disease as well as less side- steroid-dependent Atopic Dermatitis with Rhinitis and Asthma; wheezing, couth and shortness of breath on dust exposure. recommend combined therapy is effective therapeutic regime by Though the exact mechanism by which exposure to the dust in

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Central worsening AD is still unclear nevertheless in patient with AD are on epidemiology, diagnosis, and disease course of atopic dermatitis. the patch of skin that is suggestive of eczematous characteristics. 2. Semin Cutan Med Surg. 2016; 35: S84–S88. patch tested with HDM CD4 T-cells specific to HDM are found in atopic dermatitis: essential topics to prevent the atopic march. J It is worthy to note in Figure 1, that a good response was Egawa G, Kabashima K. Multifactorial skin barrier deficiency and observed in our patient after 6 months of combined therapy by House Dust Mite Subcutaneous Allergen Immunotherapy Allergy Clin Immunol. 2016; 138: 350–358, e1. safe alternative therapy in severe refractory atopic dermatitis: A case 3. report.Sirufo MM,Medicine De Martinis (Baltimore). M, Ginaldi 2018; 97: L. Omalizumabe10897. an effective and (HDM SCIT Greer Laboratories, Inc) and Anti-IgE (Omalizumab- Novartis Ltd). Immunologic effects of omalizumab in children with severe refractory 4. atopicIyengar dermatitis: SR, Hoyte EG,a randomized, Loza A, Bonaccorso placebo-controlled S, Chiang D, Umetsuclinical DT,trial. et Int al. Our findings concur with a similar study made by Ramirez del Pazo et al., in age group of 12-52 years old patients, treated with Omalizumab as an adjuvant therapy and found significant 5. ArchDarsow Allergy U, Wollenberg Immunol. 2013;A, Simon 162: D, 89-93. Taieb A, Werfel T, Oranje A, et al. al.,decrease showed in that Dermatological in the AIT-treated Life Qualitygroup with Index AD (DLQI),there was a questionnaire for adults similar to CDLQI [18]. Carabello et ETFAD/EADV eczema task force 2009 position paper on diagnosis SCORAD as well as reduction in overall OCS [19]. Research in and treatment of atopic dermatitis. J Eur Acad Dermatol Venereol. a statistically significant improvement over control group in 6. 2010;Novak 24: N, 317-28. Bieber T, Hoffmann M, Regina Fölster-Holst, Bernhard with a dose-dependent decline in SCORAD after 1 year of AIT therapyAIT efficacy and ina decrease HDM-sensitized in OCS use patients [20]. Ashowed similar similar meta-analysis results Homey, Thomas Werfel, et al. Efficacy and safety of subcutaneous conducted by Bae at al., included 8 randomized control trials and allergen-specific immunotherapy with depigmented polymerized found that patients with improvements in their AD symptoms mite extract in atopic dermatitis. J Allergy Clin Immunol. 2012; 130: 7. 925–31.Banerjee S, Resch Y, Chen KW, Kuan-Wei Chen, Ines Swoboda, Margit Focke-Tejkl, et al. Der p 11 is a major allergen for house dust mite- compared to placebo [21]. allergic patients suffering from atopic dermatitis. J Invest Dermatol. had an odds-ratio (OR) of 5.35 of being treated with AIT when Dupilumab, an monoclonal antibody (mAb) that targets the 8. 2015;Cartledge 135: N, 102-109. Chan S. Atopic dermatitis and food allergy: a paediatric blocks TH2 immune response, was recently approved for shared a subunit of the IL-4 and IL-13 receptors and effectively the treatment of moderate to severe AD in adults 18 years 9. approach. Curr Pediatr Rev. 2018; 14: 171–179. or older whose disease is not adequately controlled with allergy. Current Opinion in Allergy and Clinical Immunology. 2020; Graham F, Eigenmann P. Atopic dermatitis and its relation to food monotherapy is unknown [22]. Currently there are no published 10. topical treatments but long term safety profile of dupilumab 20: 305-310. studies combining dupilumab with AIT. of omalizumab in the treatment of atopic dermatitis: a pilot study. Sheinkopf LE, Rafi AW, Do LT, Katz RM, Klaustermeyer WB. Efficacy We attribute that combined therapy by House Dust Mite Subcutaneous Allergen Immunotherapy (HDM SCIT Greer 11. Allergy Asthma Proc. 2008; 29: 530–7. Belloni B, Ziai M, Lim A, Lemercier B, Sbornik M, Weidinger S, et al. potentially effective, safe, and steroid-sparing and improves Low-dose anti-IgE therapy in patients with atopic eczema with high Laboratories, Inc) and Anti-IgE (Omalizumab- Novartis Ltd) is 12. serum IgE levels. J Allergy Clin Immunol. 2007; 120: 1223–5.

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Cite this article Kathuria PC, Rai M (2020) Successful Treatment by Combination Therapy of Omalizumab (Anti-IgE) and House Dust Mite Allergen Immunotherapy for Severe Refractory Steroid-Dependent Atopic Dermatitis with Rhinitis and Asthma - A Case Report-Follow Up for 5 Years. JSM Allergy Asthma 4(1): 1026.

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