Final - HIES Effectiveness of Omalizumab - Kim Han Nguyen - Read-Only.pptx

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1. Autosomal recessive Hyper- IgE Syndrome & Effectiveness of Omalizumab Kim Han Nguyen, MD Internal medicine resident College of Health Sciences, VinUniversity , Vietnam Kim Han Nguyen , Quynh Anh Nguyen, Mai Hoang Tran, Thu Thuy Can, Mai Thi Vu, Nam Sy Vo , Hieu Chu Chi , Sheryl van Nunen , Dinh Van Nguyen

2. objectives Overview of Autosomal Recessive Hyper- IgE Syndrome (AR-HIES) To describe the biologics used in AR-HIES treatment.

3. Chief complaint A 30-year-old Japanese male living in Vietnam presented with vesicular eruption and high fever for 5 days. History of present illness Multiple pruritic, painful vesicles firstly appeared in the right axilla, then quickly spread to the chest, abdomen, back and arms. Episodic fever (40 o C) and chills. CASE REPORT

4. Past medical history Severe chronic atopic dermatitis from childhood. A similar episode 10 years ago, without fever and chills. No clear-cut diagnosis. The lesions resolved with topical steroid. Social history Office staff, sexually active with one partner, no recent traveling, no smoking, no alcohol, no illicit drugs. Allergy Severe food allergy (egg, shrimp, seafood, orange,...) Medication None Family history None CASE REPORT

5. Vital signs T 40 o C , HR 86 bpm, BP 128/64 mmHg, RR 18 bpm, SpO2 100%. General Acute mild distress. Multiple axillary lymph nodes on both sides, size 2cm x3cm, tender and mobile. HEENT No thrush, no vesicles, no retained primary teeth. CV Normal rhythm; no murmurs, rubs, or gallops Respiratory Clear to auscultation bilaterally Abdominal Normal bowel sounds, no organomegaly, no guarding or rebound tenderness Skin Multiple 1 – 2 mm vesicles and pustules on erythematous base were noted in chest, abdomen, back, arms. Eczematous lesions with dry, flaky, erythematous and thickened skin. CASE REPORT

6. Hanifin JM. M. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol. 2001 Feb;10(1):11-8. EASI (Eczema Area and Severity Index) = 22.7   CASE REPORT

7. CASE REPORT Young adult male Severe food allergy Severe chronic atopic dermatitis Recurrent cutaneous infection No skeletal or dental abnormalities

8. Lab test Normal range Result Unit EOS 30 – 500 1000 cells/mm 3 IgE <1000 33554 U/mL IgA 70 – 400 269.2 U/mL IgG 700 – 1600 1660.9 U/mL IgM 40 – 230 33.9 U/mL T CD3 600 – 2800 260 (57.43%) Cell/ L T CD4 500 – 1600 184 (40.53%) Cell/ L T CD8 200 – 800 72 (15.96%) Cell/ L CD4 / CD8 >1.0 2.6 C3 90 – 180 125 mg/dL C4 10 40 35.1 mg/dL HSV PCR (+) Lab test Normal range Result Unit EOS 30 – 500 1000 cells/mm 3 IgE <1000 33554 U/mL IgA 70 – 400 269.2 U/mL IgG 700 – 1600 1660.9 U/mL IgM 40 – 230 33.9 U/mL T CD3 600 – 2800 260 (57.43%) T CD4 500 – 1600 184 (40.53%) T CD8 200 – 800 72 (15.96%) CD4 / CD8 >1.0 2.6 C3 90 – 180 125 mg/dL C4 10 40 35.1 mg/dL HSV PCR (+) Immunologic assessment suggested AR-HIES Hypereosinophilia Elevated serum IgE levels Low serum IgM level Decreased circulating T cells Herpes Simplex Virus infection Screening for malignancy showed no significant abnormality. CASE REPORT

9. CASE REPORT EUROLINE Atopy Screening testing detected high levels of specific IgE against several allergens : Dermatophagoides pteronyssinus Dermatophagoides farinae Cat Egg white Candida albicans Bermuda grass Orange

10. Whole exome sequencing by Novaseq6000 150PE platform (Illumina, Hayward, CA, USA) with SureSelect Human Whole Exome V6 Capture kit (Agilent, Santa Clara, CA, USA) Focus on the gene set related to Hyper IgE Syndrome (STAT3, DOCK8, ZNF431, TYK2, PGM3, CARD11, SPINK5). 2 missense variants in DOCK8 gene 5 missense mutations in SPINK5 gene CASE REPORT

11. Diagnosis Eczema herpeticum / Autosomal Recessive Hyper- IgE Syndrome Treatment Supportive treatment: Aciclovir , methylprednisolone, moisturizer, dietary elimination. Anti- IgE therapy: Omalizumab (300mg SQ every 4 weeks) Follow-up Significant clinical improvement and no side effects EASI decreased from 22.7 (pre-treatment) to 10.8 after 3 months of treatment. 1b 1c 1d 1a CASE REPORT

12. A patient with recurrent viral infections , severe allergies , eosinophilia and markedly elevated IgE should be investigated for AR-HIES and for mutations in the DOCK8 gene. Supportive treatment base d on management of infection , skin care and elimination of dietary allergens is essential. A nti -IgE therapy with Omalizumab should be considered as a targeted treatment for this syndrome . CASE CONCLUSION

13. Atopic dermatitis in Hyper IgE Syndrome and role of biologics

14. objectives Overview of Autosomal Recessive Hyper- IgE Syndrome (AR-HIES) To describe the biologics used in AR-HIES treatment.

15. Middleton, E., Burks, A. W., Holgate, (2020). 69. In Middleton's allergy: Principles and practice, Elsevier, p1133. Autosomal Dominant Hyper- IgE Syndrome (AD-HIES) Autosomal Recessive Hyper- IgE Syndrome (AR-HIES) Heterozygous, dominant-negative mutations in gene: STAT3 (signal transducer and activator of transcription 3) Homozygous, recessive mutations in genes: DOCK8 (Dedicator of cytokinesis 8) – 70% TYK2 (Tyrosine kinase 2) Others: PGM3, SPINK5, ZNF341, IL6R Clinical features: Recurrent staphylococcal skin abscesses Recurrent pneumonia Unusual facial features Pneumatoceles Osteopenia with fractures Delayed shedding of baby teeth Clinical features: Severe skin viral infections Severe allergies Frequent neurologic complications Early death Without skeletal or dental abnormalities Immunologic assessment: Serum IgE levels >10 times the UNL Normal circulating T cells and B cells Immunologic assessment: Elevated IgE, low IgG Reduced circulating T cells and B cells Extreme eosinophilia Two Major Types of Hyper- IgE Syndrome

16. Middleton, E., Burks, A. W., Holgate, (2020). 69. In Middleton's allergy: Principles and practice, Elsevier, p1133. Autosomal Dominant Hyper- IgE Syndrome (AD-HIES) Autosomal Recessive Hyper- IgE Syndrome (AR-HIES) Heterozygous, dominant-negative mutations in gene: STAT3 (signal transducer and activator of transcription 3) Homozygous, recessive mutations in genes: DOCK8 (Dedicator of cytokinesis 8) – 70% TYK2 (Tyrosine kinase 2) Others: PGM3, SPINK5, ZNF341, IL6R Clinical features: Recurrent staphylococcal skin abscesses Recurrent pneumonia Unusual facial features Pneumatoceles Osteopenia with fractures Delayed shedding of baby teeth Clinical features: Severe skin viral infections Severe allergies Without skeletal or dental abnormalities Frequent neurologic complications Early death Immunologic assessment: Serum IgE levels >10 times the UNL Normal circulating T cells and B cells Immunologic assessment: Elevated IgE, low IgG Reduced circulating T cells and B cells Extreme eosinophilia Two Major Types of Hyper- IgE Syndrome

17. Middleton, E., Burks, A. W., Holgate, (2020). 69. In Middleton's allergy: Principles and practice, Elsevier, p1133. Autosomal Dominant Hyper- IgE Syndrome (AD-HIES) Autosomal Recessive Hyper- IgE Syndrome (AR-HIES) Heterozygous, dominant-negative mutations in gene: STAT3 (signal transducer and activator of transcription 3) Homozygous, recessive mutations in genes: DOCK8 (Dedicator of cytokinesis 8) – 70% TYK2 (Tyrosine kinase 2) Others: PGM3, SPINK5, ZNF341, IL6R Clinical features: Recurrent staphylococcal skin abscesses Recurrent pneumonia Unusual facial features Pneumatoceles Osteopenia with fractures Delayed shedding of baby teeth Clinical features: Severe skin viral infections Severe allergies Frequent neurologic complications Early death Without skeletal or dental abnormalities Immunologic assessment: Serum IgE levels >10 times the UNL Normal circulating T cells and B cells Immunologic assessment: Elevated IgE, low IgG Reduced circulating T cells and B cells Extreme eosinophilia Two Major Types of Hyper- IgE Syndrome

18. Autosomal Recessive Hyper- IgE Syndrome (AR-HIES) Su , Helen C. et al. (2019). Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome. Immunological Reviews, 287(1), 9–19 Cellular pathogenesis of DIDS* contributes to virus susceptibility and other skin manifestations of disease Defection in dendritic cells (1) Defection in T cells differentiate (3-4) Cytokine imbalances Increased virus replication (5), atopic dermatitis (6), and mucocutaneous candidiasis (7) Cellular pathogenesis of DIDS* contributes to virus susceptibility and other skin manifestations of disease *Not all cases but the vast majority of DOCK8 immunodeficiency syndrome (DIDS) are associated with elevated serum IgE .  DIDS was initially referred to as AR-HIES

19. Clin Immunol. 2017 August ; 181: 75–82. Screening for and treatment of complications Administration of immunoprophylaxis Definitive therapy with hematopoietic stem cell transplantation. Management of AR-HIES

20. Thomson, ; Thomson, ; Rekha Chaudhuri, (2012). Omalizumab: Clinical Use for the Management of Asthma. Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine Omalizumab is a monoclonal antibody that binds selectively to the key allergic-reaction mediator Ig E. Omalizumab was approved by the FDA in June 2003 for the treatment of moderate to severe allergic asthma in patients whose symptoms are inadequately controlled by inhaled corticosteroids. Omalizumab

21. Bard, Susan (2008). Eczematous Dermatitis in the Setting of Hyper- IgE Syndrome Successfully Treated With Omalizumab. Archives of Dermatology, 144(12) Chularojanamontri L. Role of omalizumab in a patient with hyper- IgE syndrome and review dermatologic manifestations. Asian Pac J Allergy Immunol. 2009 Dec;27(4):233-6. G. V. Marcotte (2008). Omalizumab Therapy for Hyper- IgE Syndrome. Journal of Allergy and Clinical Immunology, 121(2), S88–S88 Luis et al, (2011). HIES: Report of a New Case Treated with Omalizumab and Dexametasone . American Society of Hematology Case reports Year Characteristics Bard et al. 2008 Reduce severe recalcitrant eczematous dermatitis in the setting of HIES G. V. Marcotte 2008 Reduce asthma, atopic dermatitis, and atopic keratoconjunctivitis in HIES Chularojanamontri L. et al. 2009 Reduce recurrent multiple abscesses on scalp, recalcitrant eczema, candida onychomycosis, alopecia universalis in AD-HIES Luis et al. 2011 Reduce asthma and atopic dermatitis in HIES Gomes N et al. 2020 Reduce severe recalcitrant eczema, and frequent cutaneous infections in AR-HIES. Reduce severe recalcitrant eczema, folliculitis, onychomycosis, multiple recurrent respiratory infections, and esophageal candidiasis in AD-HIES. Omalizumab in AR-HIES – Literature review

22. Omalizumab dosage Dosage depends on pretreatment serum IgE , age and weight

23. >10% Local: Injection site reaction Headache 1% to 10% Cardiovascular: Peripheral edema (≥2%) Dermatologic: Alopecia (≥2%), dermatitis (2%), pruritus (2%), urticaria (≥2%) Gastrointestinal: Toothache (≥2%), upper abdominal pain (3%), viral gastroenteritis (children: ≥3%) Genitourinary: Urinary tract infection (≥2%) Infection: Fungal infection (≥2%) Nervous system: Anxiety (≥2%), dizziness (3%), fatigue (3%), migraine (≥2%), pain (7%) Neuromuscular & skeletal: Arthralgia (3% to 8%), bone fracture (2%), limb pain (2% to 4%), musculoskeletal pain (≥2%), myalgia (≥2%) Otic : Otalgia (2%), otitis media (children: ≥3%) Respiratory: Asthma (≥2%), cough (2%), epistaxis (children: ≥3%), nasopharyngitis (children, adolescents, and adults: 3% to 9%), oropharyngeal pain (≥2%), sinus headache (≥2%), sinusitis (5%), streptococcal pharyngitis (children: ≥3%), upper respiratory tract infection (3%), viral upper respiratory tract infection (≤2%) Miscellaneous: Fever (≥2%) Uptodate , Omalizumab: Drug information Omalizumab adverse reactions

24. AR-HIES is a relatively rare primary immunodeficiency syndrome characterized by recurrent viral infections, atopic dermatitis, severe allergies, and early-onset malignancies. Caused by homozygous or compound heterozygous loss-of-function mutations in DOCK8, TYK2, PGM3, SPINK5, ZNF431 or IL6R. Diagnosed based on clinical features, immunologic laboratory findings and confirmatory genetic analysis. Anti- IgE therapy with omalizumab should be considered as a targeted treatment for this syndrome. Take home messages

25. Dr. Duy Le Pham Dr. Dinh Van Nguyen Acknowledgments

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