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Management of Atopy with Dupilumab and Omalizumab in CADINS Disease

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Abstract

The caspase activation and recruitment domain 11 (CARD11) gene encodes a scaffold protein required for lymphocyte antigen receptor signaling. Dominant-negative, loss-of-function (LOF) pathogenic variants in CARD11 result in CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease. Patients with CADINS suffer with severe atopic manifestations including atopic dermatitis, food allergy, and chronic spontaneous urticaria in addition to recurrent infections and autoimmunity. We assessed the response of dupilumab in five patients and omalizumab in one patient with CADINS for the treatment of severe atopic symptoms. CARD11 mutations were validated for pathogenicity using a T cell transfection assay to assess the impact on activation-induced signaling to NF-κB. Three children and three adults with dominant-negative CARD11 LOF mutations were included. All developed atopic disease in infancy or early childhood. In five patients, atopic dermatitis was severe and recalcitrant to standard topical and systemic medications; one adult suffered from chronic spontaneous urticaria. Subcutaneous dupilumab was initiated to treat atopic dermatitis and omalizumab to treat chronic spontaneous urticaria. All six patients had rapid and sustained improvement in atopic symptoms with no complications during the follow-up period. Previous medications used to treat atopy were able to be decreased or discontinued. In conclusion, treatment with dupilumab and omalizumab for severe, refractory atopic disease in patients with CADINS appears to be effective and well tolerated in patients with CADINS with severe atopy.

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Abbreviations

AEC:

Absolute eosinophil count

AR:

Allergic rhinitis

AD:

Atopic dermatitis

BENTA:

B cell expansion with NF-κB and T cell anergy

CADINS:

CARD11-associated atopy with dominant interference of NF-κB signaling

CARD11:

Caspase activation and recruitment domain 11

CFSE:

Carboxyfluorescein succinimidyl ester

CSU:

Chronic spontaneous urticaria

DN:

Dominant-negative

EASI:

Eczema Area and Severity Index

FA:

Food allergies

GOF:

Gain-of-function

IBD:

Inflammatory bowel disease

IGA:

Investigator Global Assessment scale for Atopic Dermatitis

IGRT:

Immunoglobulin replacement therapy

LOF:

Loss-of-function

mTORC1:

Mechanistic target of rapamycin complex 1

MAGUK:

Membrane-associated guanylate kinase

MLR:

Mixed lymphocyte reaction

NF-κB:

Nuclear factor kappa B

SCORAD:

Scoring atopic dermatitis

TCR:

T cell receptor

UAS:

Urticaria Activity Score

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Funding

The authors thank the patients and their families for their participation. This work was supported by the Jeffrey Modell Foundation (A.L.S.), the Center for Pediatric Immunology at St. Louis Children’s Hospital and Washington University, and the Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies at St. Louis Children’s Hospital (M.A.C.). The opinions and assertions expressed herein are those of the authors and are not to be construed as reflecting the views of the Uniformed Services University of the Health Sciences or the US Department of Defense.

Author information

Author notes

  1. Andrew L. Snow and Jennifer W. Leiding contributed equally to this work.

Authors and Affiliations

  1. Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, FL, USA

    Natalie M. Diaz-Cabrera

  2. Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, C-2013, Bethesda, MD, 20814, USA

    Bradly M. Bauman, Gina Dabbah-Krancher & Andrew L. Snow

  3. The Henry M. Jackson Foundation, Bethesda, MD, USA

    Bradly M. Bauman & Gina Dabbah-Krancher

  4. Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK

    Mildred A. Iro & Anthony Williams

  5. Pediatric Dermatology Service, Department of Dermatology and Venereology, The Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel

    Vered Molho-Pessach

  6. Department of Dermatology and Venereology, The Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel

    Vered Molho-Pessach, Abraham Zlotogorski & Gil Armoni-Weiss

  7. Clinical Immunology and Allergy Unit, Department of Medicine, The Faculty of Medicine, Hadassah Medical Organization, Hebrew University of Jerusalem, Jerusalem, Israel

    Oded Shamriz

  8. The Lautenberg Center for Immunology and Cancer Research, The Faculty of Medicine, Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem, Jerusalem, Israel

    Oded Shamriz

  9. Department of Bone Marrow Transplantation and Cancer Immunotherapy, The Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical Center, Jerusalem, Israel

    Yael Dinur-Schejter & Polina Stepensky

  10. Clinical Immunology and Allergy Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Tatyana Dubnikov Sharon & Yuval Tal

  11. Department of Pediatrics, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel

    Eli M. Eisenstein

  12. Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    Leonora Pietzsch & Catharina Schuetz

  13. UniversitätsCentrum Für Seltene Erkrankungen, Medizinische Fakultät Carl-Gustav-Carus, Technische Universität Dresden, Dresden, Germany

    Catharina Schuetz

  14. Division of Dermatology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA

    Damien Abreu

  15. Division of Dermatology, Departments of Medicine & Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA

    Carrie C. Coughlin

  16. Division of Rheumatology/Immunology, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA

    Megan A. Cooper

  17. Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA

    Joshua D. Milner

  18. Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Jennifer W. Leiding

  19. Institute for Clinical and Translational Research, Johns Hopkins All Childrens Hospital, 600 Fifth Street South, Suite 3200, St. Petersburg, FL, 33701, USA

    Jennifer W. Leiding

Authors
  1. Natalie M. Diaz-Cabrera
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  2. Bradly M. Bauman
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Contributions

N.M.D.-C., A.L.S., and J.W.L. developed the concept and collected data. N.M.D.-C. and A.L.S. wrote and revised the original manuscript. B.M.B., G.D.-K., and A.L.S. created expression plasmids, performed transfection experiments, and analyzed associated data. M.A.I., V.M.-P., A.Z., O.S., Y.D.-S., T.D.S., P.S., Y.T., E.M.E., L.P., C.S., D.A., C.C.C., M.A.C., J.D.M., A.W., G.A.-W., and J.W.L. provided clinical care to patients, documented atopic disease severity before and after treatments, and provided key edits to the manuscript.

Corresponding authors

Correspondence to Andrew L. Snow or Jennifer W. Leiding.

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All studies involving human subjects were performed in accordance with site-specific institutional review board-approved protocols, as well as guidelines in the 1964 Declaration of Helsinki and its later amendments, with written informed consent obtained from the patients.

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Diaz-Cabrera, N.M., Bauman, B.M., Iro, M.A. et al. Management of Atopy with Dupilumab and Omalizumab in CADINS Disease. J Clin Immunol 44, 48 (2024). https://doi.org/10.1007/s10875-023-01636-y

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