Abatacept as a Long-Term Targeted Therapy for LRBA Deficiency

  • J Allergy Clin Immunol Pract. 2019 Nov-Dec;7(8):2790-2800.e15. doi: 10.1016/j.jaip.2019.06.011.
Ayca Kiykim  1 ,  Ismail Ogulur  1 ,  Esra Dursun  1 ,  Louis Marie Charbonnier  2 ,  Ercan Nain  1 ,  Sukru Cekic  3 ,  Dilek Dogruel  4 ,  Neslihan Edeer Karaca  5 ,  Mujde Tuba Cogurlu  6 ,  Ozlem Arman Bilir  7 ,  Murat Cansever  8 ,  Hasan Kapakli  9 ,  Dilek Baser  1 ,  Nurhan Kasap  1 ,  Seyhan Kutlug  10 ,  Derya Ufuk Altintas  4 ,  Ahmad Al-Shaibi  11 ,  Nourhen Agrebi  11 ,  Manolya Kara  12 ,  Ayla Guven  13 ,  Ayper Somer  12 ,  Cigdem Aydogmus  14 ,  Nuray Aktay Ayaz  15 ,  Ayse Metin  16 ,  Metin Aydogan  17 ,  Aysen Uncuoglu  17 ,  Turkan Patiroglu  8 ,  Alisan Yildiran  10 ,  Sukru Nail Guner  9 ,  Sevgi Keles  9 ,  Ismail Reisli  9 ,  Guzide Aksu  5 ,  Necil Kutukculer  5 ,  Sara S Kilic  18 ,  Mustafa Yilmaz  4 ,  Elif Karakoc-Aydiner  19 ,  Bernice Lo  11 ,  Ahmet Ozen  19 ,  Talal A Chatila  2 ,  Safa Baris  20
Affiliations
  • 1. Division of Pediatric Allergy and Immunology, Marmara University School of Medicine, Istanbul, Turkey.
  • 2. Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass.
  • 3. Division of Pediatric Allergy and Immunology, Faculty of Medicine, Uludag University, Bursa, Turkey.
  • 4. Division of Pediatric Allergy-Immunology, Faculty of Medicine, Çukurova University, Adana, Turkey.
  • 5. Division of Pediatric Allergy and Immunology, Faculty of Medicine, Ege University, Izmir, Turkey.
  • 6. Division of Pediatric Allergy and Immunology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey.
  • 7. Division of Pediatric Hematology, Ankara Children's Hematology Oncology Training and Research Hospital, Ankara, Turkey.
  • 8. Division of Pediatric Immunology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
  • 9. Division of Pediatric Allergy and Immunology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey.
  • 10. Division of Pediatric Allergy and Immunology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey.
  • 11. Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar.
  • 12. Division of Pediatric Infectious Diseases, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
  • 13. Division of Pediatric Endocrinology Clinic, Medical Faculty, Zeynep Kamil Women and Children Hospital, Saglik Bilimleri University, Istanbul, Turkey.
  • 14. Division of Pediatric Allergy and Immunology, Kanuni Sultan Suleyman Training Hospital, Istanbul, Turkey.
  • 15. Division of Pediatric Rheumatology, Kanuni Sultan Suleyman Training Hospital, Istanbul, Turkey.
  • 16. Division of Pediatric Immunology, Ankara Children's Hematology Oncology Training and Research Hospital, Ankara, Turkey.
  • 17. Division of Pediatric Gastroenterology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey.
  • 18. Division of Pediatric Immunology and Rheumatology, Faculty of Medicine, Uludag University, Bursa, Turkey.
  • 19. Division of Pediatric Allergy and Immunology, Marmara University School of Medicine, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.
  • 20. Division of Pediatric Allergy and Immunology, Marmara University School of Medicine, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey. Electronic address: [email protected].
PMID: 31238161 DOI: 10.1016/j.jaip.2019.06.011
Abstract

Background: LPS-responsive beige-like anchor (LRBA) deficiency presents with susceptibility to infections, autoimmunity, and lymphoproliferation. The long-term efficacy of cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (abatacept) as targeted therapy for its immune dysregulatory features remains to be established.

Objective: To determine the clinical and immunologic features of LRBA deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations.

Methods: Twenty-two LRBA-deficient patients were recruited from different immunology centers and followed prospectively. Eighteen patients on abatacept were evaluated every 3 months for long-term clinical and immunologic responses. LRBA expression, lymphocyte subpopulations, and circulating T follicular helper cells were determined by flow cytometry.

Results: The mean age of the patients was 13.4 ± 7.9 years, and the follow-up period was 3.4 ± 2.3 years. Recurrent infections (n = 19 [86.4%]), immune dysregulation (n = 18 [81.8%]), and lymphoproliferation (n = 16 [72.7%]) were common clinical features. The long-term benefits of abatacept in 16 patients were demonstrated by complete control of lymphoproliferation and chronic diarrhea followed by immune dysregulation, most notably autoimmune cytopenias. Weekly or every Other week administration of abatacept gave better disease control compared with every 4 weeks. There were no serious side effects related to the abatacept therapy. Circulating T follicular helper cell frequencies were found to be a reliable biomarker of disease activity, which decreased on abatacept therapy in most subjects. However, high circulating T follicular helper cell frequencies persisted in 2 patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy.

Conclusions: Long-term abatacept therapy is effective in most patients with LRBA deficiency.

Keywords
Abatacept; Autoimmunity; Immune dysregulation; LPS-responsive beige-like anchor; T follicular helper cells.
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