GRANULOMATOUS-LYMPHOCYTIC INTERSTITIAL LUNG DISEASE (GL-ILD) WITH CYTOTOXIC T-LYMPHOCYTE-ASSOCIATED PROTEIN-4 (CTLA-4) HAPLO INSUFFICIENCY TREATED WITH ABATACEPT: A CASE REPORT

SESSION TITLE:

Treatment of Associated Lung Disease

SESSION TYPE:

Rapid Fire Case Reports PRESENTED ON.: 10/11/2023 09:40 am - 10:25 am

INTRODUCTION:

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by impaired immunoglobulin (Ig) production and low serum Ig levels. Various genetic defects have been identified in CVID including cytotoxic T-lymphocyte associated protein-4 (CTLA-4) haploinsufficiency. CTLA-4 is a surface protein on T-regulatory cells that facilitates regulation of B and T-cell immunity and CTLA-4 haploinsufficiency results in an immune dysregulation syndrome with clinical manifestations of combined immunodeficiency and multisystem autoimmune disease. Granulomatous-lymphocytic interstitial lung disease ILD (GL-ILD) is the most common ILD in CVID occurring in 10-30% of patients. Immunomodulatory precision therapy with Abatacept can rectify the protein deficiencies of CTLA-4 and is an effective treatment option for GL-ILD due to CTLA-4 haploinsufficiency.

CASE PRESENTATION:

A 61 year old female former smoker was initially diagnosed with granulomatous lung disease by fine needle aspiration cytology of mediastinal lymph nodes and transbronchial biopsy at age 44. She subsequently developed recurrent respiratory tract infections and was diagnosed with CVID at age 49. Intravenous Ig infusions were initiated with improvement in infectious exacerbations. She however developed progressive dyspnea and cough with worsening pulmonary function tests (PFTs). Computed tomography (CT) showed reticulation, traction bronchiectasis, multifocal nodular infiltrates and diffuse ground lass opacities. Surgical lung biopsy showed nodular lymphoid hyperplasia and a diagnosis of GL-ILD was made at age 53. She was initially treated with prednisone followed by combination therapy with rituximab and azathioprine. Azathioprine was discontinued due to development of cytopenias. With continued disease progression, genetic testing was performed which revealed CTLA-4 haploinsufficiency. Abatacept was added to her treatment regimen with resultant stability on CT imaging and PFT parameters of forced vital capacity and diffusion capacity. Soluble interleukin 2 levels are being monitored for disease activity and T-cell activation. She was also diagnosed with pulmonary hypertension and is also being treated with inhaled Treprostinil and has other multisystem autoimmune disease manifestations of CTLA-4 haploinsufficiency including immune thrombocytopenia and neutropenia, hypothyroidism, type 1 diabetes mellitus, inflammatory arthritis, and autoimmune enteropathy.

DISCUSSION:

GL-ILD is associated with poor outcomes in CVID and has been reported to reduce life expectancy by more than 50%. Currently, guidelines for management of GL-ILD are based on expert opinion due to the lack of robust scientific evidence. Preferred second line agents in patients requiring steroid sparing therapy include azathioprine and rituximab. However, in cases of GL-ILD with specific genetic defect causing CTLA 4 haploinsufficiency, Abatacept is an effective treatment option. Abatacept is a fusion protein composed of the Fc region of immunoglobulin IgG1 fused to CTLA-4 which prevents excessive T lymphocyte proliferation in patients with CTLA-4 haploinsufficiency. Although the evidence is not robust, previous studies have reported improvement in lung function and radiological findings after treatment with Abatacept. A small case series showed an association of CVID with precapillary pulmonary hypertension.

CONCLUSIONS:

GL-ILD is a complication of CVID and has been shown to be a significant cause of morbidity and mortality. Abatacept has shown promising results as second line therapy targeting the underlying pathophysiology of GL-ILD in CTLA-4 deficient patients and further research in this area is warranted. REFERENCE #1: Egg, David, Ina Caroline Rump, Noriko Mitsuiki, Jessica Rojas-Restrepo, Maria-Elena Maccari, Charlotte Schwab, Annemarie Gabrysch et al. "Therapeutic options for CTLA-4 insufficiency." Journal of Allergy and Clinical Immunology 149, no. 2 (2022): 736-746. REFERENCE #2: Hurst, John R., et al. "British Lung Foundation/United Kingdom Primary Immunodeficiency Network consensus statement on the definition, diagnosis, and management of granulomatous-lymphocytic interstitial lung disease in common variable immunodeficiency disorders." The Journal of Allergy and Clinical Immunology: In Practice 5.4 (2017): 938-945. REFERENCE #3: Lamers, Olivia AC, Bas M. Smits, Helen Louisa Leavis, Godelieve J. de Bree, Charlotte Cunningham-Rundles, Virgil ASH Dalm, Hsi-en Ho et al. "Treatment strategies for GLILD in common variable immunodeficiency: a systematic review." Frontiers in Immunology 12 (2021): 60609

DISCLOSURES:

No relevant relationships by Asif Abdul Hameed No relevant relationships by ALAA ABU SAYF No relevant relationships by Javardo McIntosh No relevant relationships by Krishna Thavarajah