Lymphocyte-Directed Immunomodulation Remits Thymoma-Associated Autoimmune Pneumonitis

Abstract

Background: Thymoma presents with several autoimmune manifestations and is associated with secondary autoimmune regulator (AIRE) deficiency. Pneumonitis has recently been described as an autoimmune manifestation associated with thymoma presenting with similar clinical, radiographic, histological, and autoantibody features as seen in patients with inherited AIRE deficiency who suffer from Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) syndrome.

Objectives: To treat two patients with biopsy-proven thymoma-associated pneumonitis with lymphocyte-directed immunomodulation.

Methods: Two patients with thymoma were enrolled on IRB-approved protocols at the NIH Clinical Center. We performed history and physical examination; laboratory, radiographic, histologic and pulmonary function evaluations; and measurement of the lung-directed autoantibodies KCNRG and BPIFB1 prior to and at 1- and 6-months following initiation of lymphocyte-directed immunomodulation with azathioprine with or without rituximab.

Results: Combination T- and B-lymphocyte-directed immunomodulation resulted in improvement of clinical, functional, and radiographic parameters at 6-month follow-up evaluations in both patients with sustained remission up to 12-36 months following treatment initiation.

Conclusion: Lymphocyte-directed immunomodulation remitted autoimmune pneumonitis in two patients with thymoma.

Keywords: Azathioprine; Bronchiectasis; KCNRG; Pneumonitis; Rituximab; Thymoma.

Fig. 1

Radiographic, autoantibody, and histological features of thymoma-associated pneumonitis. Representative chest CT images for A) Patient 1 following azathioprine monotherapy at baseline and at 1-month and 6-months post-treatment initiation, B) Patient 1 following azathioprine with rituximab at baseline (before rituximab) and at 1.5-months and 12-months post-treatment initiation, and C) Patient 2 at baseline and at 3-months and 6-months post-treatment initiation. Baseline CT scans depict tree-in-bud nodularity (orange circles), bronchial wall thickening (red circles), and focal consolidations (yellow circle). Repeat CT scans demonstrate improvement at 1–3 months and resolution at 6-months following initiation of lymphocyte-directed immunomodulatory treatment. Note: Patient 1’s 1-month post-azathioprine monotherapy follow-up CT is complicated by right hemi-diaphragm elevation secondary to herpes zoster associated right phrenic nerve neuropathy. Abbreviations: AZA, azathioprine

Fig. 2

A) Autoantibody immunoreactivity against BPIFB1 and KCNRG presented as light units (LU). Dotted lines represent the cutoff values for determining autoantibody seropositivity. B) Hematoxylin and eosin (H&E) staining of endobronchial biopsy from patient 2 depicting chronic inflammatory infiltrate within intraepithelial and submucosal areas and thickened epithelial basement membrane. C) CD3 immunostaining showing that the infiltrate is composed primarily of CD3⁺ T lymphocytes. D) CD4 and CD8 double immunostaining showing that CD4⁺ T lymphocytes (brown) outnumber CD8⁺ T lymphocytes (magenta). E) CD20 immunostaining showing aggregates of B lymphocytes scattered throughout the lung parenchyma. F) CD79 immunostaining of the B cell receptor. G) H&E staining of the hepatic portal area of Patient 2 shows lymphocytic inflammation with scattered eosinophils and interface hepatitis. Masson trichrome shows mild periportal fibrosis (inset). Scale bars for panels B-G, 50 μm. Magnification for panels B-F, 10x. Magnification for panel G, 200x. H) Autoantibody immunoreactivity against KCNRG presented as LU in Patient 2 before treatment (baseline) and at 3- and 18-months following treatment with azathioprine and rituximab