Acquired Hemophilia A in IgG4-Related Disease: Case Report, Immunopathogenic Study, and Review of the Literature

Abstract

We report the observation of a 75-year-old patient referred for cervical lymphadenopathies. A pre-lymphadenectomy blood work revealed an asymptomatic elevation of aPTT with low factor VIII (FVIII) levels and high anti-FVIII antibodies titers, consistent with acquired hemophilia A (AHA). Histological work-up of a cervical lymphadenopathy revealed benign follicular hyperplasia with IgG4⁺ lymphoplasmacytic infiltration; and serum IgG4 levels were markedly elevated, compatible with IgG4-related disease (IgG4-RD). He was successfully treated with a 9-month course of prednisone, secondarily associated with rituximab when an AHA relapse occurred. As this patient presented with an unusual association of rare diseases, we wondered whether there was a link between the two conditions. Our first hypothesis was that the anti-FVIII autoantibodies could be directly produced by the proliferating IgG4⁺ plasma cells as a result of broken tolerance to autologous FVIII. To test this assumption, we determined the anti-FVIII IgG subclasses in our patient and in a control group of 11 AHA patients without IgG4-RD. The FVIII inhibitor was mostly IgG4, with an anti-FVIII IgG4/IgG1 ratio of 42 at diagnosis and 268 at relapse in our patient; similar values were observed in non-IgG4-RD AHA patients. As a second hypothesis, we considered whether the anti-FVIII activity could be the result of a non-specific autoantibody production due to polyclonal IgG4⁺ plasma cell proliferation. To test this hypothesis, we measured the anti-FVIII IgG4/total IgG4 ratio in our patient, as well as in several control groups: 11 AHA patients without IgG4-RD, 8 IgG4-RD patients without AHA, and 11 healthy controls. We found that the median [min-max] ratio was higher in AHA-only controls (2.4 10^-2 [5.7 10^-4-1.79 10^-1]), an oligoclonal setting in which only anti-FVIII plasma cells proliferate, than in IgG4-RD-only controls (3.0 10^-5 [2.0 10^-5-6.0 10^-5]), a polyclonal setting in which all IgG4⁺ plasma cells proliferate equally. Our patient had intermediate ratio values (2.7 10^-3 at diagnosis and 1.0 10^-3 at relapse), which could plead for a combination of both mechanisms. Although no definitive conclusion can be drawn, we hypothesized that the anti-FVIII autoantibody production in our IgG4-RD AHA patient could be the result of both broken tolerance to FVIII and bystander polyclonal IgG4⁺ plasma cell proliferation.

Keywords: IgG4 antibodies; IgG4-related disease; acquired hemophilia A; anti-factor VIII autoantibodies; plasma cell.

Figure 1

Clinical course of our patient. Anti-FVIII, anti-FVIII activity; aPTT, activated partial thromboplastin time; CS, corticosteroids; FVIII, coagulation factor VIII; Ig, immunoglobulin; RTX, rituximab.

Figure 2

Representative images of the axillary lymph node biopsy histological examination. (A) Lymph node showing reactive follicular hyperplasia. The reactive follicle comprises germinal center surrounded by a thin mantle zone. The interfollicular area contains numbers of mature plasma cells. Hematoxylin and Eosin staining x400. (B) Lymph node showing reactive follicular hyperplasia and mature plasma cells. CD79a staining. (C, D) IgG (C) and IgG4 (D) staining. Numerous IgG4⁺ cells are present between follicles. The IgG4⁺/IgG⁺ cell proportion is over 40%, with more than 200 IgG4⁺ cells per high power field.

Figure 3

Assessment of TFH and Treg infiltrates in the lymph node biopsy. (A) IgG4 staining. The interfollicular area contains numbers of IgG4⁺ cells. (B–E) CD4 (B), CD8 (C), FOXP3 (D) and PD1 (E) staining. Expansion of CD4⁺ PD1⁺ cells within follicles. Numerous CD4⁺ FOXP3⁺ cells are present in interfollicular areas.

Figure 4

Schematic representation of the putative mechanisms responsible for anti-FVIII antibody production in healthy controls (first row), AHA patients (second row), IgG4-RD patients (third row), and in our patient (fourth row). We hypothesized the ratios of anti-FVIII IgG4/total IgG4 in four populations: First row: healthy controls. A small fraction of the IgG4 repertoire has anti-FVIII activity (plain red) compared to non-anti-FVIII IgG4 (green). The anti-FVIII IgG4/total IgG4 ratio is 0.1. Second row: AHA. The anti-FVIII IgG4 fraction (dotted red) is produced by an antigen-driven oligoclonal expansion of a small contingent of pathogenic plasma cells. The rest of the IgG4 repertoire (green) remains similar to healthy controls. The anti-FVIII IgG4/total IgG4 ratio is 0.5. Third row: IgG4-RD. The anti-FVIII IgG4 fraction (plain red) is the result of an overall expansion of the IgG4 repertoire. As the anti-FVIII (plain red) and non-anti-FVIII (green) IgG4 fractions are both increased in similar proportion to healthy controls, the anti-FVIII IgG4/total IgG4 ratio is 0.1 (identical to healthy controls and lower than AHA). Fourth row: our patient. The anti-FVIII is a combination of both previous mechanisms: bystander production by polyclonal proliferation of IgG4⁺ plasma cells (plain red) and antigen-driven production due to broken tolerance to FVIII leading to (dotted red). The non-anti-FVIII (green) is increased in similar proportion to IgG4-RD patients. The anti-FVIII IgG4/total IgG4 ratio is 0.2 (higher than IgG4-RD and lower than AHA). In order to simplify the explanation, qualitative values are displayed. AHA, acquired hemophilia A; anti-FVIII, anti-FVIII activity; aPTT, activated partial thromboplastin time; FVIII, coagulation factor VIII; HC, healthy controls; Ig, immunoglobulin; IgG4-RD, IgG4-related disease.