Acquired Hemophilia A in IgG4-Related Disease: Case Report, Immunopathogenic Study, and Review of the Literature
Authors: Sébastien Sanges, Emmanuelle Jeanpierre, Benjamin Lopez, Jules Russick, Sandrine Delignat, Benjamin Carpentier, Romain Dubois, Sylvain Dubucquoi, Thomas Guerrier, Éric Hachulla, Pierre-Yves Hatron, Camille Paris, Sophie Susen, David Launay, Sébastien Lacroix-Desmazes, Louis Terriou
Journal: Front Immunol (2020)
Keywords: igg4 antibodies, igg4-related disease, acquired hemophilia a, anti-factor viii autoantibodies, plasma cell
MeSH terms: Disease Susceptibility / immunology, Hemophilia A / diagnosis, Hemophilia A / etiology, Immunoglobulin G4-Related Disease / complications, Immunoglobulin G4-Related Disease / immunology, Case Reports, Review, Aged, Autoantibodies / immunology, Blood Coagulation, Blood Coagulation Tests, Factor VIII / immunology, Female, Hemophilia A / blood, Hemophilia A / therapy, Humans, Immunoglobulin G / immunology, Immunohistochemistry, Lymph Nodes / immunology, Lymph Nodes / metabolism, Lymph Nodes / pathology, Male, T-Lymphocytes, Regulatory / immunology, T-Lymphocytes, Regulatory / metabolism, Autoantibodies, Immunoglobulin G, F8 protein, human, Factor VIII, Factor 8 deficiency, acquired

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.