title: Profound symptomatic hypogammaglobulinemia: a rare late complication after rituximab treatment for immune thrombocytopenia. Report of 3 cases and systematic review of the literature.
abstract: BACKGROUND
  B-cell depletion with rituximab (RTX) is widely used to treat autoimmune diseases, especially as second-line therapy for immune thrombocytopenia (ITP). The incidence of RTX-induced hypogammaglobulinemia is unknown because of heterogeneous follow-up and confounding factors such as concomitant immunosuppressive treatments in most patients. We describe 3 cases and attempted to determine the incidence of RTX-induced hypogammaglobulinemia by a systematic review of the literature.
  
  
  METHODS
  We retrospectively analyzed 189 ITP patients receiving RTX in 3 referral centers in France and conducted a systematic review of 32 studies (results published 2001-2014) reporting the use of RTX for ITP, particularly searching for symptomatic secondary hypogammaglobulinemia. We also searched for case reports of hypogammaglobulinemia after RTX initiation for ITP.
  
  
  RESULTS
  Of the 189 patients, 3 showed symptomatic hypogammaglobulinemia more than 2years after RTX infusion (initial immunoglobulin level was normal). All 3 presented recurrent severe infections. In 2, the outcome suggested common variable immunodeficiency. In patient 3, the peripheral blood lacked CD19(+)CD20(+) B cells and the bone-marrow B-cell precursor level was impaired. Among 1245 ITP patients in the literature who received RTX for ITP, gammaglobulin level was monitored before and after RTX initiation for 351 (28%). For 192 (55%), dosages were available and we identified 21 patients with secondary hypogammaglobulinemia, usually not symptomatic, 14 of whom had received concomitant dexamethasone. Finally, we found 4 case reports of ITP and symptomatic hypogammaglobulinemia possibly related to RTX according to the authors.
  
  
  CONCLUSIONS
  This large analysis led us to recommend monitoring serum immunoglobulin level before and repeatedly after RTX initiation for ITP. Physicians should be aware of hypogammaglobulinemia as a rare but severe complication of RTX.
authors.affiliation: Service de Médecine Interne, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Levy
authors.affiliation: Service de Médecine Interne, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France; Etablissement Français du Sang Ile de France, Inserm U955, Equipe 2, Créteil, Hôpital Henri Mondor, Paris, France. Electronic address: matthieu.mahevas@hmn.aphp.fr.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Mahévas
authors.affiliation: Service d'Immunologie Clinique, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Université Paris Diderot Paris VII, Paris, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Galicier
authors.affiliation: Service d'Immunologie Clinique, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Université Paris Diderot Paris VII, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Boutboul
authors.affiliation: Service d'Anatomie et Cytologie Pathologiques, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Moroch
authors.affiliation: Service de Médecine Interne, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.
authors.forename: Valentine
authors.initials: V
authors.lastname: Loustau
authors.affiliation: Service de Médecine Interne, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.
authors.forename: Constance
authors.initials: C
authors.lastname: Guillaud
authors.affiliation: Service de Médecine Interne, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.
authors.forename: Laeticia
authors.initials: L
authors.lastname: Languille
authors.affiliation: Service de Médecine Interne, Hôpital Jean-Verdier, Assistance Publique-Hôpitaux de Paris, Université Paris XIII, Bondy, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fain
authors.affiliation: Service de Médecine Interne, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bierling
authors.affiliation: Service de Médecine Interne, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.
authors.forename: Medhi
authors.initials: M
authors.lastname: Khellaf
authors.affiliation: Service de Médecine Interne, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Michel
authors.affiliation: Service d'Immunologie Clinique, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Université Paris Diderot Paris VII, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Oksenhendler
authors.affiliation: Service de Médecine Interne, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Godeau
mesh_terms: D000293:Adolescent; D000328:Adult; D000361:Agammaglobulinemia / Q000139:chemically induced*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000009:adverse effects*; D001402:B-Lymphocytes / Q000276:immunology; D005260:Female; D005602:France; D006801:Humans; D006886:Hydroxychloroquine / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000009:adverse effects; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use; D012189:Retrospective Studies; D000069283:Rituximab; D013921:Thrombocytopenia / Q000150:complications / Q000188:drug therapy*
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D007166:Immunosuppressive Agents; D000069283:Rituximab; D006886:Hydroxychloroquine; D011241:Prednisone