title: Platelet-associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia.
abstract: Rituximab is widely used in autoimmune diseases including immune thrombocytopenia (ITP), although the mechanism of effect remains unclear. This study describes the effects of rituximab on platelet-associated antibodies (PA-APAs), B and T cell counts and clonality ( IGHV and TRG@ gene rearrangements), FCGR3A (FcγRIIIa) and FCGR2A (FcγRIIa) polymorphisms and correlation to anti-CD40 ligand (CD40L) response. PA-APA levels fell more frequently in responders (6/8) than in non-responders (2/10: P = 0·08-0·15). Two responders had no PA-APAs. Two non-responders with a fall in PA-APAs had very high CD8 levels. One non-responder had a B cell clone, one responder and one non-responder had a T cell clone. 15/16 patients had the same responses to rituximab and antiCD40L. Patients with FCGR3A V/V polymorphisms were more likely to respond to rituximab (P = 0·03). In summary, the fall in PA-APAs in responders confirms the humoural effect of rituximab. Failure to respond in patients with very high CD8 levels, despite PA-APA fall indicates a role for T cell-mediated platelet/megakaryocyte destruction. Concordance of response to anti-CD40L suggests autoantibody-producing cells are under T cell control. Finally, the effect of FCGR polymorphisms on response confirms the importance of FCGR-mediated depletion of B cells in autoimmunity. This has implications on the pathology of ITP as well as the immunological effect of B cell depletion.
authors: Department of Haematology, Hammersmith Hospital, Imperial Health Care NHS Trust, London, UK. n.cooper@imperial.ac.uk
authors: Nichola
authors: N
authors: Cooper
authors: Roberto
authors: R
authors: Stasi
authors: Susanna
authors: S
authors: Cunningham-Rundles
authors: Ethel
authors: E
authors: Cesarman
authors: Janice G
authors: JG
authors: McFarland
authors: James B
authors: JB
authors: Bussel
mesh_terms: D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D018951:Antigens, CD20 / Q000276:immunology; D001323:Autoantibodies / Q000097:blood*; D001792:Blood Platelets / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000037:antagonists & inhibitors; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006801:Humans; D007111:Immunity, Cellular; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology; D011110:Polymorphism, Genetic; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics*; D000069283:Rituximab; D013926:Thrombopoietin / Q000097:blood; D016896:Treatment Outcome
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D001323:Autoantibodies; C496124:FCGR3A protein, human; D007166:Immunosuppressive Agents; D017452:Receptors, IgG; D023201:CD40 Ligand; D000069283:Rituximab; D013926:Thrombopoietin