Platelet-associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia

• Published in: British journal of haematology 2012-08, Vol.158 (4), p.539-547
• Main Authors: Cooper, Nichola, Stasi, Roberto, Cunningham-Rundles, Susanna, Cesarman, Ethel, McFarland, Janice G., Bussel, James B.
• Format: Article
• Language: English
• Subjects: Adult; Aged; anti-CD20; anti-platelet antibodies; Antibodies, Monoclonal, Murine-Derived - therapeutic use; Antigens, CD20 - immunology; Autoantibodies - blood; Biological and medical sciences; Blood Platelets - immunology; CD4-Positive T-Lymphocytes - immunology; CD40 Ligand - antagonists & inhibitors; CD8; CD8-Positive T-Lymphocytes - immunology; Drug Therapy, Combination; Fc receptors; Female; Genotype; Hematologic and hematopoietic diseases; Humans; Immunity, Cellular; Immunophenotyping; Immunosuppressive Agents - therapeutic use; Killer Cells, Natural - immunology; Leukocyte Count; Male; Medical sciences; Middle Aged; neutrophils; Neutrophils - immunology; Platelet diseases and coagulopathies; Polymorphism, Genetic; Purpura, Thrombocytopenic, Idiopathic - drug therapy; Purpura, Thrombocytopenic, Idiopathic - genetics; Purpura, Thrombocytopenic, Idiopathic - immunology; Receptors, IgG - genetics; Rituximab; T cells; Thrombopoietin - blood; Treatment Outcome
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2012.09184.x

Summary 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.