title: Abatacept or tocilizumab after rituximab in rheumatoid arthritis? An exploratory study suggests non-response to rituximab is associated with persistently high IL-6 and better clinical response to IL-6 blocking therapy.
abstract: OBJECTIVE
  To evaluate the efficacy and safety of two different targeted approaches-abatacept or tocilizumab-after rituximab therapy in rheumatoid arthritis, and to explain observed difference in efficacy using blood and synovial studies of interleukin 6 (IL-6) and B cells in patients receiving rituximab therapy.
  
  
  METHODS
  Consecutive series of patients who had discontinued rituximab therapy owing to inefficacy or toxicity were treated with abatacept (n=16) or tocilizumab (n=35). Clinical response and reasons for discontinuation were evaluated. Serial blood and synovial samples were obtained from a group of 57 and 25 rituximab-treated patients, respectively, and were analysed for B cells and IL-6 using flow cytometry, immunohistochemistry and quantitative real-time PCR.
  
  
  RESULTS
  In the abatacept group, mean (SEM) Disease Activity Score in 28 joints calculated using the erythrocyte sedimentation rate (DAS28-ESR) reduced from 5.69 (0.42) at baseline to 4.94 (0.44) at 6 months (p=0.12). In the tocilizumab group: mean (SEM) DAS28- ESR reduced from 5.75 (0.21) at baseline to 3.28 (0.26) at 6 months (p<0.001). This was paralleled by a significant swollen joint count reduction in the tocilizumab (5.47 (0.70) to 2.70 (0.61), p=0.033), but not abatacept (6.23 (1.3) to 4.15 (1.2), p=0.26), group. In the synovium, despite complete depletion of B cells in 19/22 patients, IL-6 mRNA expression was not significantly reduced after rituximab. Blood B cell numbers remained low 12 months after rituximab. Serum IL-6 was raised at baseline and significantly higher in rituximab clinical non-responders (p=0.035) than responders. A significant reduction in serum IL-6 was seen in rituximab clinical responders (p=0.005) but not in non-responders (p=0.237).
  
  
  CONCLUSIONS
  In patients with rheumatoid arthritis for whom rituximab therapy failed despite adequate B cell depletion, IL-6-directed therapy might be a more logical and effective treatment choice than T cell costimulation blockade. Further controlled studies investigating other possible mechanisms are needed to validate these initial findings.
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, , Leeds, UK.
authors.forename: Sudipto
authors.initials: S
authors.lastname: Das
authors.forename: Edward M
authors.initials: EM
authors.lastname: Vital
authors.forename: Sarah
authors.initials: S
authors.lastname: Horton
authors.forename: Domini
authors.initials: D
authors.lastname: Bryer
authors.forename: Yasser
authors.initials: Y
authors.lastname: El-Sherbiny
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Rawstron
authors.forename: Frederique
authors.initials: F
authors.lastname: Ponchel
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: Maya H
authors.initials: MH
authors.lastname: Buch
mesh_terms: D000069594:Abatacept; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000032:analysis; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D000069283:Rituximab; D013583:Synovial Membrane / Q000737:chemistry / Q000276:immunology; D055815:Young Adult; D000093242:Interleukin-6 Inhibitors
chemical_list: D000069594:Abatacept; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D018796:Immunoconjugates; D015850:Interleukin-6; D000069283:Rituximab; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; C502936:tocilizumab