title: Outcome of intensive immunosuppression and autologous stem cell transplantation in patients with severe rheumatoid arthritis is associated with the composition of synovial T cell infiltration.
abstract: OBJECTIVE
  To determine clinical and immunological correlates of high dose chemotherapy (HDC) + autologous stem cell transplantation (ASCT) in patients with severe rheumatoid arthritis (RA), refractory to conventional treatment.
  
  
  METHODS
  Serial samples of peripheral blood and synovial tissue were obtained from seven patients with RA treated with HDC and autologous peripheral blood grafts enriched for CD34+ cells. Disease activity was assessed with the Disease Activity Score (DAS), serum concentrations of C reactive protein (CRP), and human immunoglobulin (HIg) scans, and the extent of immunoablation was determined by immunophenotyping of peripheral blood mononuclear cells, and immunohistochemistry and double immunofluorescence of synovium.
  
  
  RESULTS
  Clinical responders (n = 5) had a larger number of cells at baseline expressing CD3, CD4, CD27, CD45RA, CD45RB, and CD45RO in synovium (p < 0.05), higher activity on HIg scans (p = 0.08), and a trend towards higher concentrations of CRP in serum than non-responders (n = 2). Subsequent remissions and relapses in responders paralleled reduction and re-expression, respectively, of T cell markers. A relatively increased expression of CD45RB and CD45RO on synovial CD3+ T cells was seen after HDC + ASCT. No correlations were found between DAS and changes in B cells or macrophage infiltration or synoviocytes.
  
  
  CONCLUSIONS
  HDC + ASCT results in profound but incomplete immunoablation of both the memory and naïve T cell compartment, which is associated with longlasting clinical responses in most patients. The findings provide strong circumstantial evidence for a role of T cells in established RA, and demonstrate a role for the synovium in post-transplantation T cell reconstitution.
authors.affiliation: Department of Rheumatology, Division of Nuclear Medicine, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: R J
authors.initials: RJ
authors.lastname: Verburg
authors.forename: R
authors.initials: R
authors.lastname: Flierman
authors.forename: J K
authors.initials: JK
authors.lastname: Sont
authors.forename: F
authors.initials: F
authors.lastname: Ponchel
authors.forename: L
authors.initials: L
authors.lastname: van Dreunen
authors.forename: E W
authors.initials: EW
authors.lastname: Levarht
authors.forename: M M
authors.initials: MM
authors.lastname: Welling
authors.forename: R E M
authors.initials: RE
authors.lastname: Toes
authors.forename: J D
authors.initials: JD
authors.lastname: Isaacs
authors.forename: J M
authors.initials: JM
authors.lastname: van Laar
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000097:blood; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000628:therapy; D002097:C-Reactive Protein / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D016130:Immunophenotyping; D007165:Immunosuppression Therapy; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D015703:Antigens, CD; D018501:Antirheumatic Agents; D007136:Immunoglobulins; D002097:C-Reactive Protein