title: Towards personalised treatment in primary Sjögren's syndrome: baseline parotid histopathology predicts responsiveness to rituximab treatment.
abstract: OBJECTIVE
  The aims of this study were (1) to assess the effect of rituximab (RTX; anti-CD20) treatment in patients with primary Sjögren's syndrome (pSS) based on sequential parotid biopsies obtained in a placebo-controlled, randomised clinical trial, and (2) to assess the prognostic value of the histological characteristics of parotid gland tissue with regard to responsiveness to RTX treatment.
  
  
  METHODS
  In a double-blinded, placebo-controlled trial, sequential parotid gland biopsies were taken from 20 RTX-treated and 10 placebo-treated patients with pSS, at baseline and 12 weeks after treatment. The relative amount of lymphocytic infiltrate (stained for CD45), absolute number of T cells and B cells per mm2parenchyma (stained for CD3 and CD20, respectively), focus score, number of germinal centres and of lymphoepithelial lesions per mm2in parotid gland parenchyma were assessed. Histopathological data were compared between clinical responders (decrease in European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) score of ≥3 at 12 weeks compared with baseline) and non-responders (change in ESSDAI<3) to RTX treatment.
  
  
  RESULTS
  In RTX-treated patients, a significant reduction in the number of CD20+ B cells/mm2parenchyma was observed, while no such reduction was observed in placebo-treated patients. The number of CD3+ T cells/mm2in parenchyma did not change in either group. Furthermore, the number and the severity of lymphoepithelial lesions/mm2and number of germinal centres/mm2was significantly reduced in RTX-treated patients, but did not change in placebo-treated patients. When comparing the pretreatment characteristics of clinical responders with non-responders, the median number of CD20+ B cells/mm2parenchyma at baseline was significantly higher in responders (1871 vs 353 cells/mm2, p<0.05). Other histopathological baseline characteristics were not predictive for response to RTX treatment.
  
  
  CONCLUSIONS
  RTX treatment in pSS leads to a major reduction of lymphocytic infiltration and to fewer B cells, germinal centres and lymphoepithelial lesions in parotid gland parenchyma. A high pretreatment number of CD20+ B cells/mm2parotid gland parenchyma predicts better responsiveness of patients with pSS to RTX treatment. Pretreatment parotid gland histopathological characteristics could therefore contribute to a more personalised treatment approach to pSS.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Delli
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Erlin A
authors.initials: EA
authors.lastname: Haacke
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Kroese
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Rodney P
authors.initials: RP
authors.lastname: Pollard
authors.affiliation: Laboratory for Dermatohistology & Oral Pathology, Munich, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ihrler
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: van der Vegt
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Arjan
authors.initials: A
authors.lastname: Vissink
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hendrika
authors.initials: H
authors.lastname: Bootsma
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Frederik K L
authors.initials: FK
authors.lastname: Spijkervet
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism; D001706:Biopsy; D002452:Cell Count; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D008297:Male; D010306:Parotid Gland / Q000166:cytology / Q000473:pathology*; D057285:Precision Medicine; D000069283:Rituximab / Q000627:therapeutic use*; D012720:Severity of Illness Index; D012859:Sjogren's Syndrome / Q000188:drug therapy / Q000473:pathology*; D013601:T-Lymphocytes / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D007155:Immunologic Factors; D000069283:Rituximab
keywords: B cells; Disease Activity; Outcomes research; Sjøgren's Syndrome