title: A plasmablast biomarker for nonresponse to antibody therapy to CD20 in rheumatoid arthritis.
abstract: An important goal for personalized health care is the identification of biomarkers that predict the likelihood of treatment responses. Here, we tested the hypothesis that quantitative mRNA assays for B lineage cells in blood could serve as baseline predictors of therapeutic response to B cell depletion therapy in subjects with rheumatoid arthritis (RA). In samples from the REFLEX trial of rituximab in inadequate responders to antibodies to tumor necrosis factor-α, a 25% subgroup of treated subjects with elevated baseline mRNA levels of IgJ, a marker for antibody-secreting plasmablasts, showed reduced clinical response rates. There were no significant efficacy differences in the placebo arm subjects stratified by this marker. Prospective testing of the IgJ biomarker in the DANCER and SERENE rituximab clinical trial cohorts and the SCRIPT ocrelizumab cohort confirmed the utility of this marker to predict nonresponse to anti-CD20 therapy. A combination mRNA biomarker, IgJhiFCRL5lo, showed improved test performance over IgJhi alone. This study demonstrates that baseline blood levels of molecular markers for late-stage B lineage plasmablasts identify a ~20% subgroup of active RA subjects who are unlikely to gain substantial clinical benefit from anti-CD20 B cell depletion therapy.
authors.affiliation: Department of Immunology Biomarker Discovery, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Kasia
authors.initials: K
authors.lastname: Owczarczyk
authors.forename: Preeti
authors.initials: P
authors.lastname: Lal
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Abbas
authors.forename: Kristen
authors.initials: K
authors.lastname: Wolslegel
authors.forename: Cecile T J
authors.initials: CT
authors.lastname: Holweg
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dummer
authors.forename: Ariella
authors.initials: A
authors.lastname: Kelman
authors.forename: Paul
authors.initials: P
authors.lastname: Brunetta
authors.forename: Nicholas
authors.initials: N
authors.lastname: Lewin-Koh
authors.forename: Marco
authors.initials: M
authors.lastname: Sorani
authors.forename: Diane
authors.initials: D
authors.lastname: Leong
authors.forename: Paul
authors.initials: P
authors.lastname: Fielder
authors.forename: David
authors.initials: D
authors.lastname: Yocum
authors.forename: Carole
authors.initials: C
authors.lastname: Ho
authors.forename: Ward
authors.initials: W
authors.lastname: Ortmann
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Townsend
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D018951:Antigens, CD20 / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D019070:Cell Lineage / Q000235:genetics; D015331:Cohort Studies; D003710:Demography; D005260:Female; D006801:Humans; D007144:Immunoglobulin J-Chains / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010950:Plasma Cells / Q000276:immunology*; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics; D011956:Receptors, Cell Surface / Q000276:immunology; D011961:Receptors, Fc; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000069283:Rituximab; D016896:Treatment Outcome
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D015415:Biomarkers; C432367:FCRL5 protein, human; D007144:Immunoglobulin J-Chains; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011961:Receptors, Fc; D000069283:Rituximab