title: From synovial tissue to peripheral blood: myeloid related protein 8/14 is a sensitive biomarker for effective treatment in early drug development in patients with rheumatoid arthritis.
abstract: OBJECTIVE
  The change in number of CD68-positive sublining macrophages in serial synovial biopsies has been successfully used to discriminate on the group level between effective and ineffective treatment during early drug development in rheumatoid arthritis (RA) patients. Measurement of a soluble biomarker would clearly have practical advantages. Therefore, we investigated the sensitivity to change of myeloid related protein (MRP)8/14 in serum.
  
  
  METHODS
  139 RA patients who received known effective biologics (infliximab, adalimumab and rituximab) and 28 RA patients who received placebo/ineffective therapies were included. MRP8/14 levels were analyzed in baseline and follow-up serum samples and the standardized response mean (SRM) was calculated to determine the sensitivity to change of MRP8/14 in comparison to C-reactive protein (CRP) levels and the disease activity score evaluated in 28 joints (DAS28).
  
  
  RESULTS
  In patients treated with effective treatment, the SRM for MRP8/14 was moderate (0.56), but in patients treated with placebo/ineffective treatment the SRM was 0.06, suggesting that this biomarker is perhaps not susceptible to placebo effects in proof-of-concept studies of relatively short duration. In contrast, the SRM for DAS28 was high for effective treatment (1.07), but also moderate for ineffective treatment (0.58), representing the placebo effect. The SRM for CRP was low in the effective (0.33) and ineffective (0.23) treatment groups.
  
  
  CONCLUSIONS
  These data support the notion that quantification of changes in MRP8/14 serum levels could be used to predict potential efficacy of novel antirheumatic drugs in an early stage of drug development. A positive result would support the rationale for larger, conventional clinical trials to determine whether the effects are clinically relevant.
authors.affiliation: Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Ivy Y
authors.initials: IY
authors.lastname: Choi
authors.affiliation: Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Gerlag
authors.affiliation: Department of Paediatric Rheumatology and Immunology, University Children's Hospital Muenster, Muenster, Germany; Institute of Immunology, University Hospital Muenster, Muenster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Holzinger
authors.affiliation: Institute of Immunology, University Hospital Muenster, Muenster, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.affiliation: Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000097:blood*; D000068879:Adalimumab; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D040502:Calgranulin B / Q000097:blood*; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D000069283:Rituximab; D016896:Treatment Outcome
chemical_list: C435500:ABCC11 protein, human; D018528:ATP-Binding Cassette Transporters; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D015415:Biomarkers; D040502:Calgranulin B; D000069283:Rituximab; D002097:C-Reactive Protein; D000069285:Infliximab; D000068879:Adalimumab