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

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 wo...

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Bibliographic Details
Published in:PloS one 2014-08, Vol.9 (8), p.e106253-e106253
Main Authors: Choi, Ivy Y, Gerlag, Danielle M, Holzinger, Dirk, Roth, Johannes, Tak, Paul P
Format: Article
Language:English
Subjects:
Adalimumab
Adult
Analysis
Antibodies, Monoclonal - administration & dosage
Antibodies, Monoclonal - pharmacology
Antibodies, Monoclonal, Humanized - administration & dosage
Antibodies, Monoclonal, Humanized - pharmacology
Antibodies, Monoclonal, Murine-Derived - administration & dosage
Antibodies, Monoclonal, Murine-Derived - pharmacology
Antirheumatic agents
Antirheumatic Agents - administration & dosage
Antirheumatic Agents - pharmacology
Arthritis
Arthritis, Rheumatoid - blood
Arthritis, Rheumatoid - drug therapy
ATP-Binding Cassette Transporters - blood
Bioindicators
Biological effects
Biology and Life Sciences
Biomarkers
Biomarkers - blood
Biopharmaceuticals
Biopsy
C-reactive protein
C-Reactive Protein - metabolism
Calgranulin B - blood
Care and treatment
Chemokines
Clinical trials
Developmental stages
Drug development
Drugs
Endothelium
Female
Gangrene
Hospitals
Humans
Immunology
Inflammation
Infliximab
Joint diseases
Macrophages
Male
Material requirements planning
Medical research
Medicine and Health Sciences
Middle Aged
Monoclonal antibodies
Patients
Peripheral blood
Placebo effect
Placebos
Prospective Studies
Proteins
R&D
Research & development
Rheumatoid arthritis
Rheumatoid factor
Rheumatology
Rituximab
Sensitivity
Serum levels
Treatment Outcome
Tumor necrosis factor-TNF
Tumor necrosis factor-α
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Description
Summary: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. 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). 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. 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0106253