Leucine-rich α2 -glycoprotein as a potential biomarker for joint inflammation during anti-interleukin-6 biologic therapy in rheumatoid arthritis.
OBJECTIVE
To investigate whether leucine-rich α2 -glycoprotein (LRG) could be a biomarker for disease activity during interleukin-6 (IL-6) blockade treatment of rheumatoid arthritis (RA).


METHODS
In 59 RA patients who were treated with tocilizumab for 24 weeks, serum LRG levels were determined by enzyme-linked immunosorbent assay. RA disease activity was evaluated by the Clinical Disease Activity Index (CDAI). Receiver operating characteristic (ROC) curve analysis was used to examine the diagnostic performance of LRG and other biomarkers. In monkeys with experimental autoimmune arthritis, swollen joint counts, joint pathologic changes, and blood levels of C-reactive protein (CRP) and LRG were evaluated after treatment with anti-IL-6 receptor antibody.


RESULTS
Among tocilizumab-treated RA patients, those with active disease (CDAI >2.8) had significantly higher serum LRG levels compared to those whose disease was in remission. ROC curve analysis suggested that the LRG level was more useful than the CRP or matrix metalloproteinase 3 level or the erythrocyte sedimentation rate in discriminating between remission and active disease during therapy with tocilizumab. In monkeys treated with IL-6 blockade, joint scores were more closely correlated with LRG levels than with CRP levels. Histologic analysis of joints revealed that LRG levels correlated significantly with granulomatous tissue formation, cartilage degeneration, and bone destruction in IL-6 blockade-treated monkeys with low levels of CRP.


CONCLUSIONS
Under conditions of IL-6 inhibition, LRG was more useful than other biomarkers in discriminating between active and inactive disease in human RA and in detecting joint inflammation in experimental arthritis. LRG may serve as a convenient biomarker for RA disease activity during IL-6 blockade treatment.
National Institute of Biomedical Innovation, Osaka, Japan.
Minoru
M
Fujimoto
National Institute of Biomedical Innovation, Osaka, Japan.
Satoshi
S
Serada
Keio University School of Medicine, Tokyo, Japan.
Katsuya
K
Suzuki
Keio University School of Medicine, Tokyo, Japan.
Ayumi
A
Nishikawa
Osaka University Graduate School of Medicine, Osaka, Japan.
Atsushi
A
Ogata
Tokyo Medical and Dental University and Teikyo University, Tokyo, Japan.
Toshihiro
T
Nanki
Chugai Pharmaceutical, Gotemba, Japan.
Kunihiro
K
Hattori
Tokyo Medical and Dental University, Tokyo, Japan.
Hitoshi
H
Kohsaka
Tokyo Medical and Dental University, Tokyo, Japan.
Nobuyuki
N
Miyasaka
Keio University School of Medicine, Tokyo, Japan.
Tsutomu
T
Takeuchi
National Institute of Biomedical Innovation, Osaka, Japan.
Tetsuji
T
Naka
D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015415:Biomarkers; D006023:Glycoproteins; C508603:IL6R protein, human; C015246:LRG1 protein, human; D019947:Receptors, Interleukin-6; D002097:C-Reactive Protein; C502936:tocilizumab