Effect of tocilizumab combined with methotrexate on circulating biomarkers of synovium, cartilage, and bone in the LITHE study.
OBJECTIVE
We investigated the effects of tocilizumab (TCZ) on joint tissue remodeling in patients with moderate to severely active RA by measuring tissue-specific biomarker.


METHODS
The LITHE biomarker study (n = 740) was a phase III study of 4- and 8-mg/kg TCZ in combination with MTX. Early response was evaluated at week 16 as ±20% improvement in swollen/tender joint counts; and ACR50 was evaluated at week 52. Biomarkers (tissue inflammation: C3M, CRPM, and VICM; cartilage degradation: C2M; and bone turnover: CTx and osteocalcin) were tested in serum from baseline, week 4, 16, 24, and 52, and dose-dependent effect was investigated. Patients were divided into the following three groups: early non-responders (ENR), ACR50 responders, and non-responders; their biomarker profiles were compared.


RESULTS
At week 52, CRP was inhibited to 4% and 40% of baseline by TCZ8 and TCZ4, respectively. CRPM (63%), C2M (84%), C3M (69%), and VICM (42%) were significantly (p < 0.05) reduced by TCZ8, but not by TCZ4. MMP3 and osteocalcin changed to <58% and >111%, respectively, in response to TCZ. CTx was not changed significantly. ENRs had significantly less inhibition of CRPM (p < 0.05), C2M (p < 0.01), and C3M (p < 0.01) compared to early responders. There was a significant difference in the C2M, C3M, and CRPM profiles of the ENRs, non-responders, and responders. ACR50 responders had significantly inhibited levels (p < 0.001), irrespective of dose.


CONCLUSIONS
TCZ8 strongly inhibited the biomarkers of joint tissue remodeling suggesting that TCZ actively suppresses key pathobiological processes at the site of inflammation in RA patients. The differences in biomarkers' profiles of responders and non-responders indicate that specific responder profiles exist.
Nordic Bioscience, Herlev Hovedgade, DK-2730 Herlev, Denmark. Electronic address: acbj@nordicbioscience.com.
Anne C
AC
Bay-Jensen
Roche Products Ltd, Welwyn Garden City, United Kingdom.
Adam
A
Platt
Nordic Bioscience, Herlev Hovedgade, DK-2730 Herlev, Denmark.
Inger
I
Byrjalsen
Synarc Laboratories, Lyon, France.
Philippe
P
Vergnoud
Nordic Bioscience, Herlev Hovedgade, DK-2730 Herlev, Denmark.
Claus
C
Christiansen
Nordic Bioscience, Herlev Hovedgade, DK-2730 Herlev, Denmark.
Morten A
MA
Karsdal
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein; D024043:Collagen Type II / Q000097:blood; D024061:Collagen Type III / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D015675:Osteocalcin / Q000097:blood
D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015415:Biomarkers; D024043:Collagen Type II; D024061:Collagen Type III; D015675:Osteocalcin; D002097:C-Reactive Protein; C502936:tocilizumab; D008727:Methotrexate