PMID- 28850021
OWN - NLM
STAT- MEDLINE
DCOM- 20180424
LR  - 20180424
IS  - 0392-856X (Print)
IS  - 0392-856X (Linking)
VI  - 36
IP  - 1
DP  - 2018 Jan-Feb
TI  - Suppression of active, but not total MMP-3, is associated with treatment response 
      in a phase III clinical study of rheumatoid arthritis.
PG  - 94-101
AB  - OBJECTIVE: Biologics for rheumatoid arthritis (RA) patients with moderate to 
      severe disease may preserve joint function. Matrix metalloproteinase 3 (MMP-3), a 
      key tissue degrading protease, is highly elevated in RA. MMP-3, which measures 
      the total pool of circulating MMP-3 species (cMMP3), is a commonly measured 
      biomarker in rheumatology. The aim was to investigate the association of 
      activated MMP-3 (actMMP3) species with treatment response compared to cMMP-3. 
      METHODS: The LITHE biomarker study (n=741) was a 1-year phase III, double-blind, 
      placebo-controlled, parallel group study of TCZ in RA patients on stable 
      methotrexate. cMMP-3 and actMMP-3 were assessed in fasting serum at baseline, 
      week 4, 16, 24 and 52. Patients not achieving ACR20 remission at week 16 or 28 
      received rescue treatment (escapers). Spearman's correlation was analysed between 
      biomarker baseline level or biomarker delta and clinical measures. Changes in 
      biomarker levels were studied as a function of time and treatment. RESULTS: 
      ActMMP-3 16-week change in treatment groups was predictive of 1-year radiographic 
      progression; a small change in actMMP3 was equal to worsening radiographics. 
      Baseline cMMP-3 was associated with 52-weeks' radiographic status and cMMP3 
      16-weeks' change was predictive of 1-year change in disease activity. ActMMP-3 
      was dose-dependently decreased by TCZ, and escapers decreased in actMMP-3 upon 
      treatment. CONCLUSIONS: ActMMP-3 and cMMP-3 were found to be efficacy biomarkers 
      of TCZ and actMMP-3 were able to differentiated doses. Moreover, the suppression 
      of actMMP3, but not cMMP3 was associated with treatment response. This study 
      illustrates that two biomarkers of the same protein may have different predictive 
      capacities.
FAU - Siebuhr, Anne Sofie
AU  - Siebuhr AS
AD  - Biomarkers and Research, Nordic Bioscience, Herlev, Denmark. aso@nordicbio.com.
FAU - Kjelgaard-Petersen, Cecilie F
AU  - Kjelgaard-Petersen CF
AD  - Biomarkers and Research, Nordic Bioscience, Herlev; Bioengineering, Technical 
      University of Denmark, Kgs. Lyngby, Denmark.
FAU - Sun, Shu
AU  - Sun S
AD  - Biomarkers and Research, Nordic Bioscience, Herlev, Denmark.
FAU - Byrjalsen, Inger
AU  - Byrjalsen I
AD  - Biomarkers and Research, Nordic Bioscience, Herlev, Denmark.
FAU - Christiansen, Claus
AU  - Christiansen C
AD  - Centre of Clinical and Basic Research, Ballerup, Denmark.
FAU - Karsdal, Morten Asser
AU  - Karsdal MA
AD  - Biomarkers and Research, Nordic Bioscience, Herlev, Denmark.
FAU - Bay-Jensen, Anne-Christine
AU  - Bay-Jensen AC
AD  - Biomarkers and Research, Nordic Bioscience, Herlev, Denmark.
LA  - eng
PT  - Clinical Trial, Phase III
PT  - Comparative Study
PT  - Controlled Clinical Trial
PT  - Journal Article
DEP - 20170828
PL  - Italy
TA  - Clin Exp Rheumatol
JT  - Clinical and experimental rheumatology
JID - 8308521
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Biological Products)
RN  - 0 (Biomarkers)
RN  - 0 (Enzyme Precursors)
RN  - EC 3.4.24.- (Metalloendopeptidases)
RN  - EC 3.4.24.- (prostromelysin)
RN  - EC 3.4.24.17 (MMP3 protein, human)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - I031V2H011 (tocilizumab)
RN  - YL5FZ2Y5U1 (Methotrexate)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal, Humanized/*therapeutic use
MH  - Antirheumatic Agents/*therapeutic use
MH  - Arthritis, Rheumatoid/blood/diagnosis/*drug therapy/enzymology
MH  - Biological Products/*therapeutic use
MH  - Biomarkers/blood
MH  - Double-Blind Method
MH  - Down-Regulation
MH  - Enzyme Activation
MH  - Enzyme Precursors/blood
MH  - Female
MH  - Humans
MH  - Male
MH  - Matrix Metalloproteinase 3/*blood
MH  - Metalloendopeptidases/blood
MH  - Methotrexate/therapeutic use
MH  - Middle Aged
MH  - Remission Induction
MH  - Time Factors
MH  - Treatment Outcome
EDAT- 2017/08/30 06:00
MHDA- 2018/04/25 06:00
CRDT- 2017/08/30 06:00
PHST- 2016/12/19 00:00 [received]
PHST- 2017/05/24 00:00 [accepted]
PHST- 2017/08/30 06:00 [pubmed]
PHST- 2018/04/25 06:00 [medline]
PHST- 2017/08/30 06:00 [entrez]
AID - 11449 [pii]
PST - ppublish
SO  - Clin Exp Rheumatol. 2018 Jan-Feb;36(1):94-101. Epub 2017 Aug 28.