rheumatoid arthritis ( ra ) is the most frequent chronic autoimmune inflammatory rheumatism , with a worldwide prevalence around 1% .
ra severity is related to joint destruction characterised by erosion and space narrowing that is responsible for joint functional disability [ 24 ] .
early diagnosis and treatment are crucial in order to prevent joint destruction and preserve joint function defining the  window of opportunity  concept [ 5 , 6 ] . since few years , the concept  outside - inside  suggested a beginning of ra disease also in the subchondral bone marrow .
in fact , a subchondral bone loss at the metacarpal phalangeal head starts since the early phase of ra disease .
furthermore , joint inflammation due to synovitis is one of the most powerful predictors of new bone erosion .
so , the synovial membrane was the first actor mainly described by production of some mediators induced by inflammatory cytokines such as tnf or others .
these mediators induced cartilage matrix degradation and subchondral bone loss [ 10 , 11 ] .
these data support a strong interaction between synovial membrane , cartilage , and subchondral bone .
inflammatory joint induced the release of specific protein fragments from its various compartments into the serum and the urine , which may be used as tissue specific biomarkers . by this way
, biomarkers of each component of the joint could be useful to manage ra patients .
tnf inhibitors and other biologics reduce synovitis , biomarkers of inflammation , and bone destruction .
these tnf inhibitors are able to block joint destruction , even if ra disease is still active [ 1315 ] . in 2014 , in front of early ra patient , the goal of early ra therapy is to obtain remission according to the new criteria for remission acr / eular . however , though clinical remission was obtained , in some patients a structural progression can occur   probably due to persistence of joint inflammation [ 18 , 19 ] .
exploration with specific biomarkers of each component of the joint could be helpful to investigate this paradigm . in daily practice in 2014 ,
only das28 combining clinical parameters with erythrocyte sedimentation rate ( esr ) or c - reactive protein ( crp ) is used .
so , they are not strongly correlated with joint involvement . despite its large usefulness in daily practice , das28 fails to strongly predict the joint progression or a real remission .
at the time of  personalized medicine ,  which aims to individually improve treatment management , biomarkers of the joint will be useful in ra especially at the early stage .
the aim of this paper is to review some biomarkers of synovial , cartilage , and bone turnover in ra , clarify their utility in ra management , and analyze data in remission .
matrix metalloproteinase-3 ( mmp-3 or stromelysin 1 ) is a proteinase secreted by synovial fibroblasts and chondrocytes .
its activity results in degradation of aggrecan core protein , cartilage link protein , fibronectin , and collagen types iv , vii , ix , and xi .
mmp-3 is present in ra synovial fluid and overexpressed in rheumatoid synovium [ 23 , 24 ] .
one mmp-3 polymorphism was described to be associated with higher joint damage in ra [ 25 , 26 ] .
otherwise , serum mmp-3 level was suggested as a predictor for joint destruction in early ra [ 27 , 28 ] or established ra [ 29 , 30 ] .
correlation between serum mmp-3 level and joint damage progression appeared to be independent of rheumatoid factor ( rf ) or acpa status .
the next step was to assess mmp-3 variation induced by ra therapy and particularly during biological therapies .
anti - tnf therapy decreased mmp-3 expression in ra patients [ 32 , 33 ] .
similar results were observed with tocilizumab ( il-6 blocker )   or abatacept ( inhibitor of costimulation ) .
its level was similar in ra patients in remission or not induced by anti - tnf therapy . however , normal mmp-3 level in ra patients treated with tocilizumab was predictive to absence of relapse after tocilizumab cessation . to summarize ,
high mmp-3 level was associated with disease activity and joint progression in ra patients and should be used in association with usual inflammatory markers to follow therapy efficiency . however
, this biomarker was never tested in patients in clinical remission to predict structural remission .
another synovial biomarker considered in ra is the glycosylated form of pyridinoline ( pyd ) .
pyd is mainly a bone resorption biomarker but is also related to remodeling of cartilage and synovium .
the glycosylated analogue of pyd , glucosyl - galactosyl - pyd ( glc - gal - pyd ) , can be assessed in urine and appeared to be specific to synovial tissue .
urinary glc - gal - pyd level was higher in patients with early ra than controls and its high level is associated with higher risk for the progression of joint damage . in established ra , urinary glc - gal - pyd was associated with changes of the erosion , joint space narrowing ( jsn ) , and the total sharp score .
after one year of anti - tnf therapy , the levels of urinary glc - gal - pyd was similar in ra patients with or without progressive joint damage over one year of anti - tnf therapy , but its reduction over one year was higher in patients with progressive joint damage .
these results suggested that , in some patients , other mechanisms were possibly involved than tnf related inflammation .
the last synovium biomarker recently developed is the nitrated type iii collagen ( iiinys ) , which was explored in both osteoarthritis ( oa ) and ra patients . in patients with joint disorder ,
its level was the highest in ra patients which suggests that it is related to synovial tissue inflammation .
we attempted to describe synovial biomarkers and put out their interest in ra management . despite many studies reviewed , no data are currently available to predict relapse in ra patients in remission
then , we focused on three main cartilage biomarkers with a summary of their characteristics in table 2 .
two are biomarkers of cartilage breakdown , whereas the third one is a biomarker of cartilage formation .
cartilage is mainly composed of collagen type ii ( 70% ) and proteoglycans including aggrecan which is the most abundant one . mmps and aggrecanases are mediators of cartilage degradation .
collagen type ii c - telopeptide ( ctx - ii ) is a neoepitope generated from mmps , derived from the carboxy - terminal part of type ii collagen . in early ra , urinary ctx - ii level was higher than in controls , and patients with high ctx - ii level have a higher risk for the progression of joint damage over 1 year , independent of the extent of joint destruction at baseline and of clinical indices of disease activity . in established ra ,
urinary ctx - ii level was associated with rapid radiologic progression   or changes of the jsn sharp score over one year .
then , ctx - ii was assessed during anti - tnf therapy in ra patients .
after one year of anti - tnf therapy , the levels of urinary ctx - ii were similar in ra patients with or without progressive joint damage over one year of anti - tnf therapy . in patients with progressive joint damage , reduction of urinary ctx - ii was higher than in others .
cartilage oligomeric matrix protein ( comp ) is a noncollagenous extracellular matrix protein mainly found in cartilage maintaining the integrity of the collagen network .
serum comp was reduced in ra patients in remission induced by anti - tnf therapy compared to other patients . in early ra ,
early changes in serum comp levels were related to radiological outcome over the first 5 years .
serum propeptide of type iia procollagen ( piianp ) arises from the maturation of type iia procollagen .
its level was decreased in patients with oa or ra . in ra patients treated with low - dose corticosteroids ,
no data are at this time available to describe their interest to predict relapse in ra patient in remission .
bone homeostasis is highly regulated by balance between new bone formation and removing old bone .
bone formation markers included the serum bone formation markers total osteocalcin ( oc ) , the alkaline phosphatase bone isoenzyme ( balp ) , and the c- and n - propeptide of type i collagen ( picp and pinp ) . bone degradation is driven by osteoclasts and results in stimulation by rankl induced by il-1 , il-6 , or tnf .
osteoclasts secrete cathepsin k , which degrades the collagen type i and releases c - terminal crosslinked telopeptide of type i collagen ( ctx - i ) , or n - terminal crosslinked telopeptide of type i collagen ( ntx ) neoepitope .
the crosslinked carboxyterminal telopeptide of type i collagen ( ictp ) is another fragment of c - telopeptide end , which is not released with cathepsin k action but probably mmps [ 52 , 53 ] .
other type i collagen crosslinks are pyridinoline ( pyd ) and deoxypyridinoline ( dpd ) . in established ra , uncoupling with low level of bone formation markers and high bone resorption markers was described in 1999 .
oc , a bone formation marker , was reduced in ra without destruction compared to controls . on the contrary ,
ctx - i , a catabolic bone marker , is higher in ra patients with destruction compared to other ra patients .
this uncoupling was recently confirmed by using an innovative way to assess bone damage in ra by high - resolution peripheral quantitative computed tomography ( hr - pqct ) .
trap 5b level , a catabolic bone marker , was associated with bone erosions , whereas bone alkaline phosphatase ( bap ) was associated with osteophytes .
furthermore , in longitudinal studies , catabolic bone markers ( ctx - i or pyd ) are also good predictors for radiologic progression in ra [ 47 , 58 , 59 ] . like cartilage and synovium turnover markers ,
ratio between bone formation markers and bone resorption markers increased during one year of treatment , suggesting improvement of the bone remodeling balance , mainly due to a decrease in bone resorption .
a differential effect was observed at one year of anti - tnf therapy between ictp and ctx - i .
ictp , which is related to mmps activity , remained decreased at one year , whereas ctx - i level , which is related to cathepsin k , returned to its baseline level at one year .
this suggests a strong effect of anti - tnf on local subchondral bone related to joint inflammation . since tnf blockers already showed a reduction of the bone biomarker unbalance , tnf blockers also demonstrated a positive effect on bone mineral density in ra patients with or without a clinical response as observed at the joint level .
all these data support that anti - tnf therapy is not only able to prevent joint destruction , but it is also able to prevent bone loss in ra patients .
similarly , with tocilizumab , bone formation biomarker pinp increased whereas bone resorption markers , ictp and ctx - i , decreased .
this suggests a nonspecific effect of a pathway but an effect on suppression of joint inflammation .
denosumab reduced both serum pinp and ctx - i levels over one year , whereas urinary ctx - ii decreased only at 3 months . since denosumab targets rankl , but not a proinflammatory cytokine , ra disease was not improved , but it reduced erosion progression . so according to the target , drugs have different effects .
blocking inflammation reduces bone loss , but blocking pathway induced in bone loss reduced it without effect on ra activity . among all these biomarkers ,
only ctx - i has demonstrated its ability to be associated with joint destruction , sensitivity to treatment , and prediction of joint progression
we showed that synovium , cartilage , and bone turnover biomarkers are correlated with ra activity . to summarize
furthermore , these biomarkers could be useful to identify ra patients with high risk of rapid disease progression .
since these biomarkers reflected different compartments involved in ra , they will be useful to define structural remission in ra .
some of these reviewed biomarkers compose the multibiomarker disease activity ( mbda ) test developed to quantify ra disease activity .
recent data suggested that low mbda was associated with clinical remission criteria [ 67 , 68 ] .
treat - to - target strategy emerged since few years to manage early ra patients .
only one study combining clinical and biomarkers demonstrated its utility in the treat - to- target strategy .
however , we need more studies to generate more data to define the place of these biomarkers in ra remission . at this time
 
 objective . 
 the aim of this review is to clarify the usefulness of bone , cartilage , and synovial biomarker in the management of rheumatoid arthritis ( ra ) therapy in remission . 
 synovial biomarkers . 
 high mmp-3 levels are associated with joint progression in ra patients , but there is no data about their utility in clinical remission . 
 iiinys and glc - gal - pyd seem to be more specific to synovium , but more studies are required . 
 cartilage biomarkers . 
 unbalance between cartilage break - down biomarkers ( urinary ctx ii and comp ) and cartilage formation biomarker ( piianp ) was described . 
 this unbalance is also associated with joint destruction and prognosis of destruction . 
 no data are available on patients in remission . 
 bone biomarkers . 
 ra activity is correlated with an increase of bone resorption markers such as ctx i , pyd , and tracp 5b and a decrease of bone formation markers such as oc and balp . 
 ra therapies seem to improve bone turnover in limiting bone resorption . there is no study about bone marker utility in remission 
 . conclusion . 
 biomarkers seem to correlate with ra activity and progression . 
 they also could be used to manage ra therapies , but we need more data on ra remission to predict relapse . 
1. Introduction
2. Synovial Biomarkers
3. Cartilage Biomarkers
4. Bone Biomarkers
5. Discussion