Activated et al., 2002) that it may be

cells in RA are highly differentiated and are not expected to survive for long
time unless apoptosis of these cells is actively suppressed (Bokarewa et al.,
2005). The inhibition of apoptosis was observed
downstream of caspase-3 and may involve the caspase-3 inhibitors survivin (Dharmapatni et
al., 2009). Our systematic review shows that survivin
levels were clearly increased in SF and plasma of RA patients compared with the
healthy controls. The serum survivin values in different studies were approximately
close to each other (330-335pg/ml and 120-160pg/ml for RA and healthy subjects
respectively). P53 suppresses transcription of survivin and mutations and
functional deregulation of p53 have detected in the ST of RA patients (Hoffman et al.,
2002) that it may be possible reasons for increased
survivin production in this non-malignant condition such as RA. Also about the
origin of survivin in RA, higher levels of survivin in cell culture from BM
compared to culture from lymph node (LN) suggest that the BM to be a probable
source of the extracellular survivin found in serum during RA (Wasén et al.,
2017) although in other studies, FLS and peripheral
blood leukocytes as potential sources of extracellular survivin in the SF of RA
patients have been considered. Moreover, RTX treatment affects homeostasis of B
cells by elimination of the naïve and short-lived memory B cell from the
peripheral blood and in the BM. Depletion of B cells by RTX decreases serum
levels of RF, aCCP and also survivin-WT (Turkkila et al.,
2015). Decrease of survivin-WT in B cells after RTX
treatment suggests that IgD+ B cells depleted by RTX are either the major source
of survivin-WT (Ahn et al.,
2010). In current study possible roles of survivin in
RA pathogenesis have been investigated:  extracellular
survivin has been shown to be biologically active inducing surface expression
of adhesion molecules on leukocytes of RA patients. (Shi et al.,
2017). RA FLS secretes inflammatory cytokines and
tissue degradation enzyme such as MMPs in addition to survivin production (Ritchlin, 2000). Survivin helps the tumor-like proliferation of
RA-FLS and is involved in the secretion of the proinflammatory cytokine IL-6 and
MMPs. IL-6 promotes B cell growth and differentiation, Th17 cell generation, and
osteoclast formation. The levels of MMPs were proved to correlate with the
degree of articular surface erosion and involving in the angiogenesis and the
pannus formation in RA synovium tissues (Chen et al.,
2017). It should be mentioned that survivin can be
considered as a self-antigen because the presence of antibodies to survivin in
the plasma and synovial of RA patients was detected. The association of high
level of antibodies against survivin with non-erosive joint disease was shown
that it may be a reflection of a protective autoimmune mechanism existing in RA
patients. Activation of pathways including tyrosine kinases, mitogen-activated
protein kinases and PI3-kinase that were prerequisite for uPA and survivin
production has been recently shown to be critical for the expansion of erosive
arthritis in mice (Paniagua et al.,
2006, Dehlin et al., 2008). UPA modulates cell adhesion, migration and
proliferation. Survivin regulates the production and release of uPA by fibroblasts,
so it can be declared that survivin also regulate cell migration indirectly
through the uPA. Positive Association of survivin with IL-9, IL-12 and also
IL-2 indicates that this protein may play role in formation of Th1 and Th17
proinflammatory T-cell subsets and effector T cells according to mentioned
cytokines respectively. The relationship between survivin and smoking history
at baseline draws attention to a known predictive value of smoking for the
development of RA in addition to its clinical symptoms. On the other, smoking,
and nicotine in particular, shift the phenotype of CD8? T cells toward a nonexhausted state and
promotes the release of survivin. As well high survivin transcription in the
peripheral blood leukocytes of RA patients was associated with smoking and
deregulation of miR processing machinery specially Dicer enzyme. Survivin
regulates Dicer production and in this way limits apoptosis in the inflamed
arthritic joints. Since the microRNAs (miRs) characterize a part of epigenetic
control of autoimmunity, up-regulation of survivin in smokers introduces its
role as regulator of epigenetic mechanisms in RA disease. Reported relation
between RA and 2 established biomarkers predicting development of RA namely the
HLA-DRB1 shared epitope (SE) alleles and aCCP (Chun-Lai et al.,
2015) reflects common biological pathways in RA. So, the
high levels of survivin can be measured in the preclinical stage of the disease
and predicted development of RA. Also, the high correlation observed between
the presence of autoantibodies (RF and/or aCCP) and survivin suggested us to
combine survivin measurement with aCCP and/or RF in order to enhance the
predictive power for the development of joint destruction. Positive correlation
of aCCP with serum survivin may be because of that the overexpression of survivin
in RA patients extends survival time of synoviocyte and lymphocytes, retaining
their activation and infiltration and leading to breakdown of tolerance and bone erosion, as aCCP
is an important predictor of bone erosion (Long et al.,
2014). Strong predictability of survivin for radiological
progression both in the group of patients with and without erosions suggests a
value of survivin as a marker of insufficient anti-rheumatic treatment,
identifying patients requiring change of treatment. The measurement of serum survivin
is useful for planning treatment strategies in patients with early RA. The
effects of drugs on the level of survivin in the blood seem to be profound. Survivin
has higher expression in the early untreated group than in the treatment effective
group suggesting that methotrexate and leflunomide may inhibit the expression
of survivin, so inducing apoptosis of synovial cells (Isgren et al.,
2012). Moreover survivin measurement should be
considered as an additional tool for aiding the selection of antirheumatic
treatments because patients with high survivin levels were unlikely to respond
to infliximab treatment and achieve remission compared with patients with low
survivin levels. Generally, a decrease of serum survivin levels is shown to be
an overall consequence of antirheumatic treatment. Furthermore, up-regulation
of serum survivin level in ETN responder than in nonresponders (Shi et al.,
2017)  reveals
that survivin expression can be considered a predictive factor for clinical
response to ETN treatment as well. Inclination of survivin to decrease in
survivin-positive patients and mediation of its level by treatment with DMARDs
suggests that survivin is a transient phenomenon in the course of RA. Taken
together, recent trials using antisense oligonuclotide targeting survivin mRNA
in treatment of cancers may be similarly tried in RA to be added to the already
exisisting list of new therapies. According to results of survivin including
studies in RA, this molecule can be used as a potential prognostic factor for
the destructive course of disease in RA and measuring survivn might help
optimize treatment strategies if used in conjunction with other biomarkers. What
is clear is that survivin have pathological effects in RA disease but further
analyses with larger sample studies are still needed to determine the precise
relationships between survivin and RA

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