ROS and other oxidants have been shown to be
formed even in the normal physiological process
19,20.
It is known that activated inflammatory cells lead to ROS
production in RA a systemic autoimmune disease
1,2.
Increased ROS, in turn, increase LPO products and
cause tissue injury
1-5.
Hydrogen peroxide and other derivatives of
peroxides, produced physiologically and which increase
in some conditions, diffuse into plasma. When TP is
measured, it means that the sum of many peroxides like
protein peroxide, lipid peroxide and H2O2 are measured
19. Although it is known that H2O2 and lipid peroxides
increase in RA 1-3,7,8, oxidative stress has not been
evaluated via measurement of TP. However, it has been
reported that TP level increases in passive smokers 21,
preeclampsia cases 22 and skin leishmaniasis 23. It
was shown in our study that TP level also increased in
RA cases. Possible causes of this increase in TP might
be the inevitable increase in lipid peroxides and ROS
including H2O2 in RA.
Many antioxidant molecules found in blood prevent or
inhibit the harmful effects of free radicals 11. Whenever
there is a decrease in antioxidants and/or an increase in
oxidants, oxidant/antioxidant balance is impaired in favor
of oxidants and this is known as oxidative stress 19,20.
It is known that oxidative stress is responsible for tissue
injury in many diseases and contributes to the
development of atherosclerosis 19,24,25. Antioxidant
activity indicates the antioxidant characteristics of only
one antioxidant, whereas total antioxidant capacity (TAC)
represents the total antioxidant characteristics of all
antioxidants found in the plasma. TAR and total
antioxidant status (TAS) are used synonymously with
TAC 20. It is doubtlessly more advantageous to
evaluate TAR, instead of individual antioxidant activities.
Many methods have been developed recently for this
aim. Total radical trapping antioxidant parameter (TRAP),
oxygen radical absorbance capacity (ORAC) and ferric
reducing antioxidant power (FRAP) are colorimetric
methods previously developed to assess TAC
12,13,20. It has been reported that TAR, a new
measurement method developed by Erel 12,13 has
correlated with the data obtained by other measurement
methods and has had some additional advantages
12,13.
Blood has an important function in the
oxidant/antioxidant balance, as it carries and distributes
antioxidants through the body 20. Plasma has various
antioxidant molecules. Albumin, uric acid, bilirubin and
ascorbic acid are the major antioxidant components of
plasma 12,13,20. TAR represents practically all of them
12,139. Albumin consists of about half of the TAC of the
plasma 12,13. Albumin has several biological functions,
particular as a ligand binder 26. Plasma thiol contents
originate from albumin. Thiol groups, on the surface of
albumin, bind oxidants 26. Low level of albumin can
cause oxidative stress via leading to increase oxidants
like homocysteine 26. In chronic inflammation, albumin
is reduced. We attribute the low albumin level in our
patient group to this protein's being a negative acute
phase reactant, but this decrease is also expected to
negatively influence antioxidant capacity. Bilirubin, a
powerful endogenous antioxidant, is one of the catabolits
of heme oxygenases 27. However, Harma et al. 22
have reported that bilirubin did not correlated with TAR,
in their clinical study. Uric acid is another well-known low
molecular weight water-soluble plasma antioxidant
12,13. Uric acid has a strong antioxidant activity and its
concentration in the plasma is about 10 fold than
antioxidants like vitamin C and vitamin E 20. In the
present study, although a significant decrease was found
in the level of albumin, an individual antioxidant, in the
patient group, uric acid and bilirubin levels were not
significantly different from those in the control group. A
positive correlation was reported amongst uric acid,
bilirubin and total protein levels, and TAC level 20.
However, uric acid concentration changes depending on
gender, diet, heavy exercise, renal failure, and in some
metabolic diseases 20,28. Methotrexate treatment
might alter uric acid level has been also reported in RA
cases 29. We suggest that uric acid might not
appropriately reflect the TAC. However, it has been also
reported that uric acid was not a strong antioxidant and
might not protect against free radicals 30.
Orem et al. 31 have reported a decrease in TAR
level in Behcet's disease. It was established in our study
that TAR level decreased, while TP and OSI levels
increased and these increases negatively correlated with
TAR level in the patient group. We think that the
decrease in TAR level may have resulted from increased
oxidative stress. As uric acid and bilirubin levels have not
been significantly different in the patient and control
groups, it has seemed reasonable to assume that the
decrease in TAR level is a result of the decrease in other
antioxidants. It has been reported that PON1 activity
32,33 and SH level 34, both of which are antioxidants, have decreased in RA. Ece et al. 35 have noted that
PON1 is positively correlated with TAR and negatively
correlated with TP and OSI in cases with nephrotic
syndrome. The decrease in TAR level in RA may be
associated with the decrease in PON1 and other
antioxidants.
Plasma TAR level has been reported to be lower in
those with CVD, compared with without CVD, in
smokers, compared with non-smokers, in diabetic cases,
compared with non-diabetic cases, and in hyperlipidemic
cases, compared with those who have a normal lipid
profile 36. Additionally, children who are exposed to
passive cigarette smoking have found to have a
decrease in TAR level, and an increase in TP and OSI
levels 21. As TAR is a fairly good representative of
antioxidant capacity, while TP and OSI are indicators of
oxidant capacity, decreased TAR and/or increased TP
levels indicate oxidative stress 12,13,28.
It has been reported in the literature that
atherosclerotic diseases increase in RA cases, but the
causes of this accelerated atherosclerosis cannot always
be explained by classical risk factors 5. Oxidative stress
is blamed to be responsible in the pathogenesis of
atherosclerosis 24,25. Atherosclerosis must also be
considered when evaluating RA cases, as it has been
shown that oxidative stress relates with atherosclerosis
and TAR levels decrease in atherosclerosis 36,37.
It is possible that the administration of DMARDs and
steroids affect the levels of oxidants and antioxidants
either negatively or positively. Previous experimental
studies had demonstrated that using steroid impaired
antioxidant systems and leading to overproduction of
ROS 38,39. In RA patients, it has been reported that
MTX alone 40 or combined with sulfasalazine 41 lead
to increased plasma homocysteine level. In our study, we
did not observe any difference between the cases with
use or without use of these medications with regard to
oxidant and antioxidant levels. Not observing this
difference might be resulted from that the cases enrolled
to the study were in their active phases.
The limitation of our study might be not to evaluate
relationships amongst drugs used in our cases, level of
cytokines like IL-1, Il-6 and TNF-α, rheumatological data
reflecting the activity, severity and function of RA patients
(pain, DAS-28, disability, articular index, radiological
severity etc.).
In conclusion, oxidant/antioxidant balance is impaired
in RA and TAR, a new measurement method, effectively
shows this balance.