Key words
C-reactive protein - albumin - inflammation - rheumatoid arthritis
Schlüsselwörter
C-reaktives Protein - albumin - entzündung - rheumatoide arthritis
Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory disease in which autoimmune
processes and impaired cytokine cycle play a role in its pathophysiology [1]. The inflammation process is triggered by
various cytokines, affects synovial joints, and causes irreversible articular damage
and functional impairment [2]
[3]. Disease activity and remission duration are
associated with joint damage, and thus functional competence. The close monitoring
of disease activity is the main factor for treatment decision and affects long-term
results. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are
inflammation markers commonly used in laboratory measurements to assess disease
activity in RA [4]. On the other hand, these
laboratory markers have known limitations, such as short duration of inflammation
and possibility of indicating various inflammatory conditions [5]
[6].
There is evidence that various current biomarkers reflect inflammatory processes
regarding malignancy. Some studies have also reported that these new markers can
show recanalization in myocardial infarctions [3]. Since circulating blood cell composition is related with systemic
inflammation, researchers have investigated blood cell components such as derived
neutrophil to lymphocyte ratio (dNLR) as a sign of inflammatory activity [6]
[7].
Data available in the literature have established that systemic inflammation and
malnutrition may be related to disease activity and contributed to the progression
of RA. Albumin is a negative inflammatory marker indicating both nutritional status
and systemic inflammation. In addition, serum albumin acts as an antioxidant in the
immune system [2]
[8]. Based on this information, it has been
shown that the albumin-dNLR score reflects systemic inflammation and disease
activity in patients with RA [2]. A novel
inflammation-based score, the CRP-to-albumin ratio (CAR), was initially shown to be
associated with inflammatory status in patients with cancer [9]
[10].
To date, only a few studies have analyzed CAR as an inflammation marker and useful
indicator of disease activity in patients with established RA [3]
[4].
It is known that the early diagnosis and treatment of RA in the period defined as
“window of opportunity” changes the long-term results of the disease
and reduces functional loss [11]. In this
context, close monitoring of disease activity is critical in patients with early RA.
To the best of our knowledge, there is no study investigating CAR as an inflammatory
marker in patients with early RA. In this study, we aimed to explore the association
between CAR and disease activity in patients with early RA and to determine the
cut-off value of CAR in early and established RA.
Materials and Methods
This was a case-control study performed between January 2020 and March 2021. The
study was approved by the local ethics committee. Written consent was taken from all
participants. All procedures were undertaken in compliance with the current version
of the Declaration of Helsinki.
The study included 177 patients who presented to the rheumatology outpatient clinic
and met the 2010 American College of Rheumatology (ACR)/European League
Against Rheumatism (EULAR) classification criteria for RA, and 111 age- and
gender-matched healthy controls. The exclusion criteria were as follows: age below
18 years, coexistence of other autoimmune and/or inflammatory connective
tissue diseases, overlap syndromes, diabetes mellitus, surgery, infections,
malignancy, pregnancy, renal or hepatic function disorders, chronic obstructive
pulmonary disease, proteinuria in spot urinalysis, weight loss more than 5%
of their body weight within the last three months, and trauma. Patients with RA
accompanied by vasculitis and myositis were also excluded, as these conditions can
influence the analyzed data. In addition, patients with juvenile-onset arthritis
were not included in the study.
Age, gender and body mass index (BMI) values of patients and controls were recorded.
In addition to blood tests for liver and kidney functions, urinalysis of all the
patients with RA were evaluated. Medical treatments [glucocorticoids, conventional
and biological disease-modifying anti-rheumatic drugs (DMARD)] that the patients
were receiving were recorded. For the RA group, the ages of the patients at the
onset of disease were also noted. The RA cases with a disease duration of less than
1 year were classified as early RA [12].
The activity of the disease was assessed using the Disease Activity Score (DAS28-ESR)
and Clinical Disease Activity Index (CDAI). The disease activity scores were
interpreted as remission (≤2.6 and≤2.8), low disease activity
(2.6<and≤3.2; 2.8<and≤10), moderate disease activity
(3.2<and≤5.1; 10<and≤22), and high disease activity
(>5.1 and>22) for DAS28 and CDAI, respectively [13]
[14]
[15]. The Health Assessment
Questionnaire (HAQ) was applied for functional evaluation [16].
ESR was estimated using the Westergren method. CRP and rheumatoid factor (RF) were
quantified with the immuno-turbidimetric method. Blood biochemical test analyses
were performed with a biochemistry analyzer (Dimension RXL system, Siemens, Munich,
Germany). Values of>14 IU/L and 5 mg/L were
accepted as positive for RF and CRP, respectively. Anti-cyclic citrullinated peptide
was measured with the AxSYM analyzer (Abbot, Wiesbaden, Germany) using the
enzyme-linked fluorescent assay method, and values>5 U/mL
were accepted as positive. The patients’ blood count was analyzed with the
Sysmex XE-2100 device (Sysmex, Kobe, Japan), and the peripheral venous blood
analysis was performed within 1 hour.
Statistical analysis
All analyses were carried out using the Statistical Package for the Social
Sciences (SPSS) version 23.0 for Windows. Categorical variables were presented
as number and percentages, and continues variables as mean±standard
deviation or median (interquartile range) values. The Kolmogorov-Smirnov test
was used to determine whether the data followed a normal distribution. According
to the results, parametric and non-parametric tests were used. Student’s
t-test and the Mann-Whitney U test were used in the comparison of two
independent groups for continuous variables. Categorical variables were compared
between the groups with the chi-square test. The Kruskal-Wallis test and one-way
analysis of variance were performed for multiple-group comparisons. The
Games-Howell test was used as a post hoc method in pairwise comparisons. The
Spearman correlation analysis was undertaken to examine the relationship between
CAR and laboratory and clinical variables. The receiver operating characteristic
(ROC) curve was drawn to determine the cut-off value of CAR in determining
moderate to high disease activity. Significance was evaluated at the level of
p<0.05.
Results
A total of 177 patients with RA and 110 controls were included in the study. The mean
age was 56.23±13.94 and 52.77±13.04 years in the RA and control
groups, respectively (p=0.182). The percentage of females was 79.1 and
75.7% in the RA and control groups, respectively (p=0.591). The
median [interquartile range (IQR)] value of disease duration was 26 (4–96)
months. Except three patients using bDMARD as monotherapy, all the remaining
patients with RA were receiving at least one cDMARD agent (methotrexate,
leflunomide, sulfasalazine, and hydroxychloroquine) as monotherapy or in
combination. A total of 20 patients with RA were on bDMARD therapy (tumor necrosis
factor blockers in 15, tocilizumab in three, and rituximab in two). The median (IQR)
CAR value was 2.44 (0.89–6.01) in the RA group and 0.45 (0.25–0.95)
in the control group, revealing a significant difference (p<0.001).
Of the total 177 cases with RA, 87 (49.15%) were classified as early RA and
90 as established RA (50.85%). There was no statistically significant
difference between the two RA groups in terms of mean age, sex, and BMI. Fourteen
(15.6%) patients in the early RA group and six (6.7%) in the
established RA group were taking glucocorticoids at a dose of lower than
7.5 mg/day, with no statistically significant difference
(p=0.163). Six patients with early RA and 14 with established RA were on
bDMARD therapy, indicating no statistically significant difference
(p=0.070). It is important that no difference was detected between the early
and established RA groups concerning medical treatments, as the drugs that used for
the treatment of RA affect not only the disease activity, but also may have an
influence on the albumin balance. The analyses indicated that the ESR, CRP and CAR
values of the patients with early RA were significantly higher than those of the
patients with established RA and controls. In addition, the DAS28, CDAI and HAQ
scores were significantly higher in the early RA group than in the established RA
group (p<0.001 for all). The demographic, clinical and laboratory
characteristics of the 3 groups (early RA, established RA, and controls) are
summarized in [Table 1].
Table 1 Clinical and laboratory variables in the rheumatoid
arthritis and control groups.
|
Early RA (n=87)
|
Established RA (n=90)
|
Healthy controls (n=111)
|
p value
|
|
Age (years)
|
56.53±16.07
|
55.93±11.60
|
52.77±13.04
|
0.109
|
|
Sex (female)
|
64 (73.6%)
|
76 (84.4%)
|
84 (75.7%)
|
0.176
|
|
BMI (kg/m
2
)
|
29.37±4.88
|
30.75±4.48
|
29.76±4.61
|
0.097
|
|
Disease duration (months)
|
4 (3–8)
|
94.50 (50–150)
|
NA
|
<0.001
|
|
RF positive
|
65 (74.7%)
|
63 (70%)
|
NA
|
0.485
|
|
Anti-CCP positivity
|
64 (73.6%)
|
63 (70%)
|
NA
|
0.600
|
|
Neutrophil count
(×10
3
/μL)
|
5.66±1.88
|
4.88±1.78
|
4.79±1.74
|
<0.001
|
|
p1=0.015
|
|
p2<0.001
|
|
p3=0.001
|
|
Lymphocyte count
(×10
3
/μL)
|
2.06±0.66
|
2.19±0.73
|
2.48±1.44
|
0.016
|
|
p1=0.458
|
|
p2=0.020
|
|
p3=0.153
|
|
Platelet count
(×10
3
/μL)
|
319.87±78.15
|
288.50±69.23
|
272.06±59.69
|
<0.001
|
|
p1=0.015
|
|
p2<0.001
|
|
p3=0.180
|
|
Albumin (g/L)
|
4.09±0.36
|
4.18±0.36
|
4.40±0.27
|
<0.001
|
|
p1=0.207
|
|
p2<0.001
|
|
p3<0.001
|
|
ESR (mm/hr)
|
31 (20–46.30)
|
26 (15–40)
|
13 (7–21)
|
<0.001
|
|
p1=0.038
|
|
p2<0.001
|
|
p3<0.001
|
|
CRP (mg/L)
|
15.70 (6–40)
|
6.65 (2.30–14.75)
|
2.1 (1.10–3.80)
|
<0.001
|
|
p1<0.001
|
|
p2<0.001
|
|
p3<0.001
|
|
CAR
|
3.64 (1.51–9.46)
|
1.63 (0.58–3.92)
|
0.46 (0.25–0.95)
|
<0.001
|
|
p1<0.001
|
|
p2<0.001
|
|
p3<0.001
|
|
DAS28
|
4.19±1.19
|
3.44±0.80
|
NA
|
<0.001
|
|
CDAI
|
17.77±8.47
|
12.84±8.73
|
NA
|
<0.001
|
|
HAQ score
|
1.20±0.48
|
0.89±0.47
|
NA
|
<0.001
|
|
Medications
|
|
cDMARD
|
87
|
87
|
|
NA
|
|
bDMARD
|
6
|
14
|
|
0.070
|
|
Glucocorticoid
|
16
|
11
|
|
0.176
|
Data presented as n (%) for categorical variables and
mean±standard deviation or median (interquartile range) for
continuous variables depending on distribution. RA: rheumatoid arthritis;
BMI: body mass index; RF: rheumatoid factor; Anti-CCP: anti-cyclic
citrullinated peptide; CRP: C-reactive protein; ESR: erythrocyte
sedimentation rate; CAR: C-reactive protein-to-albumin ratio; DAS28: Disease
Activity Score with 28-Joint Counts; CDAI: Clinical Disease Activity Index;
HAQ: Health Assessment Questionnaire; cDMARD: Conventional disease-modifying
anti-rheumatic drugs; bDMARD: Biological disease-modifying anti-rheumatic
drugs; NA: not applicable. P<0.05 considered statistically
significant; p1, p value for the comparison of early RA and established RA;
p2, p value for the comparison of early RA and controls; p3, p value for the
comparison of established RA and controls. Significant p values presented in
bold.
All the patients with RA (both early and established) were further categorized into
three groups based on their DAS28 score: remission or low disease activity
(DAS28≤3.2), moderate disease activity (3.2<DAS28≤5.1), and
high disease activity (DAS28>5.1). In the early RA group, remission and low,
moderate and high disease activity were seen in four, 17, 45 and 21 patients,
respectively. The median (IQR) values of ESR, CRP and CAR and the mean HAQ score
were significantly higher in the high disease activity group than the low disease
activity-remission and moderate disease activity groups (p<0.001 for all).
The laboratory parameters and HAQ scores of the patients with early RA according to
disease activity with DAS28 are demonstrated in [Table 2]. According to the CDAI score, remission, low, moderate and high
disease activity was seen in two (2.3%), 18 (20.7%), 40
(46.0%), and 27 (31.0%) patients, respectively.
Table 2 Laboratory parameters and HAQ scores in disease
activity groups of early rheumatoid arthritis.
|
Early RA
|
Group 1 Remission+low disease activity (n=21)
|
Group 2 Moderate disease activity (n=45)
|
Group 3 High disease activity (n=21)
|
p value
|
|
Neutrophil count
(×10
3
/μL)
|
5.05±1.52
|
5.77±2.06
|
6.03±1.73
|
0.206
|
|
Lymphocyte count
(×10
3
/μL)
|
2.31±0.51
|
1.93±0.62
|
2.09±0.82
|
0.097
|
|
Platelet count
(×10
3
/μL)
|
301.95±68.23
|
316.76±75.52
|
344.76±95.08
|
0.198
|
|
Albumin (g/L)
|
4.32±0.36
|
4.11±0.31
|
3.81±0.25
|
<0.001
|
|
p1=0.065
|
|
p2<0.001
|
|
p3<0.001
|
|
ESR (mm/hr)
|
15 (8.5–19.5)
|
29 (24–42)
|
62 (42.50–66)
|
<0.001
|
|
p1<0.001
|
|
p2<0.001
|
|
p3<0.001
|
|
CRP (mg/L)
|
3 (1.1–7.6)
|
16 (10.20–33)
|
46 (26.50–73)
|
<0.001
|
|
p1<0.001
|
|
p2<0.001
|
|
p3=0.001
|
|
CAR
|
0.67 (0.25–1.83)
|
3.72 (2.43–8.44)
|
12.70 (6.72–19.23)
|
<0.001
|
|
p1<0.001
|
|
p2<0.001
|
|
p3=0.001
|
|
HAQ score
|
0.61±0.31
|
1.26±0.36
|
1.61±0.24
|
<0.001
|
|
p1<0.001
|
|
p2<0.001
|
|
P3<0.001
|
RA: rheumatoid arthritis; ESR: erythrocyte sedimentation rate; CRP:
C-reactive protein; CAR: C-reactive protein-to-albumin ratio; HAQ: Health
Assessment Questionnaire. Data given as mean±standard deviation for
parametric variables and median (interquartile range) for non-parametric
variables. P<0.05 considered statistically significant; p1, p value
for the comparison of Group 1 and Group 2; p2, p value for the comparison of
Group 1 and Group 3; p3, p value for the comparison of Group 2 and Group 3.
Significant p values shown in bold.
Of the total 90 patients in the established RA group, 19 were in remission, 26 had
low disease activity, 33 had moderate disease activity, and 12 had high disease
activity. Further analysis of the disease activity groups revealed that the median
ESR, CRP and CAR values and the mean HAQ scores were significantly higher in the
high disease activity group than the low disease activity-remission and moderate
disease activity groups ([Table 3]). The CDAI
scores of the established RA group indicated that two (2.2%) patients were
in remission, 40 (44.4%) had low disease activity, 32 (35.6%) had
moderate disease activity, and 16 (17.8%) had high disease activity.
Table 3 Laboratory parameters and HAQ scores in disease
activity groups of established rheumatoid arthritis.
|
Established RA
|
Group 1 Remission+low disease activity (n=45)
|
Group 2 Moderate disease activity (n=33)
|
Group 3 High disease activity (n=12)
|
p value
|
|
Neutrophil count
(×10
3
/μL)
|
4.44±1.62
|
4.84±1.69
|
6.46±1.89
|
0.001
|
|
p1=0.536
|
|
p2=0.007
|
|
p3=0.037
|
|
Lymphocyte count
(×10
3
/μL)
|
2.14±0.66
|
2.31±0.77
|
2.05±0.88
|
0.450
|
|
Platelet count
(×10
3
/μL)
|
278.42±59.59
|
303.59±75.63
|
286.23±82.21
|
0.291
|
|
Albumin (g/L)
|
4.39±0.28
|
3.96±0.32
|
3.88±0.17
|
<0.001
|
|
p1<0.001
|
|
p2<0.001
|
|
p3<0.407
|
|
ESR (mm/hr)
|
17 (9.5–27)
|
34 (22–47.50)
|
46.5 (39–66)
|
<0.001
|
|
p1=0.001
|
|
p2<0.001
|
|
p3=0.002
|
|
CRP (mg/L)
|
4 (1–6.3)
|
11 (6.55–26)
|
47 (37–61.25)
|
<0.001
|
|
p1<0.001
|
|
p2<0.001
|
|
p3=0.001
|
|
CAR
|
0.83 (0.24–1.51)
|
3.14 (1.69–6.37)
|
12.26 (9.31–15.04)
|
<0.001
|
|
p1<0.001
|
|
p2<0.001
|
|
p3<0.001
|
|
HAQ score
|
0.59±0.35
|
1.10±0.35
|
1.44±0.29
|
<0.001
|
|
<0.001
|
|
p1<0.001
|
|
p2<0.001
|
|
P3<0.001
|
RA: rheumatoid arthritis; ESR: erythrocyte sedimentation rate; CRP:
C-reactive protein; CAR: C-reactive protein-to-albumin ratio; HAQ: Health
Assessment Questionnaire Data given as mean±standard deviation for
parametric variables and median (interquartile range) for non-parametric
variables. P<0.05 considered statistically significant; p1, p value
for the comparison of Group 1 and Group 2; p2, p value for the comparison of
Group 1 and Group 3; p3, p value for the comparison of Group 2 and Group 3.
Significant p values shown in bold.
The correlation between CAR and laboratory variables, disease activity, and HAQ score
was also investigated. The results showed that CAR was correlated with albumin, CRP,
ESR, DAS28 and HAQ score in both the early RA and established RA groups ([Table 4]).
Table 4 Correlation between CAR and laboratory parameters,
disease activity, and functional status.
|
Early RA-CAR (n=87)
|
Established RA-CAR (n=90)
|
|
r
|
p
|
r
|
p
|
|
Neutrophils
(×10
3
/μL)
|
0.271
|
0.11
|
0.400
|
<0.001
|
|
Lymphocytes
(×10
3
/μL)
|
−0.600
|
0.579
|
−0.051
|
0.634
|
|
Platelet (×103/μL)
|
0.302
|
0.004
|
0.053
|
0.620
|
|
Albumin (g/L)
|
−0.520
|
<0.001
|
−0.504
|
<0.001
|
|
ESR (mm/hr)
|
0.593
|
<0.001
|
0.521
|
<0.001
|
|
CRP (mg/L)
|
0.996
|
<0.001
|
0.996
|
<0.001
|
|
DAS28
|
0.721
|
<0.001
|
0.741
|
<0.001
|
|
CDAI
|
0.879
|
<0.001
|
0.828
|
<0.001
|
|
HAQ score
|
0.539
|
<0.001
|
0.667
|
<0.001
|
RA: rheumatoid arthritis; ESR: erythrocyte sedimentation rate; CRP:
C-reactive protein; CAR: C-reactive protein to albumin ratio; DAS28: Disease
Activity Score with 28-Joint Counts; CDAI: Clinical Disease Activity Index;
HAQ: Health Assessment Questionnaire.
Lastly, the patients with both early RA and established RA were evaluated in two
groups according to the DAS28 scores being≤3.2 (n=66 and 45 for the
early and established RA groups, respectively) and>3.2 (n=21 and 45
for the early and established RA groups, respectively). ROC curves were drawn for
the CAR levels in the determination of moderate to high disease activity in the
early and established RA groups ([Fig. 1] and
[2]). The area under the curve was
0.883±0.041 and 0.886±0.034 for the early and established RA groups,
respectively. The sensitivity (probability that a patient with moderate or high
disease activity had a CAR level over the determined cut-off value) and specificity
(probability that a patient with remission or low disease had a CAR level below the
determined cut-off value) of CAR were calculated. For the early RA group, the best
Youden index was 0.66, and at a cut-off value of 2.67, CAR showed 80%
sensitivity and 85% specificity. For the established RA group, the best
Youden index was 0.55, and at the cut-off value of 1.63, CAR had 77%
sensitivity and 72% specificity.
Fig. 1 Receiver operating characteristic curve (ROC) for prediction of
moderate to high disease activity based on the levels of CAR for the
patients with early RA. AUC (Area under the curve): 0.883.
Fig. 2 Receiver operating characteristic curve (ROC) for prediction of
moderate to high disease activity based on the levels of CAR for the
patients with established RA. AUC (Area under the curve): 0.886.
The cut-off values of CAR were also calculated according to the CDAI score. The
patients in both the early and established RA groups were further divided into 2
groups according to the CDAI scores being≤10 and>10. The area under
the ROC curve values were 0.889±0.039 and 0.912±0.029 for the early
and established RA groups, respectively. For the early RA group, the best Youden
index was 0.72, and at a cut-off value of 2.47, CAR showed 81% sensitivity
and 88% specificity. For the established RA group, the best Youden index was
0.60, and at the cut-off value of 1.68, CAR had 77% sensitivity and
82% specificity.
Discussion
The current study was conducted to investigate the association between CAR and
disease activity in patients with early RA and to determine the cut-off value of CAR
in early and established RA. The results indicated that CAR was higher in the
patients with RA than in the healthy controls and positively correlated with ESR,
CRP, and DAS28 and HAQ scores. We identified an increase in CAR among the patients
with active disease in both the early and established RA groups. The cut-off values
of CAR were 2.67 and 1.63 in the early and established RA groups, respectively. We
detected noticeably higher sensitivity and specificity for CAR at the determined
cut-off value in the early RA group compared to established RA.
RA is a progressive articular disease in which an impaired cytokine cycle plays a
role in pathophysiology and causes irreversible joint damage and functional
impairment. Acute phase reactants (increased CRP, ESR, fibrinogen, ferritin, and
decreased albumin) indicate an inflammatory state in autoimmune diseases [17]. CAR, a novel marker, is obtained by
dividing CRP by albumin, components that are both closely related to inflammation.
While serum albumin is considered to have anti-inflammatory and immunomodulating
properties, it also reflects nutritional status. There is a multifaceted association
between albumin with inflammation and malnutrition. Malnutrition, a common symptom
in patients with RA, may have an impact on immune system and lead to an increase in
inflammatory cytokines. On the other hand, systemic inflammation decreases albumin
synthesis [18]
[19]. Therefore, increased CRP and decreased albumin levels have attracted
the attention of researchers as systemic inflammation markers, and CAR has been used
to prognosticate disease severity and outcomes in various diseases, particularly
cancer [20]
[21]. Higher CAR levels have been demonstrated in patients with active RA
than those in remission. In the current study, in order to prevent the effect of any
possible reasons on the albumin value other than RA [3]
[4], diabetes, infection, cancer,
liver and kidney dysfunction, and autoimmune and other chronic inflammatory diseases
were not included in the sample. Therefore, the current study was designed to rule
out factors that could affect albumin value other than RA. As expected, the CAR
value was found to have a strong correlation with CRP and ESR (other acute phase
reactants) and DAS28 scores, which also included acute phase reactants in its
calculation [3]
[4]. Our results were similar, indicating higher
CAR values in the patients with RA than in the healthy controls and association of
CAR with disease activity in the RA group. Similarly, there was a strong correlation
between CDAI, a disease activity score calculated without a laboratory value, and
CAR. Moreover, to our knowledge, this is the first study that evaluated the
association between disease activity and CAR in patients with early RA. We
determined CAR to be a valuable marker for monitoring disease activity in this
patient group.
Early diagnosis and treatment without delay are associated with better long-term
outcomes for patients with RA. It is suggested that the treat-to-target principle,
in which treatment is concentrated until remission or low disease activity may
prevent progressive damage in early RA [22].
An appropriate follow-up of the patient is absolutely dependent on the
specialist’s ability to measure disease activity. Therefore, different
laboratory markers are frequently addressed as a current issue in addition to
clinical evaluation in disease monitoring. ESR and CRP are the most commonly used
laboratory values associated with inflammation and arthritis in RA. However, it is
known that both of these measures are also affected by factors other than
inflammation (e. g., pregnancy, obesity, and anemia) [23], and therefore research has focused on
various rational laboratory values with the aim of minimizing exposure to causes
other than inflammation [2]
[3]
[4].
Our results demonstrated a correlation between the CAR value and the DAS28 and CDAI
score which is calculating without any laboratory value. Moreover, CAR was strongly
correlated with the HAQ score, which reflects long-term damage. CAR, which is
associated with composite indexes, clinical assessments, and functional status,
presents as a promising marker of inflammation in patients with early RA, as well as
those with established RA.
Cut-off values as predictors of disease activity are helpful in the practical use of
laboratory markers. Afifi et al. [3] performed
ROC curve analyses for CAR in patients with RA with a median disease duration of
eight years. The authors found a cut of value 1.66 (specificity 66.67% and
sensitivity 81.58%) for an area under curve of 0.789. We investigated the
cut-off levels for both early and established RA. In the established RA group, the
cut-off value of CAR was 1.63, at which it had 77% sensitivity and
72% specificity while in the early RA patients, CAR showed 80%
sensitivity and 85% specificity at a cut-off value of 2.67. Furthermore, the
cut-off values of CAR according to the CDAI score were similar to the results of the
analysis we conducted with the DAS28 scores, in which we determined these values as
2.47 for early RA and 1.68 for established RA. Our result for established RA is
similar to the value reported by Afifi et al. [3]. On the other hand, the CAR cut-off value we determined for early RA
was higher than the established RA group, and sensitivity and specificity were also
higher in the former. This finding indicates that the use of CAR in early RA is even
more valuable than in established RA.
Composite disease activity scores include particular parameters (tender joint count,
swollen joint count, patient and physician global assessment and inflammatory
markers, such as CRP and ESR) in different combinations. While these parameters may
reflect active inflammation one by one, it is necessary to consider some specific
parameters (tender joint count and patient global assessment values) from different
perspectives. The possibility for irreversible joint damage may lead to confusion
concerning the disease activity of established RA, unlike early RA. Joint tenderness
is normally expected as a result of the increased innervation of pain fibers due to
inflammation. However, tenderness may also be an outcome of joint damage, secondary
osteoarthritis, or subluxation and can induce pain even when there is no active
inflammation [24]
[25]. In view of this information, it can be
considered that possible joint damage and secondary pain in patients with
established RA can increase the DAS28 scores despite lower CRP scores, which can
explain the different cut-off values of CAR in the early and established RA
groups.
Some limitations of our study are the cross-sectional and single-center design,
absence of a follow-up evaluation, and relationship between CAR and RA prognosis not
being evaluated. In addition, diet types and dietary adjustment after diagnosis
which can lead to major changes in the course of the process were not evaluated in
this study; future studies considering these dietary factors may provide better
results. Finally, albumin values may better reflect systemic inflammation in studies
to be planned by performing appropriate nutritional risk screening and providing
appropriate nutritional support.
In conclusion, CAR, a formulated ratio, can be considered as a predictor of disease
activity in patients with early RA, as well as established RA. Furthermore, at the
determined cut-off value, CAR has higher sensitivity and specificity for patients
with early RA than those with established RA. This finding supports the use of CAR
as a reliable indicator of inflammation in early RA.
