MINISTRY OF EDUCATION
MINISTRY OF DEFENCE
AND TRAINING
VIETNAM MILITARY MEDICAL UNIVERSITY

HOANG TRUNG DUNG

STUDY ON CLINICAL CHARACTERISTICS,
PLASMA CRP LEVEL, SERUM TNF-α AND AlTERATIONS
OF SOME CARDIAC MORPHOLOIC AND FUNCTIONAL
PARAMETERS IN RHEUMATOID ARTHRITIS PATIENTS

Specialty

: INTERNAL MEDICINE

Code

: 9 72 01 07

THE SUMMARY OF THE MEDICAL DOTORAL THESIS

HANOI - 2019


THIS DOCTORAL THESIS WAS COMPLETED
AT VIETNAM MILITARY MEDICAL UNIVERSITY

Scientific Instructors:
1. A/PROF. Ph.D. Doan Van De
2. Ph.D. Vien Van Doan

The leading cause of death in patients with RA is cardiovascular
damage. Cardiovascular manifestations of RA are often discreet. If not
detected early and treated promptly, heart damage will affect the quality
of life and the risk of death of patients with RA. One of the methods of
comprehensive evaluation of cardiac dysfunction is Doppler
ultrasonography.
Therefore, the thesis "Study on clinical characteristics, plasma
CRP level, serum TNF-α and alterations of some cardiac
morphologic and functional parameters in rheumatoid arthritis
patients" was conducted with two objectives:
1. To describe the clinical, subclinical features, plasma CRP
level, serum TNF-α level and some cardiac morphologic and
functional parameters in patients with rheumatoid arthritis.
2. To understand the relationship between clinical and subclinical
characteristics, plasma CRP level, serum TNF-α level, level of
disease activity with some cardiac morphologic and functional
parameters in rheumatoid arthritis patients.


2
* The scientific significance
This study investigated changes in plasma CRP level, serum TNF-α
level and some cardiac morphologic and functional indexes of RA patients
compared with that of control group and the association between some
cardiac morphologic and functional parameters with clinical and
subclinical characteristics.
* The practical significance
This research shows that plasma CRP level and serum TNF-α
level of RA patients were higher than that of the control group.
35.2% of RA patients had left ventricular (LV) diastolic dysfunction

the synovial membrane. The disease has been known since 1940 by
Waaler.
1.1.2. Clinical symptoms
The common clinical symptoms include morning stiffness,
symmetrical polyarticular joint swelling and pain in the hands, feet,
wrists, ankles, elbows, knees, shoulders, groin. RA can possibly
lead to joint deformities of hands and feet in the later stages of
the disease.
Common extra-articular manifestations: cardiac disease,
pulmonary involvement, chronic anemia, subcutaneous nodules.
1.1.3. Subclinical symptoms
Elevated CRP level, elevated ESR, RF tests, anti-CCP, hand Xray, joint ultrasound, joint MRI.
1.1.4. Diagnosis of rheumatoid arthritis
Diagnosis of RA is based on the ACR 1987 criteria. Recently, the
ACR / EULAR 2010 criteria has been used to diagnose early RA.
1.1.5. Evaluate the level of disease activity
Evaluating level of disease activity plays an important role in the
prognosis of RA and is the determinant factor (decision-making) in
choosing appropriate treatment options.
In addition to the criteria: the number of painful and swollen
joints, duration of morning stiffness, CRP concentration, erythrocyte
sedimentation rate (ESR), ACR and EULAR recommend using
DAS28 CRP, DAS28 ESR, CDAI, SDAI.
1.1.6. Treatment of rheumatoid arthritis
Internal medicine includes non-drug treatments and medication.
Medications include: anti-inflammatory medications - NSAIDs and
glucocorticoids, analgesics and DMARDs. There are two classes of
DMARDs: non-bioactive DMARDs and biological DMARDs.
1.2. Mechanism of pathogenesis and role of CRP, serum TNF-α
1.2.1. New view of the pathogenesis of rheumatoid arthritis

(TDI) in cardiac morphologic and functional evaluation
1.3.1. Cardiac involvement in rheumatoid arthritis
- Cause: inflammation induces CRP level, erythrocyte
sedimentation rate, TNF-α, RF. Due to the effects of medications:
Glucocorticoid, NSAIDs, Methotrexatr, anti-TNF-α drugs.
- Cardiac involvement includes: pericarditis, cardiomyopathy,
myocardial ischemia, amyloid cardiomyopathy, cardiac dysrhythmia,
valvular heart disease.
- Mechanism of cardiac damage: T cells, T-CD4 +, T ‘CD28null’
1.3.2. The role of Tissue Doppler Imaging in cardiac morphologic
and functional evaluation
- Left Ventricular Morphology Assessment on T mode:
Measurements for Dd, Ds, IVSTd, IVSTs, LVPWD, LVPWs, LVM,
EVD, ESV, FS, EF, CO.
- Doppler ultrasound: Measurements of E wave, A wave, E / A
ratio, DT, IVCT, IVRT, ET.
- Left ventricular (LV) Tei index = (IVCT + IVRT) / ET


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- Tissue Doppler imagining at the interventricular septum and
lateral mitral annulus: Measurements of Sm wave, Em wave, Am
wave, E / Em ratio, Em / Am ratio.
1.4. Domestic and foreign studies
1.4.1. Overseas studies
According to Shrivastava A.K. et al. (2015) and Hanan M. et al.
(2015): serum CRP, TNF-α levels were higher than that of the control
group.
Wislowska M. et al. (2008), Sitia S. et al. (2012), Fatma E. et al.
(2015): left ventricular morphologic indexes of RA patients and

Inclusion criteria:
- People at the same age and gender
- No history of arthritis, cardiovascular disease and medical conditions.
- Consent to participate in the study.
Exclusion criteria:
- Patients with definitive diagnosis or suspected cardiovascular
disease: based on clinical findings and electrocardiogram: chest pain
on examination, history of angina pectoris, history of diagnosed
myocardial infarction, heart failure, cardiac arrhythmias. Based on
echocardiography: mitral stenosis and/or aortic valve stenosis and/or
tricuspid stenosis at any grade, mitral regurgitation and/or aortic valve
regurgitation and/or tricuspid regurgitation grade 2 or more, left
ventricular
systolic
dysfunction,
regional
wall
motion
dysfunction/abnormalities, interventricular septal thickness and/or left
ventricle posterior wall thickness, left ventricular dilatation.
- Patients did not consent to participate in the study.
2.1.3. Time and place
This study was conducted from October 2014 and April 2018 at the
Department of Rheumatology, Bachmai Hospital.
2.2. Research Methods
2.2.1. Study Design: Prospective, descriptive cross-sectional study.
2.2.2. Sampling method:
2
. p.q
Sampling Size Formula:

- Doppler echocardiography: Measurements of E wave, A wave,
E/A ratio, DT, IVCT, IVRT, ET.
- Left ventricular index
- Doppler ultrasound of at interventricular septum and lateral
mitral annulus: Measurements of Sm, Em, Am, E/Em, Em/Am.
2.2.4. Criteria used in research
- Assessment of BMI according to the World Health Organization.
- Diagnosis of RA according to ACR 1987
- Assessment of clinical symptoms: duration of disease, duration
of morning stiffness, the number of tender joins, the number of
swollen joints, VAS score.
- Diagnosis of level of disease activity: DAS28 CRP
- Diagnosis of anemia based on Hb concentration according to the
World Health Organization
- Diagnosis of left ventricular systolic dysfunction: EF%
- Diagnosis of left ventricular diastolic dysfunction according to
the American Society of Echocardiography 2009
2.2.5. Research parameters
- Clinical parameters: age, sex, BMI, BSA, systolic blood
pressure, diastolic blood pressure.
- Duration of disease: divided into 3 groups: ≤ 1 year; 1 to 5 years;
≥ 5 years.
- Duration of morning stiffness: < 45 minutes; 45 to 60 minutes; >
60 minutes.
- The number of tender joints, the number of swollen joints
- VAS scores (3 levels): 10 - 40; 50 - 60; 70 - 100
- CDAI, SDAI
- DAS28 CRP: DAS28 CRP < 2.6; 2.6 ≤ DAS28 CRP ≤ 3.2; 3.2 ≤
DAS28 CRP ≤ 5.1; DAS28 CRP > 5.1
2.2.5.2. Sub-clinical parameters

+ Transmitral late diastolic peak velocity (A - cm/s).
+ E/A ratio
+ Deceleration Time (DT - ms)
+ Isovolumetric relaxation time (IVRT - ms)
+ Left ventricular Tei index
- Tissue Doppler Imaging at interventricular septum and lateral
mitral annulus:
+ Peak systolic velocity (Sm - cm/s)
+ Peak early diastolic velocity (Em - cm/s)
+ Peak late diastolic velocity (Am - cm/s)
+ E/Em ratio


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+ Em/Am ratio
2.2.6. Research ethics
- The subjects are fully explained and willing to participate in the
research. The implementation process is strictly complied with the
regulation of the Ministry of Health.
2.3. Data processing
- The collected data were processed according to the medical
statistics using Excel Plus and SPSS 20.0 statistical software.
2.6. Diagram of the study
Sửa lại:
Patient rheumatoid arthritis  Rheumatoid arthritis patients
Doppler ultrasound of cardiac muscle  Tissue Doppler Imaging
Describe…  Describe clinical and subclinical characteristics,
serum CRP level, serum TNF α level, some cardiac morphologic and
functional parameters in RA patients.
Understanding…  Understand the relationship between clinical,

> 0.05
Sex
Female, n (%)
103 (84.4%)
43 (84.3%) > 0.05
Height (cm)
155.99 ± 5.78
158.09 ± 6.47 < 0.05
Weight (kg)
51.23 ± 7.28
54.80 ± 7.52 < 0.05
BMI (kg/m²)
21.00 ± 2.65
21.87 ± 2.15 < 0.05
BSA (m²)
1.48 ± 0.12
1.54 ± 0.13 < 0.05
Systolic blood
119.30 ± 5.73
117.55 ± 8.27 > 0.05
pressure (mmHg)
Diastolic blood
77.21 ± 4.55
76.57 ± 4.74 > 0.05
pressure (mmHg)
Table 3.1 and 3.2. The most common age of RA patients was from
40 to 59 years old, accounting for 55.7%. 67.2% of patients with RA
had normal BMI.
Table 3.2. Some clinical features of rheumatoid arthritis patients
Rheumatoid arthritis (n = 122)

36.72 ± 9.08
37.00
11 - 60
SDAI index
39.28 ± 11.03
40.50
11.02 – 72.64
DAS28 CRP
5.77 ± 0.94
6.02
2.85 – 7.86


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DAS28 ESR
6.35 ± 0.89
6.54
3.50 – 8.11
Table 3.3. Duration of disease from 1 to 5 years accounted for 48.4%,
over 5 years represented 35.2%. Duration of morning stiffness from 45 to
60 minutes and over 60 minutes accounted for 45.9% and 34.4%,
respectively. Patients with severe pain (VAS score 70 – 100) made up
61.2%.
Table 3.3. Regarding DAS28 CRP, there were 74.6% of patients
with high disease activity and 23.8% of patients with moderate
disease activity.
3.1.2. Sub-Clinical characteristics of patients with rheumatoid arthritis
Table 3.4. and 3.5. Median ESR 1 hr and 2 hrs were high. There
were 25.4% of patients with anemia including 16.4% of patients with
mild anemia and 9.0% of patients with moderate anemia.

0.133 and p > 0.05.


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Table 3.9. There was no difference between median TNF-α serum
concentration in patients with DAS28 CRP> 5.1 and that of patients
with DAS28 CRP ≤ 5.1 (p> 0.05).
Table 3.10. Serum TNF-α level was not correlated with: the
number of tender joints, the number of swollen joints, duration of
morning stiffness, plasma CRP level, ESR 1hr, DAS28 CRP, DAS28
ESR, p > 0.05.
3.1.4. Some cardiac morphologic and functional parameters study
subjects
Table 3.11. Some indexes of left ventricular morphology and
systolic function of RA patients and control group were similar, p >
0.05. IVSd, IVSs and LVPWs of RA patients were higher than that of
control group, p < 0.05.
Table 3.12. Wave A in RA patients was higher than that of the
control group, p < 0.01. There was no difference between Tei index
of RA patients and of control group, p > 0.05. E/A ratio and IVRT of
RA patients were lower than that of the control group, p < 0.05.
Table 3.13. Tissue doppler imaging at the interventricular septum:
Em of RA patients was lower than that of the control group, p < 0.05.
Em/Am ratio in study group was lower than that of the control group,
p < 0.01. There was no difference in Sm, Am and E/Em ratio of study
subjects and controls, p > 0.05. Tissue Doppler Imaging at lateral
mitral annulus: Em and Em/Am ratio of RA patients were lower than
that of the control group, p < 0.05. There was no difference in Sm,
Am and E/Em ratio of study subjects and controls, p > 0.05.
Table 3.14. and 3.15. The rate of left ventricular diastolic

Figure 3.4. and 3.5. There was positive correlation between A wave,
IVRT and left ventricular Tei score, meanwhile, E / A ratio was negatively
correlated to the age of RA patients, p < 0.01.
Table 3.19. Tissue doppler imaging at the interventricular septum
and lateral mitral annulus: Em and Em/Am ratio of patients < 60
years were higher than that of patients ≥ 60 years, p < 0.05. Am index
of patients < 60 years was lower than that of patients≥60 years, p
0.05.
Figures 3.10 and 3.11: E wave was negatively correlated E/A
ratio; meanwhile, there was positive correlation between A wave,
IVRT and duration of disease, p < 0.05.
Table 3.21. Tissue doppler imaging at the interventricular septum
and mitral annulus: in RA patients, the longer duration of disease
was, the higher E/Em ratio was, meanwhile Sm, Em, and Em/Am


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ratio decreased, p < 0.01. Tissue doppler imaging at lateral mitral
annulus: Patients with RA had a longer duration of disease, Em index
and Em/Am ratio decreased, p < 0.01.

level and Am index at lateral mitral annulus, p < 0.05.
Table 3.26. and 3.27. There was positive correlation between serum
TNF-α level and DT, and E/Em ratio at interventricular septum
and mitral annulus. There was negative correlation between Em,
Em/Am interventricular septum and mitral annulus, and E/Em
at lateral mitral annulus, p < 0.05.
Figure 3.17. and 3.18. There was negative correlation between Em
index, Em/Am ratio at interventricular septum and mitral
annulus, Em at lateral mitral annulus. E/Em ratio at lateral mitral annulus
was negatively correlated to serum TNF-α level, p < 0. 05.
3.2.5. The relationship between level of disease activity and cardiac
function indexes
Table 3.28. Mitral valve Tissue doppler imaging: there was no
difference between E wave and E/A ratio of RA patients with DAS28
CRP > 5.1 and that of those with DAS28 CRP ≤ 5.1, p > 0.05.
Table 3.29. Tissue doppler imaging at the interventricular septum
and lateral mitral annulus: there was no difference between Em,
E/Em, and Em/Am in RA patients with DAS28 CRP > 5.1 and that of
RA patients with DAS28 CRP ≤ 5.1, p > 0.05.
Tables 3.30 and 3.31. DAS28 CRP index was not correlated with
mitral valve Doppler echocardiography indexes, left ventricular Tei
index and Tissue doppler imaging at the interventricular septum and
lateral mitral annulus indexes, p > 0.05.


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Table 3.32. The relationship between left ventricular diastolic
dysfunction and DAS28 CRP
Index Diastolic function
No diastolic

study subjects were similar to that of controls, p > 0.05. Height,
weight, BMI, BSA of study subjects were lower than the data of
controls, p < 0.05.
Duration of disease was 5.37 ± 5.25 years. Duration of morning
stiffness was 61.48 ± 27.64 (minutes).
The number of swollen joints was 9.95 ± 3.71, the number of
tender joints was 13.30 ± 4.34. VAS score was 67.38 ± 11.49. DAS28
CRP was 5.77 ± 0.94.
4.1.2. Sub-Clinical characteristics of patients with rheumatoid
arthritis
Hb concentration was 129.44 ± 14.32 (g/L). 25.4% of RA patients
had anemia. Among anemic RA patients, the proportions of mild
anemia and moderate anemia were 16.4% and 9%, respectively.


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RF level was 85.73 ± 73.74 (IU/mL), the percentages of patients
with negative RF, low-positive RF, and high-positive RF were 24.6%,
12.3%, 63.1%, respectively.
4.1.3. Concentration of plasma CRP levels, serum TNF-α
levels of study subjects
Plasma CRP level of patients was 2.56 ± 2.81 (mg/dL) which was
higher than that of controls, 0.12 ± 0.12 (mg/dL) (p
4.1.4.2. Some cardiac function indexes of study subjects
RA patients had significant left ventricular diastolic dysfunction
that was illustrate by E/A ratio. E/A ratio of RA patients was 1.02 ±
0.35 which was lower than that of controls, 1.11 ± 0.28 (p < 0.05). A
wave of study subjects was 71.44 ± 15.84 (cm/s) which was higher
than A wave of controls, 64.82 ± 12.41 (cm/s) (p < 0.01). Our results
are consistent with findings of Fatma, E. et al. (2015).
DT index of patients was 162.93 ± 49.79 (ms) which was lower
than DT index of controls, 184.49 ± 37.51 (ms) (p 0.05.
Tissue doppler imaging at the interventricular septum and mitral
annulus: There was no difference between Sm wave of subjects (8.26
± 1.56 (cm/s)) and of controls (8.09 ± 1.22 (cm/s)), p> 0. 05. E wave
of patients was 9.44 ± 2.91 (cm/s) which was lower than that of
controls (10.23 ± 2.42 (cm/s)), p 0.05. There was no difference
between E/Em of study research (7.82 ± 2.03) and controls 7.03 ±
1.43 with p > 0.05. Em/Am ratio of RA patients was 1.01 ± 0.48
which was lower than that of controls (1.17 ± 0.45), p < 0.01.
Our results are consistent with findings of Fatma E. et al. (2012),
Wislowska M. et al. (2008), Birdane A. et al. (2007) and Arslam S. et
al. (2006).
Tissue doppler imaging at lateral mitral annulus: there was no
difference between Sm wave of study subjects which was 9.83 ± 2.49
(cm / s) and that of controls (9.20 ± 2.27 (cm / s)), p> 0.05. E wave of
RA patients was 12.77 ± 3.98 (cm / s) which was lower than that of

correlations between EF (r = 0.24; p < 0.01) and DAS28 CRP. FS (r
= 0.27; p < 0.01) was negatively correlated to DAS28 CRP.
There were positive correlation between RF concentration and the
following indexes: IVSd (r = 0.21; p < 0.01), IVSs (r = 0.25; p

ventricular diastolic dysfunction indicates the effect of chronic
autoimmune inflammation on cardiac function in RA. There is a
relation between some left ventricular diastolic function indexes and
duration of disease.
4.2.3. The association between subclinical characteristics and some
cardiac function indexes
There was negative correlation between E/Em ratio (r = - 0.23)
(Tissue Doppler Imaging at lateral mitral annulus) and Hb
concentration, p < 0.05. According to Maradit-Kremers, H. et al.
(2007), inflammation and anemia are related to the onset of diastolic
dysfunction.
Tissue Doppler Imaging at interventricular septum and mitral
annulus: E/A ratio (r = - 0.18) and Em (r = - 0.20) were negatively
correlated to RF concentration, p < 0.05. According to Liang K.P. et
al. (2009), positive RF was statistically significant associated with
risk of heart failure (OR: 3.1; CI 95% 0.8 - 12).
Thus, anemia and RF concentration may be risk factors of heart
failure in patients with RA. This result is consistent with findings
published by some other authors.
4.2.4. The relationship between plasma CRP level and serum TNFα level with some cardiac function indexes
Plasma CRP level was positively correlated to left ventricular Tei
index (r = 0.283; p
functional parameters in RA patients.
- The mean age was 48.9 ± 11.3 years, female/male ratio was 5/1,
the average duration of disease was 5.37 ± 5.25 years, the mean
duration of morning stiffness was 61.48 ± 27.64 minutes, the average
number of tender joints was 13.30 ± 4.34 joints, the average number
of swollen joints was 9.95 ± 3.71 joints. There were 74.6% of
patients with high disease activity.


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- There were 25.4% of patients with anemia. The proportions of mild
anemia and moderate anemia were 16.4%, and 9%, respectively. There
were 75.4% of patients with positive RF.
- Plasma CRP concentration of RA patients was higher than that of
controls (2.56 ± 2.81 vs. 0.12 ± 0.12 mg/dL, p < 0.001). It was positively
correlated to: the number of swollen joints, the number of tender joints,
ESR 1hr, DAS28 CRP and DAS28 ESR (p < 0.001). There was no
correlation between plasma CRP level and serum TNF-α level.
- Serum TNF-α level of RA patients was higher than that of
controls (15.32 ± 7.37 vs. 8.84 ± 2.17 pg / mL; p