VIETNAM MILITARY MEDICAL UNIVERSITYHOANG TRUNG DUNG STUDY ON CLINICAL CHARACTERISTICS, PLASMA CRP LEVEL, SERUM TNF-α AND AlTERATIONSα AND AlTERATIONS OF SOME CARDIAC MORPHOLOIC AND FUNCT
Trang 1VIETNAM MILITARY MEDICAL UNIVERSITY
HOANG TRUNG DUNG
STUDY ON CLINICAL CHARACTERISTICS,
PLASMA CRP LEVEL, SERUM TNF-α AND AlTERATIONSα AND AlTERATIONS
OF SOME CARDIAC MORPHOLOIC AND FUNCTIONAL PARAMETERS IN RHEUMATOID ARTHRITIS PATIENTS
Specialty : INTERNAL MEDICINECode : 9 72 01 07
THE SUMMARY OF THE MEDICAL DOTORAL THESIS
HANOI -α AND AlTERATIONS 2019
Trang 2Scientific Instructors:
1 A/PROF Ph.D Doan Van De
2 Ph.D Vien Van Doan
1 st Contradictor: A/PROF PhD Le Thu Ha
2 nd Contradictor: A/PROF PhD Phan Thi Thu Anh
3 rd Contradictor: A/PROF PhD Nguyen Thi Phi Nga
The doctoral thesis will be reported to The Grading andExaminations Committee hold at Vietnam Military MedicalUniversity at ….2018
Searching for the dissertation at:
- National Library
- Vietname Military Medical University’s library
Trang 3Rheumatoid arthritis (RA) is a chronic autoimmune arthritis Inaddition to joint destruction, it can damage the heart, lungs… This is
a severe prognostic factor that can lead to death
C Reactive Protein (CRP) is a protein produced in inflammatoryresponse CRP level is also related to cardiovascular events The role
of TNF-α (Tumor Necrosis Factor-alpha) in the pathogenesis of RAhas been increasingly investigated TNF-α not only plays a role inevaluating the therapeutic response but is also a cardiovascular riskfactor
The leading cause of death in patients with RA is cardiovasculardamage Cardiovascular manifestations of RA are often discreet If notdetected 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 ofcomprehensive evaluation of cardiac dysfunction is Dopplerultrasonography
Therefore, the thesis "Study on clinical characteristics, plasma CRP level, serum TNF-α AND AlTERATIONSα 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 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 α level, level of disease activity with some cardiac morphologic and functional parameters in rheumatoid arthritis patients.
Trang 4* The scientific significance
This study investigated changes in plasma CRP level, serum TNF-αlevel and some cardiac morphologic and functional indexes of RA patientscompared with that of control group and the association between somecardiac morphologic and functional parameters with clinical andsubclinical characteristics
* The practical significance
This research shows that plasma CRP level and serum TNF-αlevel of RA patients were higher than that of the control group.35.2% of RA patients had left ventricular (LV) diastolic dysfunction(DD) The research reveals the relationship between some cardiacmorphologic and functional parameters with clinical and clinicalcharacteristics in patients with RA
* New contributions of this doctoral thesis
- This is the first scientific study in Vietnam researching TissueDoppler Imaging (Doppler myocardial imaging) in RA patients
- The study shows that serum TNF-α level of rheumatoid arthritispatients was higher than that of patients in the control group andthere is no correlation between it and clinical and subclinicalfeatures
- Even though patients had no clinical symptoms the results of thestudy shows that more than 35.2% of RA patients had left ventriculardiastolic dysfunction and there is a strong correlation between Em at septal mitral annulus and disease duration and age Therefore,screening left ventricular diastolic function should be performed onpatients with RA with a duration of more than 5 years and patientsaged over 60 years old
* The doctoral thesis arrangement: This thesis contains 132
pages (without references and appendixes): Introduction: 02 pages,Chapter 1 Overview: 34 pages, Chapter 2 Subjects and methods: 25pages, Chapter 3 Results: 33 pages, Chapter 4 Discussion: 34 pages,Conclusion: 02 pages, Recommendations: 01 page It includes 35tables, 18 graphs, 10 figures, and 135 references (17 Vietnamesereferences and 118 English references)
Trang 5CHAPTER 1: OVERVIEW 1.1 Overview of rheumatoid arthritis
1.1.1 History of research
RA is a systemic disease characterized by chronic inflammation ofthe synovial membrane The disease has been known since 1940 byWaaler
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 possiblylead to joint deformities of hands and feet in the later stages ofthe 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 ray, joint ultrasound, joint MRI
X-1.1.4 Diagnosis of rheumatoid arthritis
Diagnosis of RA is based on the ACR 1987 criteria Recently, theACR / 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 theprognosis of RA and is the determinant factor (decision-making) inchoosing appropriate treatment options
In addition to the criteria: the number of painful and swollenjoints, duration of morning stiffness, CRP concentration, erythrocytesedimentation rate (ESR), ACR and EULAR recommend usingDAS28 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 andglucocorticoids, analgesics and DMARDs There are two classes ofDMARDs: non-bioactive DMARDs and biological DMARDs
1.2 Mechanism of pathogenesis and role of CRP, serum TNF-α AND AlTERATIONSα
1.2.1 New view of the pathogenesis of rheumatoid arthritis
RA is a chronic inflammatory autoimmune disease in which immunetolerance is broken causing to abnormal immune responses to antigens.Genetic factors along with the environmental factors may activate thedevelopment of RA, activate T cell in synovial membrane via T-CD4 +
Trang 6Chronic inflammation of synovial membrane and destruction ofarticular cartilage are caused under the regulation of cells: T-CD4 +,Th1 and Th17, B lymphocytes, proinflammatory cytokines: TNF-α,IL-1, IL-6 ., as the consequence, pannus formation and articularcartilages degradation lead to joint fibrosis, adhesion and deformity.
1.2.2 C Reactive Protein
CRP is a protein synthesized during inflammation CRP level areassociated with a high risk of cardiovascular events in patients with RA.Cardiovascular disease is a chronic inflammatory disease with theincrease in level of inflammatory markers, especially CRP and TNF-α.CRP affects the pathogenesis of atherosclerosis and endothelialdysfunction CRP activates arterial endothelium to cause atherosclerosis
1.2.3 Tumor necrosis factor alpha
TNF-α is a proinflammatory cytokine that plays an important role
in the pathogenesis of RA TNF-α not only stimulates the cellssecreting it but also stimulates the production of other inflammatorycytokines such as IL-1, IL-6, IL-8 TNF-α regulates the balancebetween bone formation and bone turnover, causes arthritis andcartilage destruction
TNF-α is involved in the pathogenesis of many cardiovasculardiseases including atherosclerosis, myocardial infarction, cardiacfailure, and myocarditis
1.3 Cardiac involvement and the role of Tissue Doppler Imaging (TDI) in cardiac morphologic and functional evaluation
1.3.1 Cardiac involvement in rheumatoid arthritis
- Cause: inflammation induces CRP level, erythrocytesedimentation 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 / Aratio, DT, IVCT, IVRT, ET
- Left ventricular (LV) Tei index = (IVCT + IVRT) / ET
Trang 7- Tissue Doppler imagining at the interventricular septum andlateral mitral annulus: Measurements of Sm wave, Em wave, Amwave, 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 thecontrol group
Wislowska M et al (2008), Sitia S et al (2012), Fatma E et al.(2015): left ventricular morphologic indexes of RA patients andcontrols were the same There were changes in cardiac functions,especially left ventricular diastolic function in patients with RAcompared with the control group Studies have shown that somecardiac function indexes correlate with age, duration of disease,plasma CRP level, serum TNF-α level in patients with RA
1.4.2 Studies in Vietnam
Up to now, there have been no published studies on the role of
TNF-α and some morphological and cardiac indexes in Tissue DopplerImaging and the association between some cardiac morphologic andfunctional indexes and clinical and subclinical characteristics
CHAPTER 2: SUBJECTS AND METHODS
No clinical manifestations of cardiovascular disease
- Consent to participate in the study
Exclusion criteria:
- Patients with cardiovascular disease such as heart valve disease,congenital heart disease, valve regurgitation grade 2-4, cardiacarrhythmias
- Patients with pneumonia, pulmonary tuberculosis, pleural effusion,infectious arthritis, diabetes mellitus, hypertension, scleroderma,systemic lupus erythematosus
Trang 8- Patients did not consent to participate in the study.
2.1.1 Control group
Inclusion criteria:
- People at the same age and gender
- No history of arthritis, cardiovascular disease and medical conditions
- Consent to participate in the study
- 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 theDepartment of Rheumatology, Bachmai Hospital
2.2 Research Methods
2.2.1 Study Design: Prospective, descriptive cross-sectional study 2.2.2 Sampling method:
Sampling Size Formula:
According to Liang K.P et al (2010) 31% of patients withrheumatoid arthritis had left ventricular diastolic dysfunction Select
p = 0.31 to form a sample size of at least 82 patients This study wasconducted on 122 patients (n = 122)
2.2.3 Steps to conduct research
Research subjects were examined clinically, the followinginvestigations were done: laboratory tests, plasma CRP level, serumTNF-α level, Chest X-ray, Electrocardiography, Tissue DopplerImaging
- Patients with rheumatoid arthritis were examined clinically andassessed the level of disease activity: duration of disease, duration ofmorning stiffness, the number swollen joints, the number of pain joints,VAS scores, CDAI, SDAI, DAS28 CRP, DAS28 ESR
- Complete Blood count (CBC), erythrocyte sedimentationrate (ESR) 1 hr, 2 hrs, rheumatoid factor (RF)
1 .
Trang 9- CRP level measurement by measuring turbidity on AU 5800with Beckman Coulter test.
- TNF-α concentration measurement: using CLIA on the Immulite
1000 System from Siemens
- Posterior-anterior chest X-ray
- Electrocardiography
- Tissue Doppler Imaging
- Morphological assessment on echocardiography T mode:measurement of Dd, Ds, IVSTd, IVSTs, LVPWD, LVP, LVM, EVD,ESV, FS, EF, CO
- 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 lateralmitral 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 ofswollen joints, VAS score
- Diagnosis of level of disease activity: DAS28 CRP
- Diagnosis of anemia based on Hb concentration according to theWorld Health Organization
- Diagnosis of left ventricular systolic dysfunction: EF%
- Diagnosis of left ventricular diastolic dysfunction according tothe American Society of Echocardiography 2009
- The number of tender joints, the number of swollen joints
- VAS scores (3 levels): 10 - 40; 50 - 60; 70 - 100
Trang 10- Complete blood count, erythrocyte sedimentation rate 1hr, 2 hrs.
- Diagnosis of anemia: Hb < 130 (g/L) in men and Hb < 120 (g/L)
in women Classification: Hb > 110 (g/L): mild anemia; Hb: 80 - 109(g/L): moderate anemia; Hb < 80 (g/L): severe anemia
- Immunological tests: RF concentration (IU / mL) Evaluation:
RF < 14 IU/mL: negative; 14 IU/mL ≤ RF ≤ 42 IU/mL: low positive;
RF > 42 IU/mL: high positive
2.2.5.3 Assessment of inflammation level
Measure plasma CRP level (mg/dL)
Measure serum TNF-α level (pg/mL)
2.2.5.4 Tissue Doppler Imaging
-α Parameters for cardiac morphology:
+ Left ventricular end-diastolic diameter (Dd - mm)
+ Left ventricular end-diastolic diameter (Ds - mm)
+ Interventricular septal end diastole thickness(IVSd - mm)+ Interventricular septal end systolethickness (IVSs - mm)+ Left ventricular posterior wall end diastole thickness (LVPWd -mm)
+ Left ventricular posterior wall end systole thickness (LVPWs mm)
-+ Left Ventricular Mass (LVM - g)
-α Left ventricular systolic function indexes:
+ End Diastolic Volume (EDV - ml)
+ End Systolic Volume (ESV - ml)
+ Cardiac output (CO - l/ph)
+ Fraction Shortening (FS%)
+ Ejection Fraction (EF%)
-α Left ventricular diastolic function indexes:
+ Transmitral early diastolic peak velocity (E - cm/s)
+ Transmitral late diastolic peak velocity (A - cm/s)
+ E/A ratio
+ Deceleration Time (DT - ms)
+ Isovolumetric relaxation time (IVRT - ms)
+ Left ventricular Tei index
-α 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
Trang 11+ Em/Am ratio
2.2.6 Research ethics
- The subjects are fully explained and willing to participate in theresearch The implementation process is strictly complied with theregulation of the Ministry of Health
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 andfunctional parameters in RA patients
Understanding… Understand the relationship between clinical,subclinical characteristics, serum CRP level, serum TNF α level,level of disease activity with some cardiac morphologic andfunctional parameters in RA patients
Fig 2.1 Study diagram
Trang 12CHAPTER 3: RESULTS
3.1 Clinical, subclinical characteristics, serum CRP level, serum TNF-α level and some cardiac morphologicα level and some cardiac morphologic and functional parameters in patients with rheumatoid arthritis.
3.1.1 Clinical characteristics of patients with rheumatoid arthritis
Table 3.1 Some general characteristics of the study subjects
Characteristics Rheumatoid arthritis
(n = 122)
Controlgroup(n = 51) pAge (years) 48.9 ± 11,3 48.1 ± 11.7 > 0.05Sex Male, n (%)Female, n 19 (15.6%) 8 (15.7%) > 0.05(%) 103 (84.4%) 43 (84.3%) > 0.05Height (cm) 155.99 ± 5.78 158.09 ±6.47 < 0.05Weight (kg) 51.23 ± 7.28 54.80 ± 7.52 < 0.05BMI (kg/m²) 21.00 ± 2.65 21.87 ± 2.15 < 0.05BSA (m²) 1.48 ± 0.12 1.54 ± 0.13 < 0.05Systolic blood
pressure (mmHg) 119.30 ± 5.73 117.55 ±8.27 > 0.05Diastolic blood
pressure (mmHg) 77.21 ± 4.55 76.57 ± 4.74 > 0.05Table 3.1 and 3.2 The most common age of RA patients wasfrom 40 to 59 years old, accounting for 55.7% 67.2% of patientswith RA had normal BMI
Table 3.2 Some clinical features of rheumatoid arthritis patients
Clinical features Rheumatoid arthritis (n = 122)
Duration of RA 5.37 ± 5.25 3.60 0.3 – 25.0Duration of Morning
Trang 13Table 3.3 Regarding DAS28 CRP, there were 74.6% of patientswith high disease activity and 23.8% of patients with moderatedisease 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 Therewere 25.4% of patients with anemia including 16.4% of patients withmild anemia and 9.0% of patients with moderate anemia
Table 3.6 RF concentration was 85.73 ± 73.74 High positive ratewas 63.1%
3.1.3 Concentration of plasma CRP level, serum TNF-αα level of study subjects
Table 3.7 Characteristics of plasma CRP level, serum TNF-α α level
Index
Rheumatoid arthritis(n = 122)
0.12 ± 0.120.08 (0.01 – 0.50)
< 0.01
Serum TNF-α,
level (pg/mL)
15.32 ± 7.3713.70 (6.22 – 38.50)
8.84 ± 2.179.18 (4.51 –12.90)
Trang 140.475, 0.634, 0.632, 0.82, 0.72 with p < 0.001 There was nocorrelation between plasma CRP level and serum TNF-α level at r =0.133 and p > 0.05.
Table 3.9 There was no difference between median TNF-α serumconcentration in patients with DAS28 CRP> 5.1 and that of patientswith DAS28 CRP ≤ 5.1 (p> 0.05)
Table 3.10 Serum TNF-α level was not correlated with: thenumber of tender joints, the number of swollen joints, duration ofmorning stiffness, plasma CRP level, ESR 1hr, DAS28 CRP, DAS28ESR, p > 0.05
3.1.4 Some cardiac morphologic and functional parameters study subjects
Table 3.11 Some indexes of left ventricular morphology andsystolic function of RA patients and control group were similar, p >0.05 IVSd, IVSs and LVPWs of RA patients were higher than that ofcontrol group, p < 0.05
Table 3.12 Wave A in RA patients was higher than that of thecontrol 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 studysubjects and controls, p > 0.05 Tissue Doppler Imaging at lateralmitral annulus: Em and Em/Am ratio of RA patients were lower thanthat 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 diastolicdysfunction in RA patients was 35.2% which was higher than that ofthe control group, at 17.7% (p < 0.01) Among 35.2% of patientswith rheumatoid arthritis who had left ventricular diastolicdysfunction, the proportion of patients with left ventricular diastolicdysfunction grade I, II, III were 16.4%, 18.0, and 0.8%, respectively
3.2 The relationship between clinical, subclinical characteristics, plasma CRP level, serum TNF-α AND AlTERATIONSα level, level of disease activity