Patients with rheumatoid arthritis often use long-termglucocorticosteroids GC to treat the disease, which also contributes to the decline of HPA axis activity.. In Vietnam, no research h
Trang 11 The necessity of thesis
Rheumatoid arthritis (rheumatoid arthritis) is a typical systemicautoimmune disease, with chronic inflammatory manifestations inmany peripheral joints, accompanied by extracellular and systemicmanifestations of varying degrees, complex movements trash hasserious consequences
In patients with rheumatoid arthritis, chronic inflammation causesinternal changes to affect the function of endocrine glands, includingthe hypothalamic-pituitary-adrenal axis (hypothalamo -pituritin-adrenal, HPA) Patients with rheumatoid arthritis often use long-termglucocorticosteroids (GC) to treat the disease, which also contributes
to the decline of HPA axis activity
In the world, there are many studies in-depth about the mechanism ofimmune disorders, hormonal, cellular and humoral changes, related
to the clinical manifestations, progress and treatment response of therheumatoid arthritis disease In Vietnam, no research has focused onthe change of cortisol and related hormone levels and thepathophysiological mechanisms of interactions between endogenousanti-inflammatory hormones of patients with the stage and level ofdisease activity of rheumatoid arthritis We found that the study ofday-to-day changes in hormone levels of cortisol and hormones thatstimulate it is ACTH in patients with rheumatoid arthritis may shedsome light on the physiological mechanism of pathology ofinteractions between gland functions Endocrine and activity levels ofrheumatoid arthritis From there, we can apply more effectiveapproaches to treating rheumatoid arthritis in our country The topic
"Study on changes in blood Cortisol concentration, cortisol function
of adrenal gland in patients with rheumatoid arthritis" is conductedwith the following two objectives:
1 Survey of cortisol, ACTH, cortisol / ACTH blood ratio inrheumatoid arthritis patients
Trang 22 Analysis of the relationship between cortisol, ACTH, cortisol /ACTH blood ratio with disease activity and disease stage inrheumatoid arthritis patients.
*Scientific significance
Quantifying ACTH, cortisol partially reflects the HPA axis activitywith inflammatory response, finding an association betweeninflammation in rheumatoid arthritis and HPA axis dysfunction,according to the level of disease activity advanced stage ofrheumatoid disease
-ROC curve with cutting point of blood Cortisol concentration at 8h 35.5ng / ml is valid for diagnosis of patients using GC
2 New contributions of this doctoral thesis
1 The determination of ACTH and cortisol in plasma is 2 of 9functions that assess the adrenal glands Quantifying ACTH at thesame time as Cortisol and quantifying ACTH and cortisol levels at8am and 23h is the nocturnal rhythm of the adrenal gland
2 Determine the ratio of Cortisol / ACTH, one of the factorsassessing adrenal response to ACTH stimulation This is an indirectratio used to assess adrenal response to ACTH with the ability tomeet the theoretical basis for the synacthen test
3 The doctoral thesis arrangement: This thesis contains 122 pages
(without references and appendixes): Introduction: 02 pages, Chapter
1 Overview: 32 pages, Chapter 2 Subjects and methods: 14 pages,Chapter 3 Results: 29 pages, Chapter 4 Discussion: 42 pages,Conclusion: 02 pages, Recommendations: 01 page It includes 30
Trang 3tables, 12 graphs, 5 figures, 1 diagram and 135 references(15Vietnamese references and 133 English references).
CHAPTER 1 OVERVIEW 1.1 Overview of rheumatoid arthritis
1.1.1 Concept of disease
Rheumatoid arthritis is a typical autoimmune disease, chronicprogression with joint and systemic manifestations at different levels
1.1.2 Epidemiology
Rheumatoid arthritis occur in all countries of the world Vietnam has
a common morbidity rate of 0.5% of the adult population, morewomen than men with a rate of 2-3 / 1
1.1.3 Causes and mechanisms of pathogenesis
**Causes: the disease is not clear, people consider rheumatoid
arthritis to be a disease that has the same mechanism of actionthrough the mechanism of immune response disorder
**Mechanisms of pathogenesis: the onset of the disease is thought
to begin with T-CD4 + that identify strange antigens that haveinflammatory properties Antigenic identification leads to activation
of a series of immune response reactions in which stimulation of Blymphocytes will produce autoantibodies (RF, anti CCP .),stimulation of monocytes phagocytes produce a series ofinflammatory cytokines (TNF-α, IL-1, IL-6) that stimulate thesynovial membrane cells, fibroblasts, and cartilage cells .Tlymphocytes release cytokines activation of capillary endothelialcells synovial membrane produces adhesion molecules, attractinginflammatory cells to the joint cavity The consequence of theseprocesses is the formation of a chorionic membrane in the synovialmembrane (pannus), invading the cartilage, causing cartilage andbone cartilage destruction, causing joint disruption, leading tostickiness, stiffness and The role of HPA axis also contributesequally important to the adjustment and control of the HPA axialimmune response and dysfunction associated with the pathogenesis
of rheumatoid arthritis
1.1.4 Clinical symptoms
Trang 4** Clinical symptom: signs of morning stiffness, pain in many joints
of symmetry in hands, feet, wrists, ankles, elbows, knees, shoulders,groin Late stages may have deformations in the hands and feet.External manifestations of joint damage to the heart, pulmonaryfibrosis, chronic anemia, low grain under the skin
** Subclinical symptoms: Rate of blood sedimentation, reactive Cprotein (CRP), rheumatoid factor RF (+) at 70%, anti-CCP, handradiograph, ultrasound, magnetic resonance imaging joint
1.1.5 Diagnosis of rheumatoid arthritis
Diagnosis of rheumatology is based on ACR 1987 Recently, ACR /EULAR 2010 standards have been used to early diagnose rheumatoidarthritis
1.1.6 Treatment
Coordinate non-drug measures and medications including NSAIDsand Glucocorticoid (GC) Basic drugs for treatment of classicDMARDs and the use of biological drugs DMARDs
1.2 A number of studies on cortisol and ACTH concentrations in patients with rheumatoid arthritis
1.2.1 Research in the country
Tran Quang Nam et al 2011 studied 101 patients including manydiseases including rheumatoid arthritis Luu Thi Binh et al (2016)Study on rheumatoid patients, found a proportion of 37.5%adrenocortical insufficiency due to GC use with Cortisolconcentration <3 μg / dLg / dL
1.2.2 Study abroad
Gudbjornsson B et al (1996) The ratio of cortisol / ACTH hormones
in patients with rheumatoid arthritis at the group is not treated with
GC was significantly lower than that in the control group Ehrhart
BM et al (1998) increased cortisol / ACTH ratio due to inadequateregulatory interaction of the hypothalamic and adrenal pituitary axis.Straub et al (2002) The morning serum Cortisol levels weresignificantly higher in the non-GC group compared to healthysubjects, but there was no difference between ACTH levels and thecontrol group Kirwan et al (2006) measured the effect of low-dose
Trang 5GC treatment The HPA axis response remains within the normalrange Straub et al (2008) were not treated with GC, the improvement
in DAS28 was inversely correlated with blood cortisol concentration(R = -0.52; P = 0.011) and cortisol: ACTH ratio (R = - 0, 7; P =0.0002) Lee MK et al (2013), patients with primary adrenalinsufficiency all had cortisol / ACTH ratio <3 Li et al (2018) use theratio of Cortisol / ACTH to assess the function of adrenal cortex inpatients with excretion of Cortisol
CHAPTER 2 SUBJECTS AND METHODS
2.1 Subjects
140 patients with rheumatoid arthritis and control group of 60patients without rheumatoid arthritis, treated at Department ofosteoarthritis Cho Ray hospitals from 4/2014 - 9/2015
2.1.1 Criteria for selecting patients into research groups
- Diagnosed with rheumatoid arthritis according to the standard ofACR 1987
- Rheumatoid arthritis in non-GC group (using common inflammatory, analgesic (paracetamol, NSAIDs, using GC equivalent
anti-of prednisone 5 mg / day in short, intermittent <1 month)
- Rheumatoid disease in the GC group (Prednisone, prednisolone,methylprednisolone, hydrocortisone), equivalent to prednisone 20 mg/ day, duration of continuous use lasts> 1 month
- Accepting participation in research
2.1.2 Criteria for selecting patients into control groups
The disease does not suffer from rheumatoid arthritis: there arecommon conditions such as osteoarthritis, chronic lumbar painsyndrome Similarities in age and gender with rheumatoid diseases
2.1.3 Standards exclude the research group
- Subjects do not agree to participate in the study
- Patients with other chronic chronic diseases: heart failure, chronicbronchopulmonary disease, unstable hypertension, hepatitis,cirrhosis, alcoholism, Basedow, reactive arthritis, chronic renalfailure , chronic gout, diabetes, systemic lupus erythematosus
Trang 6-Trauma, surgery within 1 recent month, with surgical diseases,malignancy, pituitary adenoma, adrenal adenoma
2.1.4 Standards exclude the control group
- Being infected with rheumatoid arthritis has been using GC
-There are other chronic chronic diseases: heart failure, chronicbronchopulmonary disease, unstable hypertension, hepatitis,cirrhosis, alcoholism, Basedow, reactive arthritis, pituitary adenoma,adrenal adenoma
2.2.2 Steps to conduct research
- Clinical examination of patients according to a uniform medicalrecord, routine laboratory tests, instructions and interviews with thepatient to fill in the questionnaire Data collection and dataprocessing according to statistical algorithms
2.3 research content
2.3.1 Clinical examination and laboratory tests
- Exploiting history of history:
+ Age, gender, occupation, time of disease detection, factors related
to smoking, obesity time of GC drug treatment?
+ General examination of patients' condition: Pulse, blood pressure,height, weight, BMI, abdominal measurement, time of morningstiffness, joint deformation?
+ Cardiovascular examination, respiratory, digestive, urological,endocrine examination
+ Large number of joints, small joints (according to EULAR / ACR2010)
+ Assess the pain situation through the scale of pain VAS, DAS ESR disease activity point
28-Laboratory tests:
Trang 7+ Peripheral blood cells, erythrocyte sedimentation rate-ESR,Reactive protein C (CRP), Urea blood, Blood creatinine
+ Rheumatoid factor (RF) uses immunological measurement ofopacity and antibody CCP- Anti CCP using ELISA measurementmethod
+ Quantitative blood cortisol 8h and 23h by Hitachi machine ofRoche-cobac 6000, model 727-0189, by method of luminescence.+ ACTH quantification 8h and 23h by Hitachi machine of Rochecobac 6000, model 727-0189, with luminescent sandwichimmunization
Process of sampling cortisol, ACTH
Patients were given blood samples to measure cortisol levels, ACTHshould ensure that no exogenous glucocorticosteroid is used Whenmeasuring cortisol to be sure cortisol is measured by the adrenalcortex Patients need to discontinue glucocorticosteroids within 24-48h before measuring blood cortisol The patient and family membershould explain the purpose of the test Patients need to coordinate totake blood according to the time and quantity requirements Bloodsamples were taken by Osteoarthritis Nursing at 8:00-9:00am at thesame time as other basic routine tests and followed by a blood sample
of Cortisol and ACTH measurements at 22:00 - 23:00 Heterosexualblood samples are kept in ice containers to the Cho Ray HospitalBiochemistry Department within 05 minutes after taking blood.+ Conventional x-ray of neck joints - hands on both sides straight+ Cardiopulmonary X-ray, electrocardiography, general abdominalultrasound
2.3.2 Standards used in research
- Diagnostic criteria for rheumatoid arthritis according to ACR 1987
- Diagnosis of rheumatism disease stage according to Steinbroker
- Evaluate the extent of X-ray damage according to Steinbroker
- Evaluate disease activity points DAS28-ESR
- Diagnosis of anemia according to WHO 2011 standards
- Assessment of adrenal cortex function: Based on clinical standardsand some laboratory tests
Trang 8- Test indicators according to prescribed standards and tests at theDepartment of Biochemistry of Cho Ray Hospital (Hospital under theMinistry of Health)
2.3.3 Data processing
- The collected data is processed by SPSS 18.0 software
- Quantitative variables without normal distribution are presented inthe median form (quarter-quartile Q1-Q3) Variable denoted (*)
2.3.4 Ethical issues in research
-The thesis is reviewed and approved by the Science and MedicalCouncil of Cho Ray Hospital before implementation
- Patients was fully explained and voluntarily participated in thestudy
Research diagram
Research subjects Researchers
140 patients with rheumatoid
Objectives 1: Analysis of the
relationship between cortisol, ACTH, cortisol / ACTH blood ratio with disease activity and disease stage in patients with rheumatoid arthritis
Objectives 1: Survey of
cortisol, ACTH, cortisol /
ACTH blood ratio in
rheumatoid arthritis
patients
CONCLUSION
Recommendation
Trang 9CHAPTER III:
RESEARCH RESULTS 3.1 Characteristics of rheumatoid arthritis patients
3.1.1 General characteristics of the research object
Table 3.1.Age and gender characteristics of the research groupGender,
age
of both groupsn=140
53,17± 19,0215-84Women account for 85.7%, the rate of female / male isapproximately 6/1 higher than in the control group The average age
of the two groups is similar
Graphs 3.1 The clinical symptoms associated with the history of thedisease accounted for the highest proportion of 49.3% infection,2.1% injury
Table 3.2 and Table 3.3 The group that did not use GC had theabdominal ring male 74.50 ± 11.29cm; Female text 79.62 ± 13.45cm;abdominal fat (AF) male 8.3%; BB female 43.1%; BMI 22.24 ± 3.61
kg / m² is lower than GC and control group.Except abdominal ring,male abdominal fat, with P1,2 <0,05, in the GC group, there is a maletext higher than the female text, AF male 50%; BMI 22.52 ± 3.65
kg / m², except for female AF 45.2% lower The level ofhypertension of study group was lower in the control group, with P>0.05
Table (3.4; 3.5; 3.6; 3.7) The time of detection of disease from 1-10years accounted for the highest rate of 68.6%, an average of 3.87 ±2.72 years The number of swollen joints is 9.71 ± 3.95 Number of
Trang 10painful joints 11.55 ± 2.97 VAS 57.75 ± 9.04 mm, morning stiffness66.18 ± 9.49minutes The white blood cell group increased by 32.9%,red blood cells decreased by 41.1% and Hb decreased by 74.3%.Mild anemia was highest at 73.6% compared to 70% of NC, with P
<0.05
Graphs 3.2 and 3.3 There is anemia of 87.1%, according to the stage
of disease in both groups is the highest in Phase I (79.7%), the lowest
in Phase IV (0.7%)
Tables (3.8; 3.9 and 3.10) RF rates (-) 27.4%, RF (+) 72.6% and therate of anti-CCP (-) 41.1%, anti-CCP (+) 58.9% The 1 hour ESR is57.53 ± 40.62, the 1-hour ESR rate increases by 78.6%, the DAS28-ESR disease activity is 98.4%, DAS28-ESR is 5.30 ± 1.06
Graphs (3.4; 3.5).DAS28-ESR rate of disease activity is 66.4% Inthe non-GC group, ACTH levels were 8 hours <8.92 pg / ml; ACTH23h <4.15 pg / ml is lower than the GC group, higher than controlgroup In contrast, ACTH 8 hours: 8.92-22.88 pg / ml and ACTH 8hours> 22.88pg / ml higher than the GC group, lower than controlgroup and ACTH levels 23h: 4.15-12.03 pg / ml; ACTH 23h> 12.03
pg / ml is higher than the GC group, lower than control group
3.2 Concentrations of cortisol, ACTH, cortisol / ACTH ratio in patients with rheumatoid arthritis
Table 3.11 Blood levels of ACTH and Cortisol were 8 hours and 23hours of the study groups
Characte
ristics
Non-GC users (1)
(n=70) ( X ´ ± SD;median
; IQR)
GC users (2)
(n=70)(X ´ ± SD;
median;
IQR)
control group (3)
(n=60) ( X ´ ± SD;
8,34±10,564,89(2,24-8,74) *
19,39±15,214,55(8,92-22,88)
p1,2<0.001
p1,3>0,05
p2,3<0,001
Trang 115,17±6,993,39(1,6-5,89) *
11,71±20,146,54(4,15-12,03) *
25,50±43,8914,65(10,05-22,17)
67,90±43,2160,03(37,79-93,94)
17,95±20,1913,51(8,81-21,80)
34,28±34,9623,28(13,44-40,59) *
p1,2<0,05
p1,3>0,05
p2,3<0,05
(*) Variables are presented as medians (IQR-quartet)
ACTH concentration 8h, 23h; Cortisol 8h, 23h in the group that didnot use GC by median value was higher than that in the GC andlower than control group group, with p1,2 <0.001; p1,2 <0.05 Exceptfor 8 hours cortisol was 67.94 ng / ml higher than control group60.03 ng / ml, with p1.3> 0.05
The concentration of ACTH 8h, 23h, Cortisol 8h, 23h in the groupusing GC according to GTTV is lower than that of the study, p2,3
<0,001, p2,3 <0,05
Table (3.12; 3.13) The concentration of cortisol 8 hours: in the
non-GC group in men, median was higher than female, with p1 <0.05;Normal waist circumference (WC) has higher median than WCincreased; BMI ≥23 is lower than BMI <23 GC group in men haslower median than female; Normal WC has lower median than WCincreased; BMI ≥23 is higher than BMI <23 The cortisolconcentration of 23 h: the non-GC group in men had the same results
as the cortisol 8 hours, the GC group in men had median higher thanthe female; except BMI ≥23 higher than BMI <23
Table (3.14; 3.15; 3.16) The longer the detection time, the cortisolconcentration is 8 hours, 23 hours in the research group with mediandecreased, with (P1 <0.05; P2 <0.05).The cortisol concentration of 8
h, 23 h in the GC group using, median was lower than that of thenon-GC group, with (p1 <0.001; p2 <0.05) The longer the detectiontime, the more ACTH concentrations are 8 hours, 23 hours, cortisol 8hours, 23 hours in both groups with median decreases, with (P1>0.05; P2> 0.05)
Trang 12Table 3.17 Reference value of ACTH concentration, Cortisol atlower quartile threshold, upper quartile of control group
ACTH concentration
(pg/mL), Cortisol
(ng/ml)
Four quartilesbelow
Four quartilesabove
Table 3.18 The average ratio of Cortisol / ACTH concentrations at8:00, 23:00 in the study groups
Ratio:
Cortisol/ACTH
(nmol/pmol)
Non-GC users (1)
(n=70) ( X ´ ± SD;median;
IQR)
GC users (2)
(n=70)(X ´ ± SD;
median; IQR)
control group (3)
(n=60) ( X ´ ± SD;
62,67±65,5939,14(18,9-78,72) *
58,08 ± 45,8541,75(24,85-80,48)
>0,05
Cortisol 23 h
ACTH 23 h
71,31±139,4537,5(19,86-78,51)*
71,82±60,8551,48(27,52-98,91)
69,71 ± 82,0645,67(20,81-78,55)*
>0,05
(*) Variables are presented as medians (IQR-quartet)
This Cortisol / ACTH ratio is presented in units of nmol / pmol
8-hour Cortisol / ACTH ratio: Non GC users group with medianhigher than the GC users and control group In contrast, GC users
group lower than control group and the ratio of blood Cortisol /