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INTRODUCTION
1. The necessity of thesis
Rheumatoid arthritis (rheumatoid arthritis) is a typical systemic
autoimmune disease, with chronic inflammatory manifestations in
many peripheral joints, accompanied by extracellular and systemic
manifestations of varying degrees, complex movements. trash has
serious consequences.
In patients with rheumatoid arthritis, chronic inflammation causes
internal changes to affect the function of endocrine glands, including
the hypothalamic-pituitary-adrenal axis (hypothalamo -pituritinadrenal, HPA). Patients with rheumatoid arthritis often use long-term
glucocorticosteroids (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 of
immune disorders, hormonal, cellular and humoral changes, related
to the clinical manifestations, progress and treatment response of the
rheumatoid arthritis disease. In Vietnam, no research has focused on
the change of cortisol and related hormone levels and the
pathophysiological mechanisms of interactions between endogenous
anti-inflammatory hormones of patients with the stage and level of
disease activity of rheumatoid arthritis. We found that the study of
day-to-day changes in hormone levels of cortisol and hormones that
stimulate it is ACTH in patients with rheumatoid arthritis may shed
some light on the physiological mechanism of pathology of
interactions between gland functions Endocrine and activity levels of
rheumatoid arthritis. From there, we can apply more effective
approaches 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 conducted
with the following two objectives:
1. Survey of cortisol, ACTH, cortisol / ACTH blood ratio in

assessing adrenal response to ACTH stimulation. This is an indirect
ratio used to assess adrenal response to ACTH with the ability to
meet 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


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tables, 12 graphs, 5 figures, 1 diagram and 135 references(15
Vietnamese 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, chronic
progression 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, more
women 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 action
through 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 have
inflammatory properties. Antigenic identification leads to activation
of a series of immune response reactions in which stimulation of B

1.1.6. Treatment
Coordinate non-drug measures and medications including NSAIDs
and Glucocorticoid (GC). Basic drugs for treatment of classic
DMARDs 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 many
diseases 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 Cortisol
concentration
-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, chronic
bronchopulmonary disease, unstable hypertension, hepatitis,
cirrhosis, alcoholism, Basedow, reactive arthritis, pituitary adenoma,
adrenal adenoma
2.2. Research Methods
2.2.1. research design
- Research method: research, descriptive cross-section, control group
comparison.
- Sample size: convenient selection, patients diagnosed with
rheumatoid arthritis
2.2.2. Steps to conduct research
- Clinical examination of patients according to a uniform medical
record, routine laboratory tests, instructions and interviews with the
patient to fill in the questionnaire. Data collection and data
processing 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 morning
stiffness, joint deformation?
+ Cardiovascular examination, respiratory, digestive, urological,
endocrine examination ...
+ Large number of joints, small joints (according to EULAR / ACR

ultrasound
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 standards
and some laboratory tests.


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- Test indicators according to prescribed standards and tests at the
Department of Biochemistry of Cho Ray Hospital (Hospital under the
Ministry of Health)
2.3.3. Data processing
- The collected data is processed by SPSS 18.0 software
- Quantitative variables without normal distribution are presented in
the 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 Medical
Council of Cho Ray Hospital before implementation.
- Patients was fully explained and voluntarily participated in the
study
Research diagram
Research subjects
Researchers
140 patients with rheumatoid
arthritis
- 70 patients do not use GC

control group
p
Gender, age
n=140
n=60
amount
ratio % amount
ratio %
Male
20
14,3
28
46,7

Table (3.4; 3.5; 3.6; 3.7). The time of detection of disease from 1-10
years 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
painful joints 11.55 ± 2.97. VAS 57.75 ± 9.04 mm, morning stiffness


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66.18 ± 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

( ± SD;
median;
IQR)
19,39± 15 ,2
14 ,55
(8,92- 22,88)

P

p1,20,05
p2,3
p2,3
Ra ti o:
Cort i sol /A C TH
(nmol / pmol )

Non-GC
users (1)
(n=70)
(±
SD;median;
IQR)
123,81± 260 ,46
48,6 (28,21124,91 ) *
71,31± 139 ,45
37 ,5 (19,8678,51 ) *

GC users (2)
(n=70)
( ± SD;
median; IQR)

62,67 ± 65,59
39 ,14(18 ,97 8,7 2) *
71,82± 60 ,85
51,48 (27 ,5298 ,91)

control
group (3)
(n=60)
( ± SD;
median;

below
24,85

80,48

20,80
78,55
(*) Variables are presented as medians (IQR-quartet)
The ratio of Cortisol / ACTH 8h, 23h smaller than the lower quartile
is considered reduced; Higher than the above quartile is considered
an increase. in the interval between the lower quartile and the quartile
above is considered normal.
Figures 3.7 and 3.8. The ratio of blood levels of Cortisol / ACTH of 8
hours 80.48
and Cortisol / ACTH at 23h> 78.55 was higher than in the control
and GC groups and the ratio of Cortisol / ACTH 23h

Graphs 3.9: Graph of ROC curve of blood cortisol concentration
at 8pm for patients with rheumatoid disease using GC
The cut-off point of blood Cortisol concentration at 8am ≤35.5ng / ml
has a diagnostic value of BN using GC with sensitivity: 77.1%;
specificity: 91.4%; The value of 35.5 ng / ml is the most optimal
cutting point compared to other cutting points. The area under the
curve (AUC) is 0.828 with p
24,81 (9,17-46,52)
20,51 (2,94-309) *
DAS 28
ESR

p

Moderate
(3,2-5,1)

47,95±34,34
45,59(14,09-69,76)

15,29 ± 9,19
14,81 (3,17-36,54)

Strong
(>5,1)

100,35±74,6
72,93(46,87-133,75)

25,49 ± 36,64
14,78 (5,93-166) *

p1> 0,05

p2> 0,05



*
p
p1>0,05
42,46±37,86
Moderate
29,57 (12,15(3,2-5,1)
90,09)
90,88±180,56
Strong
42,26(24,45(>5,1)
91,22) *
p
p1>0,05
(*) Variables are presented as medians (IQR-quartet)
Moderate
(3,2-5,1)

GC users (2)
(n=66)
( ± SD;
median; IQR)
50,49±48,72
28,59(20,8862,78)
61,73±68,91
39,38(18,7677,28) *
p2>0,05
63,98± 41
52,72(42,1081,75)
78,54±68,11
54,36(27,26116,4)


stage 3-4
p
stage 1

Non-GC
users (1)
(n=70)
(±
SD;median;
IQR)

GC users (2)
(n=70)
( ± SD;
median; IQR)

129,57± 283,05
49,25 (27,54134,64) *
115,14±144,59
47,95 (30,03180,94) *
53,14±62,54
31,71(4,1377,65)*
p1>0,05
75,44±153,25
39,43 (18,33-

60,53±67,81
38,77 (19,6975,25)*
48,79±55,58

DISCUSSION
4.1. General features
Gender, age: female accounts for 85.7%; male accounted for 14.3%,
age <60 accounted for 67.9%; > 60 years old 32.1%, age of medium
53.49 ± 12.2. Our results are also consistent with the results of other
studies
Disease detection time 3.87 ± 2.72 years, the number of swollen
joints 9.71 ± 3.95; number of painful joints 11.55 ± 2.97, duration of
morning stiffness 66.18 ± 9.49 minutes, pain level VAS (mm) 57.75 ±
9.04 mm. Compared with Imran M.Y et al (2015) number of swollen
joints 2.6 ± 3.18; Pain joint number 4.54 ± 4.35
The rate of anemia is 87.1%, the first time ESR: 57.53 ± 40.62 mm;
RF (+) accounted for 72.6%. Osteoarthritis of stage I occupies the
highest 79.7%. According to Isik A et al (2007) RF (+) 84.1%, ESR:
42.5 ± 26.9mm. Imran M. Y et al (2015) RF (+) 100%.
* Results DAS 28 - ESR: 5,30 ± 1,06, strong activity level accounts
for 66.4%; moderate is 31.2%; mild 2.4%. According to Son K.M et
al (2011), Tran Thi Minh Hoa (2011) similar results


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4.2. Concentrations of cortisol, ACTH, cortisol / ACTH ratio in
patients with rheumatoid arthritis
4.2.1. Compare blood levels of ACTH and Cortisol 8h and 23h
between study groups
Cortisol levels of 8 hours, 23 hours in the group did not use GC
according to median respectively: (67.94, 17.18) ng / ml higher than
the GC group (14.65, 13.51) ng / ml and lower than control group
( 60.03, 23.28) ng / ml. Except for cortisol 8h, there is median with
67.94 ng / ml, higher than control group 60.03ng / ml, with p1,3>

under disease detection time (DDT)
will further clarify our research.
The concentration of Cortisol 8h group did not use GC with strong
disease activity 72.93 ng / ml, higher than average disease activity
45.59 ng / ml and mild 24.81 ng / ml. In the group using GC with
strong disease activity, median is lower than medium and mild.
According to Luu Thi Binh (2016), there is the opposite result
Cortisol 23h concentration in both groups with strong disease activity


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higher than moderate and mild. In the group, do not use GC Cortisol /
ACTH ratio 8h, 23h with moderate disease activity lower levels of
strong disease activity. In the GC group with moderate disease
activity, the ratio of Cortisol / ACTH 8 hours with median 28.59
nmol / pmol is lower than the 39,38 nmol / pmol strong disease
activity, with moderate disease activity Cortisol / ACTH 23h with
lower median than the with strong disease activity. According to
Zautra AJ et al (1994), Straub et al (2008) similar results to us
4.3.2. The relationship between ACTH concentrations, cortisol,
cortisol / ACTH ratios in the study groups with the lesion phase
according to Steinbroker
The ACTH 8h concentration without GC in GĐ1, 2 with the median
order (12.81; 14.24) pg / ml lower than GĐ3-4 was 18.03 pg / ml,
and ACTH concentration 23h at Stage 1, 2 have median lower than
Stage 3-4. In the group with GC levels of ACTH at 8 hours in Stage 1
and 2, there was a decrease in median according to Stage and ACTH
concentration at 23 h in Stage 1, with GTTV higher than Stage 3-4.
According to Yousri NA and et al. 2017, Pincus T et al. Cutolo M and
cs (2018), the results are similar to ours. Cortisol concentration of 8h,
23h in the group that did not use GC in GĐ1, 2 had median decreased

Cortisol / ACTH ratio 8h, 23h, with P> 0.05
2. Relationship between cortisol, ACTH, cortisol / ACTH blood
ratio with disease activity and rheumatism
-Patients with mild activity of the rheumatoid arthritis (both using
and not using GC) ACTH levels 8h and 23h have lower median
values than patients with moderate and strong activity levels
-Patients with mild activity of the rheumatoid arthritis do not use GC
cortisol concentration at 8h, 23h with lower median value than
patients with moderate and strong activity level.
-Patients with mild activity of the rheumatoid arthritis in the GC
group cortisol concentration of 8h is higher but cortisol 23h
concentration is lower than patients with moderate and strong activity
level, with p2> 0.05
₋ ACTH concentration 8h, 23 h in the non-GC group in the median
tends to increase gradually according to the disease phase. In
contrast, ACTH concentrations of 8 hs and 23 h in the GC group
tended to decrease gradually according to the disease history.


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-Cortisol concentration of 8h, 23h in the group that did not use GC,
the group using GC median tends to decrease gradually according to
disease phase, the most decrease is phase 3 and 4.
-Cortisol / ACTH ratio 8h, 23h in the non-GC group, the group using
GC increased with disease activity level, with p1> 0.05, p2> 0.05
-There is a moderate correlation (r=0.41; r=0.34) between ACTH and
cortisol blood levels in both groups without GC, using GC
-ROC curve with cut-off point of blood Cortisol concentration at 8h
≤35.5ng / ml is valid for diagnosis of patients using GC with
sensitivity:77.1%;Specificity:91.4%.The AUC is 0.828 with p