Objectives: To investigate whether the pituitary-adrenal axis may be altered under long-term inflammation of rheumatoid arthritis as well as the effect of steroid administration. Subjects and methods: Concentration of blood adrenocorticotropic hormone and cortisol were measured in 140 rheumatoid arthritis patients and 60 people used as control group.
Trang 1ALTERATION OF BLOOD ADRENOCORTICOTROPIC
HORMONE AND CORTISOL LEVEL IN RHEUMATOID
ARTHRITIS PATIENTS
Truong Quang Pho 1 ; Le Anh Thu 2
SUMMARY
Objectives: To investigate whether the pituitary-adrenal axis may be altered under long-term inflammation of rheumatoid arthritis as well as the effect of steroid administration Subjects and methods: Concentration of blood adrenocorticotropic hormone and cortisol were measured in
140 rheumatoid arthritis patients and 60 people used as control group Results: Concentration
of blood adrenocorticotropic hormone and cortisol in rheumatoid arthritis patients at 8 am and
11 pm were significantly lower than those in control group Among rheumatoid arthritis patients, concentration of blood adrenocorticotropic hormone and cortisol in steroid users were significantly lower than those in non-steroid users Conclusion: These results have provided evidence that the impairment of the pituitary-adrenal axis in rheumatoid arthritis patients was due to not only chronic inflammation but also steroid using
* Keywords: Rheumatoid arthritis; Adrenocorticotropic hormone; Cortisol
INTRODUCTION
Rheumatoid arthritis (RA) is one of the
most common arthritis that affects 1%
population [1] RA is a long-term autoimmune
disorder that primarily affects joints by
chronic inflammation It typically results
in warm, swollen, and painful joints Pain
and stiffness often worsen following rest,
especially in the early morning Most
commonly, the wrist and hands are
involved, with the same joints typically
involved on both sides of the body [2]
The disease may result in a low red blood
cell count, inflammation around the lungs,
and inflammation around the heart Fever and low energy may also be present often, symptoms come on gradually over weeks to months [2]
While the cause of rheumatoid arthritis
is not clear, it is believed to involve a combination of genetic and environmental factors [1] The underlying mechanism involves the body's immune system attacking the joints The question of whether patients with RA might have a defective hypothalamo-pituitary-adrenal (HPA) axis was first raised when RA patients who were treated with glucocorticoids showed dramatic improvement in their symptoms [3]
1 Vietnam Military Medical University
2 Choray Hospital, Hochiminh City
Corresponding author: Truong Quang Pho (quangpho2009@gmail.com)
Date received: 02/08/2018
Date accepted: 20/09/2018
Trang 2It was initially hypothesized that this was
due to an impaired ability of RA patients to
synthesize sufficient amounts of endogenous
glucocorticoids, but intensive investigations
over the next few decades failed to reveal
any significant defects in HPA axis activity
in RA patients In several review of the
literature, it was found no compelling
evidence for significant differences in
either basal or stress-stimulated HPA axis
activity in RA compared with normal
healthy individuals However, recent studies
highlight an inherent defect, which resided
in the inability of RA patients to mount an
appropriately enhanced glucocorticoid
response to increased secretion of
proinflammatory cytokines such as
interleukin (IL)-1, IL-6 and tumour necrosis
factor (TNF)-α In other words, the pituitary-
adrenal axis may be altered under
long-term inflammation of rheumatoid arthritis
as well as the effect of steroid administration
[4, 5] Therefore this study was carried out
to: Investigate the concentration of blood
ACTH and cortisol in rheumatoid arthritis
patients and to look for alteration of these
hormones in RA patients
SUBJECTS AND METHODS
1 Subjects
140 RA patients were admitted and
treated in Choray Hospital and 60 non-RA
people used as control group The diagnosis
of RA fulfilled the American College
Rheumatology (ACR) criteria, and informed consent to participate in the study was obtained from all the patients Patients were treated with non-steroidal anti-inflammatory drugs None was taking corticosteroids during the study
2 Methods
Blood samples were obtained at 8 am,
11 pm in both groups Quantification of serum cortisol by Hitachi machine of Roche-Cobac 6000, model 727-0189 Normal values of cortisol in blood at 8 am was 50 - 230 ng/mL; at 11 pm was 30 -
150 ng/mL Quantification of serum ACTH
at 8 am and 23 hours by Hitachi machine
of Roche-Cobac 6000, model 727-0189 Normal values of serum ACTH was 7.9 - 66.1 pg/mL
All 140 RA patients were categorized
in two groups: Non-steroid users were patients who have not yet used steroid or duration of steroid administration less than 1 month Steroid users were patients who have duration of steroid using more than 1 month
* Statistical analysis:
Statistical analysis was carried out using analysis of variance in SPSS version 18.0 The differences of serum ACTH and cortisol levels were determined
by independent-t-test The difference was considered statistical significance if p-value lower than 0.05
RESULTS
Table 1: Characteristics of age and gender of subjects
Gender, age
Trang 3Table 2: Distribution of disease duration (n = 140)
Duration of disease
Non-steroid users (n = 70)
Steroid users
Majority of patients had disease duration from 1 - 10 years, the mean duration of all
140 RA patients was 3.87 ± 2.719 years
Table 3: Clinical manifestation of RA patients
The average number of swollen joint of RA patients was 9.71 ± 3.95 and the average number of painful joint of RA patients was 11.55 ± 2.97 All 140 patients had morning stiffness of their joints
Table 4: Comparison of serum ACTH and cortisol level between two groups
( ± SD; median; IQR)
Control group(n = 60) ( ± SD; median; IQR)
p
ACTH 8am (7.9-66.1pg/mL)
13.37 ± 17.37 7.46 (3.28 - 18.93)
19.39 ± 15.30 14.55 (8.92 - 22.88)
< 0.05
ACTH 11 pm (7.9 - 66.1 pg/mL)
7.20 ± 8,9 4,64 (2.18 - 7.30)
11.71 ± 20.14 6.54 (4.15 - 12.03)
< 0.05
Cortisol 8 am (50 - 230 ng/mL)
51.78 ± 61.37 23.18 (12.54 - 72.09)
67.90 ± 43.22 60.03 (37.79 - 93.94)
< 0.05
Cortisol 23h (30 - 150 ng/mL)
22.45 ± 27.34 15.07 (9.55 - 23.25)
34.28 ± 34.97 23.28 (13.44 - 40.59)
< 0.05
(IQR: Interquartile range)
The serum concentration of ACTH and cortisol in RA patients were significantly lower than those in control group (p < 0.05)
Trang 4Table 5: Comparison of serum ACTH and cortisol level between steroid-users and
non-steroid users
Hormones
Non-steroid users (n = 70) ( ± SD; median; IQR)
Control group (n = 60) ( ± SD; median; IQR)
p
ACTH 8 am (7.9 - 66.1 pg/mL)
18.44 ± 21.08 13.25 (6.09 - 20.74)
19.39 ± 15.29 14.55 (8.92 - 22.88)
> 0.05
ACTH 11 pm (7.9 - 66.1 pg/mL)
9.24 ± 10.11 5.63 (3.75 - 9.74)
11.71 ± 20.14 6.54 (4.15 - 12.03)
> 0.05
Cortisol 8 am (50 - 230 ng/mL)
78.06 ± 65.27 67.94 (35.79 - 91.70)
67.90 ± 43.21 60.03 (37.79 - 93.94)
> 0.05
Cortisol 11 pm (30 - 150 ng/mL)
26.94 ± 32.50 17.18 (10.87 - 29.51)
34.28 ± 34.96 23.28 (13.44 - 40.59)
> 0.05
There was no significant difference between the concentration of serum ACTH and cortisol of non-steroid users and control group
Table 6: Comparison of serum ACTH and cortisol level between steroid-users and
non-steroid users
( ± SD; median; IQR)
Steroid users (n = 70) ( ± SD; median;
IQR)
p
ACTH 8 am (7.9 - 66.1 pg/mL)
18.44 ± 21.08 13.25 (6.09 - 20.74)
8.34 ± 10.56 4.89 (2.24 - 8.74)
< 0.001
ACTH 11 pm (7.9 - 66.1 pg/mL)
9.24 ± 10.11 5.63 (3.75 - 9.74)
5.17 ± 6.99 3.39 (1.6 - 5.89)
< 0.05
Cortisol 8 am (50 - 230 ng/mL)
78.06 ± 65.27 67.94 (35.79 - 91.70)
25.50 ± 43.89 14.65 (10.05 - 22.17)
< 0.001
Cortisol 11 pm (30 - 150 ng/mL)
26.94 ± 32.50 17.18 (10.87 - 29.51)
17.95 ± 20.19 13.51 (8.81 - 21.80)
< 0.05
The serum concentration of ACTH and cortisol in Steroid -users group were significantly lower than those in non-steroid users group
Trang 5DISCUSSION
Several scientists reviewed the literature
and mentioned that the interaction
between pituitary-adrenal axis activity and
inflammatory response in RA patients were
very complex [4, 5] There have been a
number of reports on pharmacodynamic
stimulation of the pituitary-adrenal axis in
RA patients, with little evidence for a
defective response [3] In the present study,
the mean cortisol level in RA patients was
51.78 ± 61.37 pg/mL and in control group
was 67.90 ± 43.22 pg/mL that were lower
as compared to the study by Straub et al
(2008) that mean concentration of serum
cortisol in RA patients was about 350
nmoL/L (or 126.7 ng/mL [9] In this study,
we provide evidences that there was
significant difference in basal morning
cortisol between RA patients and control
group Furthermore, the concentration of
both ACTH in steroid users was significantly
lower than those in non-steroid users
These results were consistent with several
previous studies that activity of
pituitary-adrenal axis in RA patients was affected
by both chronic inflammation and steroid
using [4, 5, 6, 7] In clinical practice,
exogenous steroid is the most common
cause of secondary adrenal cortical
dysfunction Although there were many
studies evaluating corticosteroid adrenal
cortical dysfunction, it is not possible to
accurately determine the frequency of
adrenocortical insufficiency in patients
receiving long-term steroid therapy [7, 8]
This ratio of adrenocortical insufficiency
depends on the number of factors, such as:
Different corticosteroids, route of administration
(site or whole body), duration of drug use,
evaluation of adrenal function, cortisol threshold diagnosis of adrenocortical insufficiency [8] For corticosteroid administration at prolonged pharmacological doses, at lower doses, adrenal cortical dysfunction has always been observed with varying degrees of research ranging from 40% to 65%
For some time it has been hypothesized that patients with RA may have a defective activity of the HPA-axis Several recent reports discuss this topic extensively Abnormalities, if any, could reside in the hypothalamus, the pituitary or the adrenal gland [3, 4, 5, 6, 7, 8] We have studied a large group of RA patients and tested the activity of the pituitary-adrenal axis by measuring ACTH and cortisol levels at two times for each patient Our results have contributed to answer the question that whether patients with RA might have
a defective HPA
CONCLUSION
Concentration of blood ACTH in RA patients at 8 am and 11 pm were 13.37 ± 17.37 and 7.20 ± 8.9 pg/mL, significantly lower than those in control group Concentration of serum cortisol in RA patients at 8 am and 11 pm were 51.78 ± 61.37 and 22.45 ± 27.34 ng/mL, significantly lower than those in control group Among RA patients, concentration
of blood ACTH and cortisol in steroid users were significantly lower than those
in non-steroid users These results have provided evidence that the impairment of the HPA in RA patients was due to not only chronic inflammation but also steroid using
Trang 6REFERENCES
1 Anderson J, Caplan L, Michaud K
Measures of RA disease activity Arthritis
Care & Research 2011, 63 (11), pp.14-36
2 Aletaha D, Neogi T, Silman A.J et al
2010 RA classification criteria: An American
College of Rheumatology/European League
Against Rheumatism collaborative initiative
Arthritis Rheum 2010, 62 (9), pp.2569-2581
3 Eijsbouts A.M, van den Hoogen F.H,
Laan R.F et al Hypothalamic-pituitary-adrenal
axis activity in patients with RA Clin Exp
Rheumatol 2005, 23 (5), pp.658-664
4 Kirwan, J R H, S H H et al The effect
of therapeutic glucocorticoids on the adrenal
response in a randomized controlled trial in
patients with RA Arthritis Rheum 2006, 54
(5), pp.1415-1421
5 Mader R, Lavi I.L R Evaluation of the
pituitary-adrenal axis function following single
intraarticular injection of methylprednisolone Arthritis Rheum 2005, 52 (3), pp.924-928
6 Mastorakos G, Ilias I Relationship
between interleukin-6 (IL-6) and hypothalamic- pituitary-adrenal axis hormones in RA
Z Rheumatol 2000, 59 Suppl 2, pp.II/75-79
7 Gulliver T, Eid N Effects of glucocorticoids
on the hypothalamic-pituitary-adrenal axis in children and adults Immunol Allergy Clin North Am 2005, 25 (3), pp.541-555
8 Hopkins, R.L & Leinung M.C Exogenous
Cushing's syndrome and glucocorticoid withdrawal Endocrinol Metab Clin North Am
2005, 34 (2), pp.371-384
9 Straub R.H, Pongratz G, Cutolo M, Wijbrandts C.A, Baeten D, Fleck M, Atzeni F, Grunke M, Kalden J.R, Schölmerich J, Lorenz HM, Tak PP, Sarzi-Puttini P Increased cortisol
relative to adrenocorticotropic hormone predicts improvement during anti-tumor necrosis factor therapy in RA Arthritis Rheum 2008, Apr, 58 (4), pp.976-984