Alteration of blood adrenocorticotropic hormone and cortisol level in rheumatoid arthritis patients

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.

Journal of military pharmaco-medicine n08-2018 ALTERATION OF BLOOD ADRENOCORTICOTROPIC HORMONE AND CORTISOL LEVEL IN RHEUMATOID ARTHRITIS PATIENTS Truong Quang Pho1; Le Anh Thu2 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 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] Vietnam Military Medical University Choray Hospital, Hochiminh City Corresponding author: Truong Quang Pho (quangpho2009@gmail.com) Date received: 02/08/2018 Date accepted: 20/09/2018 148 Journal of military pharmaco-medicine n08-2018 It 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 pituitaryadrenal axis may be altered under longterm 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 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 antiinflammatory drugs None was taking corticosteroids during the study Methods Blood samples were obtained at 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 am was 50 - 230 ng/mL; at 11 pm was 30 150 ng/mL Quantification of serum ACTH at 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 month Steroid users were patients who have duration of steroid using more than 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 RA patients (n =140) Gender, age Control group (n = 60) n % n % Male 20 14.3 28 46.7 Female 120 85.7 32 53.3 Age (years) 53.49 ± 12.20 53.17 ± 19.02 p < 0.001 > 0.05 149 Journal of military pharmaco-medicine n08-2018 Table 2: Distribution of disease duration (n = 140) Duration of disease Non-steroid users (n = 70) Steroid users (n = 70) n % < year 32 45.7 - 10 years 34 48.6 > 10 years 5.7 Mean duration n Sum % n % 7.1 37 26.4 62 88.6 96 68.6 4.3 5.0 3.73 ± 3.30 5.05 ± 2.49 3.87 ± 2.72 Majority of patients had disease duration from - 10 years, the mean duration of all 140 RA patients was 3.87 ± 2.719 years Table 3: Clinical manifestation of RA patients Symptoms Mean ± SD Min Max Number of swollen joint 9.71 ± 3.95 1,00 15.00 Number of painful joint 11.55 ± 2.97 24 VAS 57.75 ± 9.04 40 75 Duration of stiffness (min) 66.18 ± 9.49 50 100 Morning stiffness 140 (100.0) Symetrical swollen joint 140 (100.0) Number of joint deformation (0.7) Number of rheumatoid nodule (0.7) 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 Hormones ACTH 8am (7.9-66.1pg/mL) ACTH 11 pm (7.9 - 66.1 pg/mL) Cortisol am (50 - 230 ng/mL) Cortisol 23h (30 - 150 ng/mL) RA patients (n = 140) Control group(n = 60) ( ( ± SD; median; IQR) 13.37 ± 17.37 7.46 (3.28 - 18.93) 7.20 ± 8,9 4,64 (2.18 - 7.30) 51.78 ± 61.37 23.18 (12.54 - 72.09) 22.45 ± 27.34 15.07 (9.55 - 23.25) ± SD; median; IQR) 19.39 ± 15.30 14.55 (8.92 - 22.88) 11.71 ± 20.14 6.54 (4.15 - 12.03) 67.90 ± 43.22 60.03 (37.79 - 93.94) 34.28 ± 34.97 23.28 (13.44 - 40.59) p < 0.05 < 0.05 < 0.05 < 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) 150 Journal of military pharmaco-medicine n08-2018 Table 5: Comparison of serum ACTH and cortisol level between steroid-users and non-steroid users Non-steroid users (n = 70) Hormones ( ACTH am (7.9 - 66.1 pg/mL) ACTH 11 pm (7.9 - 66.1 pg/mL) Cortisol am (50 - 230 ng/mL) Cortisol 11 pm (30 - 150 ng/mL) ± SD; median; IQR) Control group (n = 60) ( p ± SD; median; IQR) 18.44 ± 21.08 19.39 ± 15.29 13.25 14.55 (6.09 - 20.74) (8.92 - 22.88) 9.24 ± 10.11 11.71 ± 20.14 5.63 6.54 (3.75 - 9.74) (4.15 - 12.03) 78.06 ± 65.27 67.90 ± 43.21 67.94 60.03 (35.79 - 91.70) (37.79 - 93.94) 26.94 ± 32.50 34.28 ± 34.96 17.18 23.28 (10.87 - 29.51) (13.44 - 40.59) > 0.05 > 0.05 > 0.05 > 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 Hormones Non-steroid users (n = 70) ( ± SD; median; IQR) Steroid users (n = 70) ( p ± SD; median; IQR) ACTH 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 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 151 Journal of military pharmaco-medicine n08-2018 DISCUSSION 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 pituitaryadrenal 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, 152 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 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 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 Journal of military pharmaco-medicine n08-2018 REFERENCES intraarticular injection of methylprednisolone Arthritis Rheum 2005, 52 (3), pp.924-928 Anderson J, Caplan L, Michaud K Measures of RA disease activity Arthritis Care & Research 2011, 63 (11), pp.14-36 Mastorakos G, Ilias I Relationship between interleukin-6 (IL-6) and hypothalamicpituitary-adrenal axis hormones in RA Z Rheumatol 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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.976-984 153 ... cortisol in rheumatoid arthritis patients and to look for alteration of these hormones in RA patients SUBJECTS AND METHODS Subjects 140 RA patients were admitted and treated in Choray Hospital and 60... joint 140 (100.0) Number of joint deformation (0.7) Number of rheumatoid nodule (0.7) The average number of swollen joint of RA patients was 9.71 ± 3.95 and the average number of painful joint... 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