The adrenal steroid status in relation to inflammatory cytokines (interleukin-6 and tumour necrosis factor) in polymyalgia rheumatica
R. H. Straub,
T. Glück,
M. Cutolo1,
J. Georgi2,
K. Helmke3,
J. Schölmerich,
P. Vaith4 and
B. Lang
Department of Internal Medicine, University Medical Center Regensburg, D-93042 Regensburg, Germany,
1 Division of Rheumatology, Department of Internal Medicine, University of Genova, I-16136 Genova, Italy,
2 Ostseeklinik, D-24349 Damp,
3 Hospital München-Bogenhausen, D-81925 München and
4 Department of Internal Medicine, University Medical Center Freiburg, D-79106 Freiburg, Germany
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Abstract
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Objectives. To determine the correlation between inflammatory cytokines and adrenal hormones in patients with polymyalgia rheumatica (PMR) and to compare the ratio of serum cortisol and androstenedione (ASD) or dehydroepiandrosterone sulphate (DHEAS) in normal subjects with PMR patients.
Methods. In 102 patients with PMR (32 beginning and 70 chronic disease) and 31 age-matched and sex-matched healthy subjects, ASD, cortisol, DHEAS, interleukin-6 (IL-6), and tumour necrosis factor (TNF) were measured by immunometric assays.
Results. Serum levels of IL-6 were elevated in patients with PMR as compared with normal subjects (10.0 ± 1.6 vs 2.1 ± 0.1 pg/ml, P = 0.01), which was not found for TNF. In PMR patients, serum levels of IL-6 were positively correlated with serum levels of ASD (P < 0.001), cortisol (P < 0.001), and DHEAS (P = 0.038) irrespective of corticosteroid treatment. Serum levels of cortisol in relation to IL-6 were significantly lower in patients with chronic disease and long-standing corticosteroid administration as compared with patients with recent onset of the disease and without corticosteroid therapy (P < 0.01).
Conclusions. In PMR, as expected, there was an increase in IL-6 serum levels that was associated with elevated serum levels of ASD, DHEAS, and cortisol which was more marked in patients with recent-onset disease and without corticosteroids. However, serum levels of cortisol in patients with and without corticosteroids were lower than expected by considering the inflammatory status (increased IL-6). This may indicate a change in the hypothalamicpituitaryadrenal (HPA) axis responsiveness to inflammatory stimuli such as IL-6 during chronic disease. Furthermore, there seems to be a shift of biosynthesis to cortisol in relation to DHEAS or ASD in chronic disease.
KEY WORDS: Polymyalgia rheumatica, Cortisol, Dehydroepiandrosterone sulphate, Androstenedione, Interleukin-6, Tumour necrosis factor.
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Introduction
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Polymyalgia rheumatica (PMR) is a chronic inflammatory disease of unknown aetiology in elderly people. Although the striking feature of PMR is the development of the disease in patients older than 50 yr of age, age-associated pathogenetic factors are not yet known. The age-specific incidence rate increases from 2.6 per 100 000 in the age group 5059 yr to 44.7 per 100 000 in the age group 80 yr and older [1], which suggests the possibility of age-associated factors in aetiology. The natural decline of several hormones such as dehydroepiandrosterone (DHEA) [2, 3] or androstenedione (ASD) [3] during ageing may represent one such factor. A pioneering study in this direction demonstrated that age-associated decline of DHEA was linked to increased secretion of interleukin-6 (IL-6) in ageing mice [4] and we have confirmed this finding in humans [3]. Hence, endocrinosenescence may be an important pathogenetic element in patients with PMR. As in patients with systemic lupus erythematosus [5, 6], rheumatoid arthritis [77], systemic sclerosis [8], inflammatory bowel disease [9], and Alzheimer's disease or vascular dementia [10], low DHEA levels have been described in patients with PMR [11]. However, the interrelation between the natural decline of these adrenal hormones and the pathogenesis of chronic inflammatory diseases such as PMR, particularly in aged people, has yet to be examined.
Another important characteristic of PMR is the rapid improvement after initial administration of corticosteroids in a dose range of about 2030 mg of prednisolone (in giant cell arteritis
60 mg) [12] which is equivalent to about 80120 mg of endogenous, adrenal gland-derived cortisol [13]. This amount of cortisol is three times the secretion rate of a healthy adrenal gland per day [13]. In cases of i.v. administration of cytokines such as tumour necrosis factor (TNF) [14] or IL-6 [15, 16] or during septic shock [17], the healthy human adrenal gland is capable of secreting up to 300 mg of endogenous cortisol daily. Hence, the question arises whether or not the adrenal glands of elderly patients with PMR are unable to produce the amount of cortisol necessary to control the inflammation.
In view of these aspects, the aim of the present study was to determine the correlation between IL-6/TNF and immunosuppressive effector hormones of the hypothalamicpituitaryadrenal (HPA) axis such as ASD, cortisol, and dehydroepiandrosterone sulphate (DHEAS) in patients with PMR. Patients with recent onset of the disease prior to corticosteroid therapy were compared with patients with chronic disease who had undergone corticosteroid therapy. Furthermore, we compared serum levels of cortisol in relation to ASD or DHEAS between PMR patients with recent-onset and those with chronic disease.
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Subjects and methods
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From a total number of 147 patients with PMR, 102 patients with complete data sets and without clinical signs of giant cell arteritis (artery tenderness, swollen scalp arteries, decreased artery pulses, fixed visual symptoms, jaw claudication, tongue claudication) were included. These patients were referred to the participating teaching hospitals specialized in rheumatology. All patients were clinically evaluated by a rheumatologist and PMR was diagnosed according to the criteria of Bird et al. [18]. Thirty-two patients had recent-onset PMR [disease duration, mean ± standard error of the mean (S.E.M.), median: 0.64 ± 0.05 yr, 0.5 yr] and had never been treated with corticosteroids at the time blood was drawn as compared with 70 patients with chronic disease who had undergone corticosteroid therapy (disease duration, mean ± S.E.M., median: 3.46 ± 0.40 yr, 2.0 yr, P < 0.001 as compared with patients without corticosteroids; prednisolone was administered before breakfast). Since patients under long-standing corticosteroid treatment had either low (50% of all patients) or moderate to high disease activity (20% of all patients including patients with unstable disease or relapses), the daily prednisolone dose was variable according to clinical requirements. The two PMR patient groups did not differ in age or gender. Clinical and demographic data are shown in Table 1
. For comparison, 31 healthy age-matched and body mass index-matched control subjects were recruited and their state of health was validated by means of a 33-item questionnaire (Table 1
). The questionnaire addressed known diseases in the past and at present, current symptoms of diseases, current medication, alcohol intake, smoking habits, family history, and surgical history. Patients and healthy controls were not on hormone replacement therapy. Blood was drawn by venipuncture between 10.00 and 12.00 a.m. and serum was immediately stored at -80°C in adequate aliquots.
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TABLE 1. Basic characteristics of the patients with PMR and healthy subjects. Data are given as mean ± S.E.M. with percentages in parentheses, the median in braces and ranges in brackets
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Radioimmunometric assays for the quantitative determination of serum ASD (DPC Biermann, Bad Nauheim, Germany; detection limit: 0.14 nmol/l) and serum cortisol (Coulter Immunotech, Marseille, France; detection limit: 10 nmol/l; cross-reactivity with prednisolone <6%, prednisone <0.1%, and methylprednisolone <0.27%) were used. Serum DHEAS (IBL, Hamburg, Germany; detection limit: 0.13 µmol/l), serum IL-6 (high sensitivity Quantikine, R&D Systems, Minneapolis, MN, USA; detection limit: 0.2 pg/ml), and serum TNF-
(high sensitivity Quantikine, R&D Systems; detection limit: 0.2 pg/ml) were measured by means of immunometric enzyme immunoassay. Intra-assay and interassay coefficients of variation were below 10% in each test.
All data are given as mean ± S.E.M. [standard deviation (S.D.) = S.E.M. ·
n] and the median is given in braces when the data were not normally distributed. Because of the exploratory nature of this investigation, no power calculations were performed before the study. The non-parametric KruskalWallis test (SPSS/PC for Windows 95 version 8.0.0, SPSS Inc., Chicago, IL, USA) was used to compare the means of the different subgroups (healthy controls, patients with PMR without corticosteroids, patients with PMR with corticosteroids). Correlations were demonstrated by linear regression lines and significance was tested by Spearman rank correlation analysis (SPSS/PC for Windows 95 version 8.0.0, SPSS Inc.). The slopes and intercepts of the regression lines were compared as previously described [19]. The significance level was set to P < 0.05.
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Results
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The serum levels of IL-6 were significantly higher in patients with PMR as compared with healthy subjects (mean ± S.E.M. {median}: 10.0 ± 1.6 {4.3} vs 2.1 ± 0.1 {2.1} pg/ml, P = 0.01). The mean serum IL-6 level in patients without corticosteroids tended to be higher as compared with patients on corticosteroids (11.4 ± 2.3 {4.9} vs 9.4 ± 2.1 {4.0} pg/ml, P = 0.15). In contrast, TNF did not significantly differ between healthy controls and patients with and without corticosteroids (2.2 ± 0.1 {1.9} vs 2.3 ± 0.2 {2.0} vs 3.0 ± 0.4 {2.4} pg/ml). In PMR patients under corticosteroid treatment, there was no correlation between the daily dose of prednisolone and serum levels of IL-6 (RRank = - 0.021, n.s.) or TNF (RRank = - 0.089, n.s.).
In comparison with healthy subjects and patients without corticosteroid treatment, patients with PMR and glucocorticoid therapy had significantly lower serum levels of cortisol, which indicates a suppression of the HPA axis by exogenous corticosteroids (Table 2
). Serum cortisol levels of patients without corticosteroid treatment did not differ from the serum cortisol levels of normal subjects (Table 2
). In PMR patients on corticosteroids, there was no correlation between the daily dose of prednisolone and serum levels of cortisol (RRank = 0.25, n.s.; cross-reactivity of the radioimmunoassay <6%).
Patients with PMR had significantly lower serum levels of DHEAS compared with normal subjects (Table 2
). Patients with PMR on glucocorticoid therapy had significantly lower serum levels of both cortisol and DHEAS, in comparison with healthy subjects and patients prior to glucocorticoid therapy, indicating suppression of the HPA axis by exogenous corticosteroids (Table 2
). With respect to serum levels of ASD, no difference was found between healthy controls and all patients with PMR, but ASD serum levels were higher in patients not on corticosteroids as compared with patients on corticosteroids (Table 2
).
Cortisol significantly correlated with serum IL-6 in patients with and without corticosteroid treatment (Fig. 1
). However, there was a significant difference in the slope of the regression lines (P < 0.001). In patients without corticosteroid treatment, the slope of the regression line was significantly steeper as compared with patients with corticosteroid treatment (Fig. 1
). Thus, patients with recent onset of the disease and without corticosteroid therapy had higher cortisol serum levels in relation to IL-6 serum levels as compared with patients with chronic disease and corticosteroid treatment (Fig. 1
). In these 32 healthy elderly subjects, in contrast to patients, serum cortisol was not correlated to serum IL-6 (Table 3
).

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FIG. 1. Correlation of serum IL-6 concentration and serum cortisol concentration in PMR patients without prior corticosteroid therapy and recent onset of the disease (upper regression line, closed circles), and patients with prior corticosteroid treatment and chronic disease (lower regression line, open circles). The equations and the statistical significance of the regression lines are given.
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TABLE 3. Correlation coefficients for the relationship between serum levels of IL-6 or TNF and steroid hormones in patients with PMR and healthy subjects
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The matrix of Spearman rank correlation coefficients for the interrelation of serum IL-6 or serum TNF and serum levels of adrenal hormones is demonstrated in Table 3
. IL-6 was significantly positively correlated to serum ASD and serum DHEAS in all patients (Table 3
). In patients with recent onset of the disease and without corticosteroid treatment and in patients with long-standing disease and corticosteroid treatment, serum IL-6 was positively correlated to serum ASD (Table 3
). In healthy subjects, in contrast to patients, serum IL-6 was not correlated to serum ASD or DHEAS (Table 3
). With respect to TNF, serum cortisol also exhibited a significant positive correlation to serum TNF in all patients with PMR and in the subgroups of patients with and without corticosteroid treatment (Table 3
). Similar results were found with respect to the correlation between serum TNF and ASD (Table 3
).
As compared with patients with PMR, the molar ratio of serum DHEAS/serum IL-6 was highest in normal subjects, as expected (Fig. 2
). In patients without corticosteroid pre-treatment this ratio was significantly higher as compared with patients with prior corticosteroid treatment (Fig. 2
).

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FIG. 2. Molar ratio of serum IL-6 and serum DHEAS in patients with PMR and normal subjects. The ratios are given as mean ± S.E.M. *P < 0.001 vs normal subjects. CS, corticosteroid treatment.
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Previous studies have demonstrated the influence of inflammatory stimuli such as IL-1 [20], transforming growth factor beta (TGF-ß [21, 22], or TNF [23] on the biosynthesis of steroids. To evaluate similar mechanisms in vivo [2022], we determined the ratios of serum levels of adrenal steroid hormones in PMR patients. The ratio of serum cortisol/serum DHEAS was significantly higher in patients as compared with healthy subjects (Fig. 3A
). With respect to the ratio of serum cortisol/serum DHEAS, patients with corticosteroid treatment demonstrated a significantly higher ratio as compared with patients without corticosteroid therapy (Fig. 3A
). Patients without corticosteroid treatment had a lower ratio of serum cortisol/ASD as compared with normal subjects and patients under corticosteroid treatment (Fig. 3B
). Furthermore, the ratio of serum DHEAS/serum ASD was significantly higher in normal subjects as compared with PMR patients, irrespective of corticosteroid treatment (Fig. 3C
).

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FIG. 3. Molar ratios of serum cortiso/serum DHEAS (A), serum cortiso/serum ASD (B), and serum DHEAS/serum ASD (C) in patients with PMR and normal subjects. Ratios are given as mean ± S.E.M. *P < 0.001 vs normal subjects. CS, corticosteroid treatment.
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Discussion
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This study demonstrates that there is a positive correlation between serum IL-6 or TNF and ASD, DHEAS, or cortisol in all patients with PMR. This is true even though the hormone levels were lower than expected (with respect to the inflammatory status). Serum IL-6 was positively correlated with serum DHEAS in all patients with PMR. In particular, patients with recent onset of the disease and higher inflammatory status who had not yet received corticosteroid therapy had significantly higher cortisol serum levels in relation to serum IL-6 as compared with patients with long-standing disease who were on chronic corticosteroid therapy. This may indicate a greater responsiveness of the HPA axis to cytokines in recent-onset disease prior to corticosteroid therapy. In addition, serum levels of adrenal hormones were shifted to cortisol in relation to DHEAS which was more significant in patients with long-standing disease and chronic corticosteroid therapy as compared with patients prior to corticosteroid therapy and healthy subjects.
Both the chronic administration of therapeutic corticosteroids and the long-standing activation of the hypothalamus by inflammatory stimuli probably led to an adaptation of the HPA axis: in cancer therapies using therapeutic IL-6 it has been demonstrated that the HPA axis responsiveness was suppressed during a few days of high-dose cytokine therapy [15, 16]. This confirms studies in a number of inflammatory and post-traumatic conditions [24], African trypanosomiasis [25], rheumatoid arthritis [26, 27], and in animal models of chronic arthritis [28] or cholestasis [29], suggesting that inflammation leads to a suppression of corticotropin-releasing hormone expression in the hypothalamus and, thus, suppression of the HPA axis [28, 29]. From these studies, it is not clear whether or not such suppression is due to elevated endogenous cortisol or to inflammatory stimuli such as IL-6 or both. Nevertheless, this may be the reason why cortisol secretion in relation to IL-6 was impaired in long-standing PMR in our study. As mentioned above, the adrenal glands are capable of secreting the amount of endogenous cortisol necessary to control the disease (about 120 mg of cortisol per day which is equivalent to 30 mg of prednisolone daily) in circumstances with strong activation of the hypothalamus including acute and chronic stress [1416]. There may be several reasons for the suppression of the HPA axis and the lack of a suitable control of the chronic inflammatory disease: chronic corticosteroid therapy; chronic systemic inflammatory stimuli with elevated IL-6 or TNF serum levels [24] the age-related increase in serum IL-6 in healthy female and male subjects and TNF (only in healthy female subjects [3]); during chronic stress. The reason for the age-dependent increase in these cytokines is not yet known, but elevated serum levels of IL-6 or TNF may increase the susceptibility to inflammatory diseases with increasing age, particularly in female subjects. This may be due to a continuous stimulation of the HPA axis at different levels which makes the system unresponsive to the acute rise of these cytokines during an inflammatory state.
Another causal mechanism may be the parallel decrease in hormones such as DHEA (and ASD), which was thought to play an important role in autoimmune and age-dependent diseases because of its rapid decline during ageing and chronic inflammatory diseases [2, 3, 5, 6, 810]. DHEA inhibits IL-6 secretion [3, 4, 30] and TNF [3034], which most probably depends on activation of the peroxisome proliferator-activated receptor alpha and the subsequent inhibition of nuclear factor (NF)-kappa B [35, 36]. The serum levels of DHEAS were significantly lower in patients with PMR as compared with normal subjects. They were also dependent on prior corticosteroid therapy, a finding which confirms an earlier study in the same patient group [11]. The reduction of DHEAS is a general feature of chronic inflammatory diseases [5, 6, 8, 9]. In the biosynthesis of steroids, the 17,20-lyase (P450c17) is suppressed during ageing [37, 38], and in response to inflammatory stimuli such as IL-1 [20] and TGF-ß1 [21, 22] (Fig. 4
). Hence, during ageing and under conditions of systemic inflammation, the suppression may be due to an inhibition of the adrenal 17,20-lyase, since cortisol under the same circumstances is increased in relation to DHEAS (Fig. 4
). Furthermore, it may also be a cytokine-induced inhibition of the sulphatase reaction (DHEA
DHEAS, Fig. 4
) [23]. This fact may be confirmed by the shift in the molar ratio of serum cortisol/serum DHEAS to higher values in patients as compared with normal subjects, particularly in patients with long-standing disease and prior corticosteroid treatment. However, the ratio of serum cortiso/serum ASD was lowest in patients with recent onset of the disease as compared with normal subjects or patients with long-standing disease and corticosteroid treatment. This might indicate that the 21-hydroxylase (P450c21) may be inhibited in patients without corticosteroids and recent onset of the disease as compared with normal subjects or patients with long-standing disease and corticosteroid treatment (Fig. 4
). With respect to this enzyme, TNF, which did not seem to play a major role in PMR patients, was shown to inhibit the 21-hydroxylase in adrenal cell cultures [39]. Furthermore, there may be an activation of the 3ß-hydroxysteroid dehydrogenase or an inhibition of the sulphatase reaction (DHEA
DHEAS) in PMR patients as compared with healthy controls because the ratio of serum DHEAS/serum ASD was significantly lower during the inflammatory disease irrespective of prior corticosteroid treatment (Fig. 4
).

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FIG. 4. Schematic diagram demonstrating the biosynthesis of important adrenal hormones. The large arrows demonstrate the main pathway in chronic PMR. Lines with bars demonstrate the inhibitory effects of indicated mediators (TGF-ß, IL-1, TNF) and lines with arrows indicate stimulatory effects of IL-6. ACTH stimulates the 20,22 desmolase (enzyme 1) to start the synthesis of adrenal hormones. 17 /17,20-hydroxylase (enzymes 5 and 6) convert pregnenolone/progesterone to DHEA/ASD. Enzymes: 1, 20,22 desmolase; 2, 3ß-hydroxysteroid dehydrogenase; 3, 21 -hydroxylase; 4, 11ß-hydroxylase; 5/6, 17 /17,20-hydroxylase(lyase); 7, sulphokinase.
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These changes in serum levels of adrenal hormones demonstrate an overall shift to cortisol in relation to DHEAS in patients under corticosteroid therapy and mainly a shift to ASD in relation to cortisol in patients without corticosteroid treatment and recent onset of PMR (Fig. 4
). Since DHEA has an immunomodulatory role in humans and in mice [3, 4, 3034], the chronic suppression of this hormone may be deleterious in some diseases with chronically elevated IL-6 or TNF. Under marked suppression of the steroid production in PMR with corticosteroids there was still a positive correlation between serum IL-6 and cortisol, ASD or DHEAS. This indicates that the activation of the HPA axis still leads to a positive but smaller signal for steroid production in the adrenal gland than expected under inflammatory conditions. In addition, in acute inflammation-induced stimulation of adrenocorticotropic hormone (ACTH), ACTH would lead to an increase of all three hormonescortisol, ASD, and DHEAS (Fig. 4
)which, with respect to cortisol, may probably be supported by IL-6 (Fig. 4
) [40, 41]. An intriguing question arises as to whether or not immunosuppression of chronic inflammatory diseases with corticosteroids should be accompanied by additional administration of DHEA or ASD, since all these are stimulated by an inflammation-induced ACTH increase under normal circumstances.
In conclusion, PMR patients without corticosteroid treatment had higher cortisol serum levels in relation to IL-6 as compared with PMR patients with long-standing disease and with corticosteroid treatment. The cortisol levels in PMR patients were generally lower than expected under inflammatory conditions. This indicates a suppression of the HPA axis in the chronic disease. Furthermore, serum levels of adrenal hormones were significantly shifted to cortisol in relation to DHEAS in PMR. From a therapeutic point of view, it would be interesting to find drugs that maintain the HPA axis responsiveness during chronic inflammatory diseases or to restore cortisol and DHEA. In further studies, combination therapy with corticosteroids and DHEA may be a better therapeutic approach than prednisolone monotherapy.
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Acknowledgments
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We thank all of our colleagues in the participating centres for their continuous support. We gratefully acknowledge H. H. Peter (Freiburg, Germany) for his critical comments and Ms Kim Hrach for correcting our English.
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Notes
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Correspondence to: R. H. Straub, Department of Internal Medicine I, University Medical Center, D-93042 Regensburg, Germany. 
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Submitted 10 June 1999;
revised version accepted 20 December 1999.