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Clinical Studies |
The Inflammatory Joint Diseases Section (L.J.C., K.T.K., J.W., K.S.K., R.L.W.), Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the Developmental Endocrinology Branch (G.M., M-A. M., G.P.C.), National Institute of Child Health and Human Development; and the Clinical Neuroendocrinology Branch (K.T.K., P.W.G.), National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Leslie J. Crofford, M.D., Department of Internal Medicine, University of Michigan, R4570 Kresge I, 200 Zina Pitcher Place, Ann Arbor, Michigan 48109-0531.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, interleukin (IL)-1,
and IL-6. These proinflammatory cytokines also are potent activators of
the hypothalamic-pituitary-adrenal (HPA) axis through increased
production and secretion of CRH and arginine vasopressin in the
hypothalamus, that lead, in turn, to increased ACTH and cortisol levels
(1). The glucocorticoid end products of HPA axis activation are the
most potent endogenous inhibitors of immune and inflammatory processes,
including proinflammatory cytokine production. Therefore,
cytokine-induced HPA axis activation should lead to restraint of
cytokine secretion and inflammation (1). IL-6 is present in high levels in synovial fluids, synovial tissue supernatants, and plasma of patients with RA. Endogenous IL-6 has wide ranging effects in RA, including causation of fever and malaise, stimulation of acute-phase protein synthesis, T cell activation, and B cell differentiation (2). Exogenously administered recombinant human IL-6 leads to markedly increased levels of both plasma ACTH and cortisol in patients with malignancy or in normal subjects (3, 4, 5, 6). In the former, the effect was sustained when IL-6 was administered daily for 7 days and led to marked enlargement of the adrenal cortices (3).
To clarify relationships between IL-6 and HPA axis hormones in patients with RA, we performed serial, frequent blood sampling over 24 h to evaluate the circadian secretory dynamics of IL-6, ACTH, and cortisol in patients with newly diagnosed and untreated RA early in the course of their disease, compared with age-, gender-, and race-matched control subjects. We also performed ovine CRH (oCRH) stimulation testing to assess the integrity of the pituitary-adrenal response. We analyzed the time-lagged cross-correlations between IL-6 and ACTH/cortisol to assess the relationships of HPA axis hormones and endogenous IL-6 levels in RA patients in the untreated state.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patients with RA referred to the NIH and diagnosed according to the 1987 American College of Rheumatology revised criteria were recruited for the study (7). Control subjects were individually age-, gender-, and race-matched with the patients, and their health status was confirmed before entering the study. Control subjects were either friends of the patient or were recruited from the NIH normal volunteer program. The average patient’s age was 43.4 ± 7.4 (mean ± SEM), compared with 43.8 ± 7.8 for control subjects, and three of five patients and controls were female. Patients were defined as new if their disease onset was less than 6 months before the study. Four of five patients studied were considered new-onset, and the fifth patient had a disease duration of 34 months. No RA patient had been treated with corticosteroids or slow-acting antirheumatic drugs. Nonsteroidal antiinflammatory drugs were discontinued for at least 5 half-lives before study, and no patient or control subject was taking any medication at the time of the study. Four of five patients were rheumatoid factor positive; the average erythrocyte sedimentation rate (ESR) was 51 ± 34 mm/h, and all patients had clinically evident synovitis at the time of study.
Study subjects were admitted to the NIH clinical center in the late afternoon. An iv catheter was inserted at least 1 h before the study. Subjects were instructed to stay in bed except for bathroom privileges for the duration of the study. Regular meals were served, and low-level lighting was maintained during nighttime hours to facilitate blood drawing. At 2000 h, serial sampling was begun with all blood drawn from the indwelling iv catheter. Ten milliliters of blood were drawn on the hour, and 2 mL were drawn on the half hour for 24 h. After the completion of 24 h serial sampling, oCRH (1 µg/kg) was administered iv at 2000 h, and blood was obtained 5, 15, 30, 60, 90, and 120 min after oCRH administration. All blood samples were kept on ice before separation. Plasma was separated, aliquoted, and frozen within 6 h. All study subjects had a 24-h urine collection simultaneously with these studies for analysis of urine-free cortisol.
Determination of circulating IL-6 levels
IL-6 was measured by solid-phase enzyme-linked immunosorbent assay using a commercially available kit (R&D Systems, Minneapolis, MN). The assay detects both the free form in plasma samples and the IL-6 bound to soluble receptors. The lower limit of detection was 0.15 pmol/L. The intra- and interassay coefficients of variation were 4.4% and 3.6% at 0.75 pmol/L, 3.1% and 2.5% at 4.55 pmol/L, and 1.7% and 1.9% at 8.52 pmol/L, respectively. The assay is specific, recognizes both natural and recombinant human IL-6, and does not exhibit any significant cross-reactivity with a number of other recombinant human cytokines tested.
Determination of ACTH and cortisol levels
Plasma cortisol and ACTH levels were measured by RIA, without prior extraction, using commercially available kits (Diagnostic Products, Los Angeles, CA and Nichols Institute, San Juan Capistrano, CA, respectively). The lower limit of detection for the cortisol and ACTH assays was 36.0 nmol/L and 0.31 pmol/L, respectively, and the half-maximal displacement of the tracer was 138.0 nmol/L and 99.0 pmol/L, respectively. The intraassay coefficient of variation was 5% for the cortisol and 7% for the ACTH assay. All samples from the same patient and from the matched control were analyzed in one assay to eliminate interassay variation. Urine-free cortisol levels were determined at the Clinical Center Laboratory (NIH), using a specific RIA, after extraction with dichloromethane (Smith Kline Bioscience, St. Louis, MO).
Cross-correlation analysis
To search for time-ordered relationships between IL-6, ACTH, and cortisol, analysis of correlations between the raw values and between the logarithms of concentration-time series of each pair of hormones was performed. These cross-correlation analyses were computed between ACTH-cortisol, IL-6-ACTH, and IL-6-cortisol at various time lags covering the 24-h period of study. For example, if release of a hormone B is regulated by a hormone A (e.g. A is the releasing hormone and B is the effector hormone), then one might expect the concentration-time series of hormone B to lag (follow) in time, quantitatively, the concentration-time series of hormone A. Cross-correlation was computed after leading or lagging the concentration-time series of hormone B relative to the concentration-time series of hormone A. If we call rk the coefficient of correlation between two concentration time-series at lagtime k for one patient with RA or control subject, then the mean rk of all patients or control subjects was considered significant when it exceeded zero by more than 2.78 SEM (P < 0.05 level of significance for n = 5 with 1 degree of freedom). The SEM at each time point was calculated from the individual values of rks for the five patients with RA or the five control subjects at the lagtime k. All correlations were performed using Statview software for the Macintosh computer (Abacus Concepts, Inc., Berkeley, CA).
Statistical analysis
The results are expressed as the mean ± SEM. Statistical comparisons of control subjects with RA patients were done using unpaired Student’s t tests with the Bonferroni correction. Because of heteroscedasticity of variance, all values were subjected to logarithmic transformation before statistical analysis. In most samples obtained from control subjects, the IL-6 levels were below the detection limit of the assay. In such a case, the value of the detection limit was used for all statistical analyses. The area under the curve (AUC) was calculated by integration of hormone levels in Systeme International units and time of testing in hours. The net AUC for the oCRH stimulation tests was the AUC from 0–120 min after injection minus the basal AUC from -30 to zero min.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Basal overall 24-h time-integrated plasma IL-6 secretion was
higher in RA patients than control subjects (7.15 ± 1.84
vs. 3.97 ± 0.29 h·pmol/L) but did not reach
statistical significance (P = 0.1) (Fig. 1
). However, when the 24-h sampling period of the study
was divided into four 6-h time periods, we found that mean plasma IL-6
levels were significantly higher in RA patients than controls
(0.40 ± 0.10 vs. 0.15 ± 0.01 pmol/L;
P < 0.05) in the second 6-h time period (0200–0800
h). No significant differences in integrated IL-6 secretion between RA
patients and controls were observed during the other three 6-h time
periods. Four of five patients had elevated levels of IL-6 during the
nighttime and early morning hours, whereas the control subjects had
only scattered detectable plasma IL-6 levels, with most below the
detection limit of the assay (<0.15 pmol/L) over the course of the
24 h. In our statistical analyses, we were conservative in using
the value of the detection limit of the assay for samples that were
undetectable, to be certain that differences were significant.
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We were unable to demonstrate significant differences between RA
patients and control subjects in mean 24-h time-integrated plasma ACTH
(77 ± 14 vs. 72 ± 12 h·pmol/L,
P = 0.8) or cortisol (4,827 ± 512 vs.
3,987 ± 364 h·nmol/L, P = 0.08) secretion (Fig. 2, A and B). We also could not demonstrate a difference
in 24-h urinary free cortisol excretion between RA patients and control
subjects (306.2 ± 53.1 vs. 298.5 ± 49 nmol/24
h).
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, A and B).
This increase occurred before the normal circadian rise, approximately
1 h after the rise in IL-6 levels also observed uniquely in RA
patients. oCRH stimulation testing
The responsiveness of the pituitary and adrenal components of the
HPA axis to administration of oCRH was determined at the end of the
24-h serial blood sampling, during the normal diurnal ACTH and cortisol
trough, and when IL-6 levels were low in RA patients. Time-integrated
and peak plasma ACTH and cortisol responses were similar in RA patients
and control subjects (Fig. 3, A and B). In addition, the
ratio of plasma cortisol to ACTH released during the oCRH stimulation
test was calculated and was similar in RA patients and control subjects
at all time points after oCRH administration.
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The mean coefficients of correlation from the cross-correlation
analyses over the 24-h observation period for the RA patients between
ACTH-cortisol, IL-6-ACTH, and IL-6-cortisol are shown in Fig. 4. A significant positive correlation over time was
observed between ACTH and cortisol concentrations, peaking at lagtime
+60 min for both the patient (Fig. 4A) and control groups (data not
shown), with ACTH leading cortisol (r+60 = 0.6;
P < 0.05). A significant positive correlation was
observed between IL-6 and ACTH concentrations for the RA group, peaking
at lagtime +60 min, with IL-6 leading ACTH (r+60 = 0.4;
P < 0.05) (Fig. 4B). A significant positive
correlation also was observed between IL-6 and cortisol concentrations
in RA patients (r+120 = 0.5; P < 0.05)
(Fig. 4C), peaking at lagtime +120 min, but present from +60 to +180
min and with IL-6 leading cortisol. A significant negative correlation
also was observed between IL-6 and cortisol in RA patients
(r+960 = -0.8, P < 0.05) (Fig. 4C),
peaking at lagtime +960 min, with IL-6 leading cortisol. Furthermore,
another significant negative correlation was observed between IL-6 and
cortisol (r-300 = -0.44; P < 0.05) (Fig. 4C), peaking at lagtime -300 min with IL-6 following cortisol. Thus,
IL-6 seems to stimulate ACTH and cortisol and cortisol then inhibits
IL-6.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There is a body of evidence that IL-6 may stimulate the HPA axis at the level of the hypothalamus, pituitary, and adrenal gland (9, 10, 11, 12). The observation that pituitary and adrenal cortical cells themselves synthesize IL-6 mRNA may indicate that paracrine production of IL-6 could contribute to maintaining glucocorticoid output during chronic inflammatory stress and could be coordinately increased with circulating IL-6 (13). On the other hand, the presence of the negative correlation between IL-6 and cortisol peaking at lagtime -300 min, with IL-6 following cortisol, may indicate an inhibitory effect of cortisol on peripheral production of IL-6 (14).
There are inherent difficulties in evaluating the appropriateness of a given level of cortisol for a particular level of ongoing inflammation in patients. One could argue that submaximal cortisol output is abnormal in the setting of sustained inflammation (15). Neeck and co-workers stratified patients on the basis of ESR and found a linear positive correlation between ESR and mean cortisol. Patients with mild disease, however, had lower than normal spontaneous cortisol secretion, suggesting insufficient adrenal cortisol secretion in these patients (16). Pituitary-adrenal responses to exogenous CRH have been shown to be normal or slightly subnormal, indicating preservation of ACTH and cortisol reserve (17, 18). In the untreated RA patients reported in this study, early in the course of their disease, oCRH stimulation testing was normal. Chikanza and colleagues (17) compared patients with RA and elevated ESR with patients with osteomyelitis and similarly elevated ESR. Patients with RA had significantly lower circadian levels of cortisol than patients with osteomyelitis, suggesting blunted HPA axis responses for a given level of inflammation (measured by ESR) in patients with RA (17). Finally, major surgical procedures in patients with RA, osteoarthritis, and osteomyelitis led to increased plasma IL-6 levels that were followed by increased cortisol levels in osteomyelitis and osteoarthritis but not in RA patients (17).
In summary, plasma IL-6 is elevated and displays circadian variation in patients with early untreated RA. It seems that endogenous IL-6 may stimulate secretion of ACTH and cortisol in RA patients; however, the level of IL-6-induced HPA axis activation seems to be compensated by adaptive changes and maintained within the normal unstressed range, which clearly is insufficient to inhibit ongoing inflammation. Further studies, including IL-6 infusions in patients at different times during the course of their disease, will be needed to clarify the role of IL-6 in the stimulation of the HPA axis in RA and the inability of these patients to maintain an activated HPA axis during their disease.
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Footnotes |
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2 Current addresses: L.J.C., Department of Internal Medicine,
University of Michigan, Ann Arbor, Michigan 48109-0531; K.T.K.,
Laboratory of Clinical Neuroendocrinology, Department of Psychiatry and
Human Behavior, The University of Mississippi Medical Center, School of
Medicine, Jackson, Mississippi 39216-4505.
Received September 6, 1996.
Revised December 5, 1996.
Accepted December 16, 1996.
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References |
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) and five RA patients (
). Samples were taken every 1 h
over a 24-h period through an indwelling iv catheter.
Inset, integrated AUC in controls (
) and RA patients
(
).
