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Long-term antitumor necrosis factor antibody therapy in rheumatoid arthritis patients sensitizes the pituitary gland and favors adrenal androgen secretion.

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ARTHRITIS & RHEUMATISM
Vol. 48, No. 6, June 2003, pp 1504–1512
DOI 10.1002/art.11036
© 2003, American College of Rheumatology
Long-Term Anti–Tumor Necrosis Factor Antibody Therapy in
Rheumatoid Arthritis Patients Sensitizes the Pituitary Gland
and Favors Adrenal Androgen Secretion
Rainer H. Straub,1 Georg Pongratz,1 Jürgen Schölmerich,1 Frieder Kees,2 Thomas F. Schaible,3
Christian Antoni,4 Joachim R. Kalden,4 and Hanns-Martin Lorenz4
tion of anti-TNF, which indicates a sensitization of the
pituitary gland (not observed for the adrenal gland).
During treatment, the ratio of serum cortisol to serum
ACTH decreased, which also indicates a sensitization of
the pituitary gland (P < 0.001), and which was paralleled by constant cortisol secretion. The adrenal androgen ASD significantly increased relative to its precursor
17(OH)progesterone (P ⴝ 0.013) and relative to cortisol
(P ⴝ 0.009), which indicates a normalization of adrenal
androgen production. The comparison of patients previously treated with prednisolone and those without
previous prednisolone revealed marked differences in
the central and adrenal level of this endocrine axis
during long-term anti-TNF therapy.
Conclusion. Long-term therapy with anti-TNF
sensitizes the pituitary gland and improves adrenal
androgen secretion in patients who have not previously
received prednisolone treatment. These changes are
indicative of normalization of the HPA axis and must
therefore be considered as evidence of an additional
antiinflammatory influence of anti-TNF treatment in
patients with RA.
Objective. New insights into the role of tumor
necrosis factor (TNF) in the pathogenesis of rheumatoid
arthritis (RA) have expanded our understanding about
the possible mechanisms by which anti-TNF antibody
therapy reduces local synovial inflammation. Beyond
local effects, anti-TNF treatment may modulate systemic antiinflammatory pathways such as the
hypothalamic–pituitary–adrenal (HPA) axis. This longitudinal anti-TNF therapy study was designed to assess
these effects in RA patients.
Methods. RA patients were given 5 infusions of
anti-TNF at weeks 0, 2, 6, 10, and 14, with followup
observation until week 16. We measured serum levels of
interleukin-6 (IL-6), adrenocorticotropic hormone
(ACTH), 17-hydroxyprogesterone (17[OH]progesterone), cortisol, cortisone, androstenedione (ASD), dehydroepiandrosterone (DHEA), and DHEA sulfate in 19
RA patients.
Results. Upon treatment with anti-TNF, we observed a fast decrease in the levels of serum IL-6,
particularly in RA patients who did not receive parallel
prednisolone treatment (P ⴝ 0.043). In these RA patients who had not received prednisolone, the mean
serum ACTH levels sharply increased after every injec-
After its initial discovery in the early 1990s (1),
anti–tumor necrosis factor (anti-TNF) antibody is now
widely used as an antiinflammatory drug in patients with
rheumatoid arthritis (RA) and in several other inflammatory diseases (2–4). The primary effect of anti-TNF
therapy is most probably direct neutralization of proinflammatory TNF, but other antiinflammatory factors
may also contribute to the favorable role of anti-TNF
therapy. We speculated that the function of the
hypothalamic–pituitary–adrenal (HPA) axis may recover under long-term anti-TNF therapy.
During acute inflammation, a normal-functioning
HPA axis is regulated by several factors (Figure 1). 1)
Supported by the Deutsche Forschungsgemeinschaft (Str
511/11-1), and by Centocor, Inc.
1
Rainer H. Straub, MD, Georg Pongratz, MD, Jürgen
Schölmerich, MD: University Hospital Regensburg, Regensburg, Germany; 2Frieder Kees, PhD: Institute of Pharmacy, University Regensburg, Regensburg, Germany; 3Thomas F. Schaible, PhD: Centocor
Inc., Malvern, Pennsylvania; 4Christian Antoni, MD, Joachim R.
Kalden, MD, Hanns-Martin Lorenz, MD: University of Erlangen–
Nürnberg, Erlangen, Germany.
Address correspondence and reprint requests to Rainer H.
Straub, MD, Laboratory of Neuroendocrinoimmunology, Department
of Internal Medicine I, University Hospital Regensburg, 93042 Regensburg, Germany. E-mail: rainer.straub@klinik.uni-regensburg.de.
Submitted for publication December 9, 2002; accepted in
revised form February 27, 2003.
1504
INFLUENCE OF ANTI-TNF TREATMENT IN PATIENTS WITH RA
Figure 1. The hypothalamic–pituitary–adrenal axis and the influence
of cytokines on adrenal steroidogenesis. A line with an arrow at the
end indicates that the respective mediator stimulates the enzyme step
(interleukin-6 [IL-6]). A line with a bar at the end demonstrates that
the respective mediator inhibits the enzyme step (tumor necrosis
factor [TNF]). 3␤HSD ⫽ 3␤-hydroxysteroid dehydrogenase; 11␤HSD
I and II ⫽ 11␤-hydroxysteroid dehydrogenase type I and type II;
ACTH ⫽ adrenocorticotropic hormone; CRH ⫽ corticotropinreleasing hormone; DHEA ⫽ dehydroepiandrosterone; DHEAS ⫽
DHEA sulfate; DST ⫽ DHEA sulfotransferase; P450c11 ⫽ 11␤hydroxylase; P450c17 ⫽ 17␣-hydroxylase and 17/20-lyase (doubleenzyme step); P450c21 ⫽ 21␣-hydroxylase; P450ssc ⫽ side-chain
cleavage enzyme; ST ⫽ DHEA sulfatase; StAR ⫽ steroidogenic acute
regulatory protein.
Corticotropin-releasing hormone (CRH) stimulates secretion of adrenocorticotropic hormone (ACTH), which
stimulates cortisol secretion, and cortisol inhibits the
hypothalamus and the pituitary gland by feedback inhibition. 2) A short-term administration of interleukin-6
(IL-6) stimulates the human hypothalamus, the pituitary
gland, and the adrenals (5,6). 3) A short-term administration of TNF stimulates the hypothalamus and pitu-
1505
itary gland (7,8), but probably leads to inhibition of the
adrenal gland (9) and other endocrine glands (10–13).
Thus, on the peripheral level of the adrenal gland, IL-6
may act in a different way as compared with TNF.
In a chronic inflammatory disease such as RA,
the HPA axis demonstrates marked alterations. 1) There
is inadequate secretion of ACTH relative to the extent
of inflammation (14). 2) It has been described that
patients with RA have inappropriately low levels of
spontaneous and stimulated cortisol secretion, particularly in relation to inflammation (14–23). 3) During a
long-term inflammatory disease such as RA, adrenal
androgens dramatically decrease (24–32). The reasons
for these changes are only partly understood, but striking changes on all levels of the HPA axis seem to play a
role. During repetitive administration of IL-6 over 3
weeks, the stimulatory capacity of IL-6 on the central
level is normally lost, but stimulation of the adrenal
glands remains stable (5). In human subjects, this has
never been tested with TNF, but one may expect similar
adaptational changes on the level of the hypothalamus
and pituitary gland. Thus, during chronic cytokine elevation, the hypothalamus and pituitary gland would not
be adequately stimulated by IL-6 (or possibly TNF).
However, IL-6–induced stimulation of the adrenal
glands most likely remains unchanged, which was also
suggested to be a mechanism during inflammatory cholestasis in rats and humans (33,34).
Since TNF is the cytokine located upstream from
IL-6, any increase or decrease in serum TNF is followed
by an increase or decrease in serum IL-6. Thus, the
effects of TNF may be mediated by the more stable and
long-lived IL-6. Furthermore, the local and systemic
concentrations of these immune mediators determine
their influence on the levels of the hypothalamus, the
pituitary gland, and the adrenals. Interactions of these
different factors in chronic inflammatory diseases are
complex. However, we believe that treatment with antiTNF opens a small window for understanding the complexity of the interwoven participants in the chronic
inflammatory process of RA.
Thus, it was the aim of the present study to
investigate the effect of long-term anti-TNF therapy on
the function of the HPA axis, including adrenal androgen secretion as well as cortisol and androgen inactivation (shuttle from cortisol to cortisone and dehydroepiandrosterone [DHEA] to DHEA sulfate, respectively)
(Figure 1). Due to the fact that inflammation-induced
changes of the HPA axis are long-lived, the patients
were observed for 16 weeks during anti-TNF therapy.
Furthermore, we compared patients with and without
1506
STRAUB ET AL
Table 1.
Characteristics of patients under investigation*
Patients without parallel
prednisolone
Patients with parallel
prednisolone
7
43.2 ⫾ 3.7 [27–55]
5/2 (female 71)
45.0 ⫾ 8.7
12
43.6 ⫾ 3.3 [26–57]
11/1 (female 92)
30.9 ⫾ 6.0
No. of patients
Age, years
Sex, no. female/no. male
Initial erythrocyte sedimentation
rate, mm/first hour
Initial C-reactive protein, mg/liter
Initial tender/swollen joint score
Initial morning stiffness, minutes
Additional therapy
Prednisolone, no. of patients
Mean daily dose prednisolone, mg
Infliximab, mg/kg per injection
Methotrexate, no. of patients
NSAID, no. of patients
34.7 ⫾ 9.4
67.0 ⫾ 13.6
48.6 ⫾ 14.8
0
0⫾0
6.1 ⫾ 1.8 [1–10]
6
6 (86)
30.0 ⫾ 10.2
73.8 ⫾ 8.6
105.4 ⫾ 25.3
12
4.7 ⫾ 0.5 [2.5–7.5]
4.1 ⫾ 1.1 [1–10]
3
9 (75)
* Except where indicated otherwise, values are the mean ⫾ SEM, with ranges in brackets and percentages
in parentheses. Except in the frequency of prednisolone and methotrexate use (P ⫽ 0.028), the study
groups were not different in the mentioned parameters. NSAID ⫽ nonsteroidal antiinflammatory drug.
parallel prednisolone therapy, because this is the strongest influencing factor on hormone secretion.
PATIENTS AND METHODS
Patients and blood samples. In this study of anti-TNF
therapy with infliximab (1–10 mg/kg per infusion), we included
19 white patients (16 women, 3 men) with long-standing RA
that fulfilled the American College of Rheumatology (formerly, the American Rheumatism Association) criteria for RA
(35). Patients of this study have been included in 2 other
studies that dealt with other aspects of anti-TNF antibody
therapy (36,37). A group of 7 patients did not receive parallel
prednisolone therapy, whereas the other 12 patients received
2.5–7.5 mg prednisolone concurrently. Some of the patients
were also administered methotrexate (Table 1). Since the
frequency of patients receiving methotrexate was higher in the
group without prednisolone versus those with prednisolone, we
determined the influence of methotrexate on the clinical and
hormonal parameters (no significant influence was detected by
Kruskal-Wallis test; see statistical analysis). The patients were
on a stable regimen with respect to prednisolone and methotrexate. Table 1 gives the characteristics of the 2 study groups.
Patients were clinically investigated and blood was
drawn between 8:00 and 9:00 in the morning when the patients
visited the outpatient clinic on day 0, as well as on weeks 1, 2,
4, 6, 8, 10, 12, 14, and 16 of anti-TNF therapy. Anti-TNF
antibodies were infused on day 0 and weeks 2, 6, 10, and 14.
The blood was immediately centrifuged and serum was stored
at ⫺80°C. The study was approved by the Ethics Committee of
the University of Erlangen–Nürnberg in Germany.
Laboratory parameters. Several adrenal hormones
were considered in order to detect major adrenal pathways of
steroidogenesis (Figure 1). We used radioimmunometric assays for the quantitative determination of serum levels of
cortisol (Coulter Immunotech, Marseilles, France; detection
limit 10 nmoles/liter, crossreactivity with prednisolone or prednisone ⬍6%). Serum levels of 17-hydroxyprogesterone
(17[OH]progesterone) (IBL, Hamburg, Germany; detection
limit 0.3 nmoles/liter), DHEA (Diagnostic Systems, Webster,
TX; detection limit 0.13 nmoles/liter), androstenedione (ASD)
(IBL; detection limit 0.3 nmoles/liter), and DHEA sulfate
(IBL; detection limit 130 nmoles/liter) were measured by
means of immunometric enzyme immunoassays. Serum levels
of IL-6 (high-sensitivity Quantikine; R&D Systems, Minneapolis, MN; detection limit 0.2 pg/ml) were measured using the
same technique. Intraassay and interassay coefficients of variation for all of the above-mentioned tests were below 10%.
Routine parameters, mentioned in Table 1, were measured by
standardized assays in the Department of Clinical Chemistry
of the University of Erlangen–Nürnberg.
Using a sensitive enzyme immunoassay for ACTH
(Sangui BioTech, Santa Ana, CA, via IBL; detection limit 0.1
pmoles/liter), we were able to demonstrate a highly significant
interrelation between ACTH measured in serum and ACTH
assayed in plasma, with the following regression equation:
ACTH (plasma) ⫽ 7.2508 ⫹ [1.8707 ⫻ ACTH (serum)] (R ⫽
0.646, P ⬍ 0.000001, n ⫽ 112 healthy subjects) (38). In the
present study, because no plasma samples were available, we
measured ACTH in serum samples of patients with RA, using
this enzyme immunoassay.
HPLC assay for cortisone. Cortisone was determined
by high-performance liquid chromatography (HPLC) with
photometric detection at 245 nm, as adapted from a published
method (39). Briefly, 200 ␮l serum was buffered with 200 ␮l of
0.2M sodium hydrogen carbonate, pH 9.6, and extracted with 2
ml dichloromethane. The organic layer was evaporated and the
residue was reconstituted with 100 ␮l mobile phase, of which
50 ␮l was injected into the HPLC system. The chromatographic apparatus consisted of the solvent delivery system
LC10AS, autosampler SIL-10A, ultraviolet detector LC10A,
and Class LC10 controller and integrator (Shimadzu, Duisburg, Germany).
Cortisol and cortisone were separated using 2 analytic
columns (length ⫻ inner diameter 150 ⫻ 4.6 mm), a Synergi
Polar-RP followed by a Synergi Max-RP (Phenomenex,
INFLUENCE OF ANTI-TNF TREATMENT IN PATIENTS WITH RA
1507
Table 2. Reduction of inflammation in rheumatoid arthritis patients under long-term anti–tumor
necrosis factor therapy*
Erythrocyte sedimentation rate,
mm/first hour
Tender/swollen joint score
Morning stiffness, minutes
Serum interleukin-6, pg/ml
Patients without prednisolone,
Day 03 Week 1
Patients with prednisolone,
Day 03 Week 1
45.0 ⫾ 8.7327.9 ⫾ 6.1
30.9 ⫾ 6.0316.9 ⫾ 4.6†
67.0 ⫾ 13.6326.1 ⫾ 4.9‡
48.6 ⫾ 14.8339.3 ⫾ 12.3§
41.0 ⫾ 11.3323.9 ⫾ 12.0§
73.8 ⫾ 8.6329.3 ⫾ 4.1†
105.4 ⫾ 25.3342.9 ⫾ 10.0‡
65.3 ⫾ 8.8314.1 ⫾ 7.1†
* Values are the mean ⫾ SEM. Week 1 results are reported because the most dramatic changes occurred
in this time period.
† P ⬍ 0.002.
‡ P ⬍ 0.005.
§ P ⬍ 0.10.
Aschaffenburg, Germany), with water–acetonitrile (70:30,
volume/volume) as mobile phase. Cortisol eluted after 13.6
minutes and cortisone after 15.5 minutes (flow rate 1.0 ml/
minute, column temperature 40°C). The recovery of cortisone
from serum was 98%. Intraassay and interassay variation
coefficients were below 9%. Calibration curves for peak
heights versus quantity were proved to be linear from 5 to 125
ng/ml cortisone, with a coefficient of correlation of ⬎0.996.
The minimal detectable amount injected (signal:noise 3:1) was
⬃200 pg. The limit of quantitation was estimated to be 4–5
ng/ml. The method also allows the separation and simultaneous determination of prednisolone (retention time 13.0
minutes) and prednisone (retention time 14.5 minutes) with
similar sensitivity and precision. The latter 2 factors were used
to test whether or not patients were really treated with
prednisolone.
Statistical analysis. Changes in group medians between 2 different time points were compared by the nonparametric Wilcoxon signed rank test for paired data (SPSS/PC,
Advanced Statistics, version 10.0.1; SPSS, Chicago, IL). The
correlation analyses were performed with the Spearman’s rank
test (SPSS/PC, Advanced Statistics, version 10.0.1; SPSS). The
regression lines were derived from linear regression. A P value
less than 0.05 was the significance level.
Since our study group was relatively small (albeit
typically large enough to study hormonal changes in a longitudinal way with 10 time points over 16 weeks), we first tested
whether methotrexate or different infliximab doses (1, 3, and
10 mg/kg per infusion) influenced the clinical and laboratory
parameters (using the Kruskal-Wallis test). With respect to all
assessed clinical and hormonal parameters (including hormone
ratios) during the entire observation period, we did not find
any influence of methotrexate or different doses of infliximab
(data not shown). Thus, patient groups were not further
stratified.
RESULTS
Decrease of inflammation. Table 2 demonstrates
the reduction in inflammatory indices during the longterm treatment with anti-TNF. All mentioned variables
(Table 2) decreased, more or less, between day 0 and
week 1 of therapy (Table 2). In order to test the
continuous antiinflammatory effect of anti-TNF treatment, the decline in serum IL-6 throughout the entire
study period is demonstrated in Figure 2. The decrease
in IL-6 was similar in both groups, although RA patients
without prednisolone demonstrated a more steady decline of serum IL-6 (Figure 2A), whereas mean serum
IL-6 levels in patients with prednisolone particularly
dropped during the first week (day 0 versus week 1 P ⫽
0.018) (Figure 2B).
Changes of serum ACTH and serum cortisol. In
patients without prednisolone therapy, the mean levels
of serum ACTH increased after every infusion of antiTNF (Figure 3A, thin, upward-directed arrows). This
indicates that reduction of the inflammatory load (serum IL-6 and serum TNF) sensitizes the central parts of
the hypothalamus and the pituitary, which induces an
Figure 2. Course of serum IL-6 during 16 weeks of anti-TNF antibody
therapy in patients with rheumatoid arthritis. The graph depicts
patients without (A) and with (B) parallel treatment with prednisolone.
The data are given as the mean and SEM. The Spearman’s rank
correlation coefficient (RRank), its P value, and the linear regression
line are shown. Arrows indicate the time point of anti-TNF antibody
infusion. n.s. ⫽ not significant (see Figure 1 for other definitions).
1508
STRAUB ET AL
both patient groups, but the changes did not reach the
significance level (data not shown).
Changes of serum cortisol relative to serum
ACTH. In patients without parallel prednisolone treatment, the ratio of serum cortisol to serum ACTH
decreased over the 16 weeks of anti-TNF therapy (Figure 4A). Under stable serum cortisol conditions, this
again indicates a sensitization of ACTH secretion, with a
relative increase of serum ACTH over serum cortisol
(Figure 4A). This was corroborated by an initial increase
in serum ACTH relative to serum IL-6 from day 0 to
week 1 of therapy (700% increase of this ratio; P ⫽
0.018) (Figure 4C). This particular ratio remained elevated up to 16 weeks of anti-TNF therapy (Figure 4C).
The stable behavior of serum cortisol was confirmed by
the relative increase in the ratio of serum cortisol to
serum IL-6 (Figure 4E) because serum IL-6 had declined (Figure 2A).
Figure 3. Course of serum ACTH and serum cortisol during 16 weeks
of anti-TNF antibody therapy in patients with rheumatoid arthritis.
The graph depicts patients without (A and C) and with (B and D)
parallel treatment with prednisolone. The data are given as the mean
and SEM. The Spearman’s rank correlation coefficient (RRank), its P
value, and the linear regression line are shown. Thick upward arrows
indicate the time point of anti-TNF antibody infusion. In A and B, the
thin upward or downward arrows demonstrate the behavior of serum
ACTH after anti-TNF antibody infusion. The plasma concentrations
of ACTH would be 7.2508 ⫹ (1.8707 ⫻ serum ACTH) (see Patients
and Methods). See Figures 1 and 2 for definitions.
increase of serum ACTH, while serum cortisol did not
markedly change (Figure 3C). This pattern was obviously different in the patients receiving prednisolone
treatment, most probably due to the glucocorticoidinduced lack of CRH from the hypothalamus (Figure
3B, thin, downward-directed arrows). In these latter
patients, the mean serum ACTH decreased after every
infusion of anti-TNF, which indicates that ACTH secretion depends on the inflammatory load (serum IL-6 and
serum TNF). Similar to the group without prednisolone,
serum levels of cortisol did not change in these RA
patients who were receiving prednisolone therapy (Figure 3D).
The consideration of the ratio of serum cortisol
to serum cortisone gives an idea about the extent of
cortisol degradation. This ratio slightly decreased in
Figure 4. Course of the ratios of serum cortisol to serum ACTH (A
and B), serum ACTH to serum IL-6 (C and D), and serum cortisol to
serum IL-6 (E and F) during 16 weeks of anti-TNF antibody therapy in
patients with rheumatoid arthritis. The graph depicts patients without
(A, C, and E) and with (B, D, and F) parallel treatment with
prednisolone. The data are given as the means and SEM. The
Spearman’s rank correlation coefficient (RRank), its P value, and the
linear regression line are shown. Arrows indicate the time point of
anti-TNF antibody infusion. See Figures 1 and 2 for definitions.
INFLUENCE OF ANTI-TNF TREATMENT IN PATIENTS WITH RA
In patients receiving prednisolone treatment, the
ratio of serum cortisol to serum ACTH remained quite
stable over the 16 weeks of anti-TNF therapy (Figure
4B). Under stable serum cortisol conditions, this does
not indicate a sensitization of ACTH secretion. Since, in
this group, serum ACTH and serum cortisol did not
markedly change during the 16 weeks of anti-TNF
treatment, the decrease in serum IL-6 led to elevated
ratios of serum ACTH to serum IL-6 (Figure 4D) and
serum cortisol to serum IL-6 (Figure 4F).
Changes of adrenal androgens. In patients without and with parallel prednisolone, serum 17(OH)progesterone and serum ASD did not markedly change over
the 16 weeks of anti-TNF treatment (Figures 5A–D).
However, the ratio of these 2 hormones significantly
increased in patients without prednisolone (Figure 5E),
Figure 5. Course of serum levels of 17-hydroxyprogesterone (17OHP)
(A and B), serum androstenedione (ASD) (C and D), and the ratio of
serum ASD to serum 17OHP (E and F) during 16 weeks of anti-TNF
antibody therapy in patients with rheumatoid arthritis. The graph
depicts patients without (A, C, and E) and with (B, D, and F) parallel
treatment with prednisolone. The data are given as the mean and
SEM. The Spearman’s rank correlation coefficient (RRank), its P value,
and the linear regression line are given. Arrows indicate the time point
of anti-TNF antibody infusion. See Figures 1 and 2 for other definitions.
1509
Figure 6. Course of the ratio of serum ASD to serum cortisol during
16 weeks of anti-TNF antibody therapy in patients with rheumatoid
arthritis. The graph depicts patients without (A) and with (B) parallel
treatment with prednisolone. The data are given as the mean and
SEM. The Spearman’s rank correlation coefficient (RRank), its P value,
and the linear regression line are given. Arrows indicate the time point
of anti-TNF antibody infusion. See Figures 1 and 5 for definitions.
which indicates an activation of this pathway toward the
direction of adrenal androgens (Figure 1). In contrast,
patients with prednisolone treatment demonstrated a
steady decrease in the ratio of serum ASD to serum
17(OH)progesterone (Figure 5F). Interestingly, serum
ASD was more influenced by parallel prednisolone
treatment as compared with 17(OH)progesterone (compare the levels of the hormones in Figures 5A and B, and
Figures 5C and D). Patients with prednisolone had a
generally lower mean serum ASD as compared with
patients without parallel prednisolone (Figures 5C and
D), which was corroborated by the ratio of serum ASD
to serum 17(OH)progesterone (Figures 5E and F). This
indicates that this particular enzyme step is subject to
exogenous prednisolone therapy.
Furthermore, the ratio of serum ASD to serum
cortisol is another indicator of a change in secretion of
androgens in relation to the glucocorticoid cortisol
(Figure 1). This ratio increased in patients without
parallel prednisolone (Figure 6A), whereas this ratio
tended to decrease in patients with parallel prednisolone
(Figure 6B). These data corroborate the results with
respect to ASD and 17(OH)progesterone (Figures 5E
and F). In both groups, there were no marked changes in
the levels of serum DHEA, DHEA sulfate, and the ratio
of serum DHEA to serum ASD or the ratio of serum
DHEA sulfate to serum DHEA throughout the 16
weeks of anti-TNF therapy (data not shown).
DISCUSSION
Long-term therapy with anti-TNF in patients
with RA leads to an overall reduction in the inflamma-
1510
tory load (serum IL-6, serum amyloid A, haptoglobin,
fibrinogen), which has also been described in an earlier
investigation of these same patients (37). In patients
without prednisolone, this led to sensitization of the
pituitary gland, which was demonstrated as a rapid
increase in the average ACTH serum concentration
after every infusion of anti-TNF. Thus, we propose that
chronically elevated serum TNF inhibits hypothalamic
CRH secretion or CRH-stimulated pituitary ACTH
secretion, but certainly does not stimulate secretion of
these 2 hormones (Figure 1). The pituitary sensitization
was also demonstrated by the decrease in the ratio of
serum cortisol to serum ACTH; since serum cortisol
remained relatively stable during the course of the
therapy and serum ACTH increased (particularly after
every infusion of anti-TNF), the numeric value of the
ratio decreased.
The ratio of serum cortisol to serum ACTH was
calculated for every patient, which better reflects the
individual relationship of serum cortisol and serum
ACTH. Consideration of the group mean ratios of one
hormone to another hormone would not give equal
insight, because we would lose the individual variation of
both hormones in one patient. In this particular case
(cortisol:ACTH), the relatively stable serum cortisol
levels in relation to the increasing serum ACTH was
only visible after building the ratio. Thus, in summary,
ACTH serum levels increase in relation to serum cortisol, which is indicative of a sensitization of the
hypothalamic–pituitary axis (the ACTH producer), but
not of the adrenal glands (the cortisol producer).
A marked increase in serum ACTH was also
demonstrated in relation to serum IL-6 between day 0
and week 1 of therapy, which remained elevated
throughout the observation period. Furthermore, the
increase in the ratio of serum cortisol to serum IL-6
indicates the relatively stable behavior of serum cortisol,
since serum IL-6 was obviously decreasing. Furthermore, the increase in the ratio of serum ASD to serum
17(OH)progesterone and serum ASD to serum cortisol
indicates a step toward a normalization of adrenal
androgen production, because ASD is the main precursor of adrenal androgens. This is a very interesting
finding, because it shows that normalization of adrenal
androgen production can occur even after long-term
inflammation, when the inhibitory break (in this case,
TNF) is removed.
As expected, parallel stable prednisolone therapy
completely changed the behavior of the HPA axis (this is
not dependent on parallel methotrexate treatment, since
we did not see any differences between patients with and
STRAUB ET AL
without methotrexate). First, after every infusion of
anti-TNF, serum ACTH rapidly decreased, which indicates that the inflammatory load (serum IL-6 and serum
TNF) stimulates the hypothalamic–pituitary axis under
prednisolone-induced conditions. This is completely opposite to the above-mentioned situation without prior
prednisolone therapy. Second, the hypothalamic–
pituitary axis was not sensitized because the ratio of
serum cortisol to serum ACTH did not change. Third,
the ratio of serum ASD to serum 17(OH)progesterone
and serum ASD to serum cortisol decreased, which
indicates that under these conditions, TNF or IL-6
downstream may even stimulate these particular enzyme
steps toward adrenal androgens (Figure 1). Under conditions with parallel prednisolone, stimulation of the
remaining HPA axis depends more on the inflammatory
load, as compared with the situation without parallel
prednisolone. One may speculate that long-term prednisolone therapy inhibits hypothalamic CRH secretion,
which removes the influence of the hypothalamus on the
pituitary gland. Thus, ACTH secretion completely depends on the inflammatory load, but not on hypothalamic CRH.
Interestingly, these patients who received parallel
prednisolone had a clinical outcome similar to that of
the patients without parallel prednisolone (36). This may
indicate that during anti-TNF therapy, both the restored
adrenal corticosteroids (in patients without parallel
prednisolone) and the administered corticosteroids (patients with parallel prednisolone) favorably influenced
the inflammatory process to a similar extent. Furthermore, parallel prednisolone therapy might have also
decreased TNF secretion, which is an additional antiinflammatory factor acting in conjunction with anti-TNF
antibodies. Such a situation would lead to a stronger
reduction in the inflammatory load as compared with
therapy with anti-TNF alone. These facts may partially
explain the different HPA axis behavior in patients with
and without parallel prednisolone therapy.
In conclusion, this study with long-term anti-TNF
therapy demonstrates a sensitization of the hypothalamus and pituitary gland in patients who have not
received parallel prednisolone therapy. In addition, the
adrenal androgen ASD increases relative to its precursor
17(OH)progesterone and cortisol, which indicates a step
toward normalization of adrenal androgen production.
As the systemic inflammation decreases, the function of
the HPA axis begins to normalize over 16 weeks. This
obviously demonstrates that during chronic inflammation, the HPA axis seems to support the systemic
inflammation (desensitization of the hypothalamus, low
INFLUENCE OF ANTI-TNF TREATMENT IN PATIENTS WITH RA
cortisol in relation to inflammation, low adrenal androgens) rather than to counterbalance the chronic inflammatory process.
16.
ACKNOWLEDGMENT
We thank Alfonse Masi for helpful discussions at our
poster at the 2002 American College of Rheumatology annual
meeting in New Orleans.
17.
18.
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