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) 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 pituitary 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.
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]). 3βHSD = 3β-hydroxysteroid dehydrogenase; 11βHSD I and II = 11β-hydroxysteroid dehydrogenase type I and type II; ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; DHEA = dehydroepiandrosterone; DHEAS = DHEA sulfate; DST = DHEA sulfotransferase; P450c11 = 11β-hydroxylase; P450c17 = 17α-hydroxylase and 17/20-lyase (double-enzyme step); P450c21 = 21α-hydroxylase; P450ssc = side-chain cleavage enzyme; ST = DHEA sulfatase; StAR = steroidogenic acute regulatory protein.
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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 anti-TNF 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 parallel prednisolone therapy, because this is the strongest influencing factor on hormone secretion.
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Long-term therapy with anti-TNF in patients with RA leads to an overall reduction in the inflammatory 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 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 cortisol in relation to inflammation, low adrenal androgens) rather than to counterbalance the chronic inflammatory process.