Tumor necrosis factor–neutralizing therapies improve altered hormone axes: An alternative mode of antiinflammatory action

Straub, Rainer H.; Härle, Peter; Sarzi-Puttini, Piercarlo; Cutolo, Maurizio

doi:10.1002/art.21946

Cited by 49 publications

(37 citation statements)

References 60 publications

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“…Secretion of cortisol and ACTH is inadequately low in relation to serum levels of proinflammatory cytokines such as IL-6 and TNF (15). Only recently, the possibility of neutralizing distinct proinflammatory cytokines such as TNF and IL-6 demonstrated that these therapies can improve altered hormonal axes (6). TNF affects several important hormoneconverting enzymes in adrenocortical cells such as P450scc, P450c17, and P450c21 (16,17).…”

Section: Discussionmentioning

confidence: 99%

“…The role of circulating or locally produced TNF as a factor influencing the human HPA axis has recently been reviewed (6). TNF seems to be an important factor in establishing a milieu with inadequately low cortisol and adrenocorticotropic hormone (ACTH) secretion in relation to ongoing inflammation (6).…”

mentioning

confidence: 99%

“…TNF seems to be an important factor in establishing a milieu with inadequately low cortisol and adrenocorticotropic hormone (ACTH) secretion in relation to ongoing inflammation (6). However, it is not known whether TNF-induced inhibition of adrenal glands leading to inadequate cortisol levels has any impact on the chronic disease process.…”

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confidence: 99%

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Increased cortisol relative to adrenocorticotropic hormone predicts improvement during anti–tumor necrosis factor therapy in rheumatoid arthritis

Straub¹,

Pongratz²,

Cutolo³

et al. 2008

Arthritis & Rheumatism

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Objective. Some patients with chronic inflammatory diseases such as rheumatoid arthritis (RA) improve rapidly from anti-tumor necrosis factor (anti-TNF) therapy. No sensitive markers are available that might predict outcome of anti-TNF therapy. We undertook this study to investigate the predictive value of hypothalamic-pituitary-adrenal (HPA) axis hormones for clinical improvement during anti-TNF therapy.Methods. An observational study in 23 RA patients was followed by a validation study in 38 RA patients. The patients receiving anti-TNF antibodies had no glucocorticoid treatment, and we measured baseline serum levels of adrenocorticotropic hormone (ACTH) and cortisol. Improvement during anti-TNF antibody treatment was judged by the Disease Activity Score in 28 joints (DAS28), and serum levels of cortisol were measured at followup.Results. The observational study demonstrated that improvement in the DAS28 correlated negatively with baseline serum levels of cortisol (R ‫؍‬ ؊0.520, P ‫؍‬ 0.011) and the cortisol:ACTH ratio (R ‫؍‬ ؊0.700, P ‫؍‬ 0.0002). In the longitudinal part of the study at followup, those patients with good improvement and initially low serum levels of cortisol demonstrated an increase of serum cortisol, in contrast to patients with little or no improvement. Findings in the observational study were supported by those in the validation study in a group of RA patients with less inflammation (correlation of improvement in the DAS28 with cortisol:ACTH ratio: R ‫؍‬ -0.320, P ‫؍‬ 0.025).Conclusion. This is the first study in a human ISRCTN 68762628. FDA: BL 125057 (adalimumab portion of the studies).This publication reflects only the authors' views. The European Community is not liable for any use that may be made of the information herein.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Increased cortisol relative to adrenocorticotropic hormone predicts improvement during anti–tumor necrosis factor therapy in rheumatoid arthritis

Straub¹,

Pongratz²,

Cutolo³

et al. 2008

Arthritis & Rheumatism

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“…Because male patients have higher levels of circulating androgens than do female patients, they probably have relatively higher local aromatase-mediated production of proinflammatory estrogens. Therefore, blockade of TNFinduced up-regulation of aromatase would particularly increase the level of androgens in males, leading to a better clinical outcome (12).…”

Section: Maurizio Cutolomentioning

confidence: 99%

Sex and rheumatoid arthritis: Mouse model versus human disease

Cutolo¹

2007

Arthritis & Rheumatism

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“…In contrast, the effect of cytokines produced during the disease might not be restricted to local actions in inflamed tissues (9,10), and afferent pathways mediated by immune products might influence the CNS. Indeed, there is clear evidence of the existence of bidirectional immune-neuroendocrine system interactions (for review, see refs.…”

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confidence: 99%

Disrupted brain–immune system–joint communication during experimental arthritis

Rey¹,

Wolff²,

Wildmann³

et al. 2008

Arthritis & Rheumatism

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Objective. To explore the hypothesis that, in parallel with alterations in the hypothalamus-pituitaryadrenal axis and the sympathetic nervous system, hypothalamic cytokine expression and monoaminergic neurotransmitter concentrations are affected during the course of arthritis development induced by type II collagen. This hypothesis was based on evidence that acute inflammatory processes induce cytokine expression in the brain and affect neuronal activity. We also studied whether depletion of hypothalamic noradrenaline can affect peripheral joint disease.Methods. Hypothalamic cytokine gene expression and neurotransmitter concentration, parameters of inflammation, and joint innervation were evaluated during arthritis development in rats induced by injection of type II collagen in Freund's incomplete adjuvant. Noradrenergic neurons in the brain were depleted with 6-hydroxydopamine.Results. Transiently increased corticosterone levels, followed by increased adrenaline levels and hypothalamic interleukin-1␤ (IL-1␤) and IL-6 overexpression were observed only during the induction phase of the disease. Hypothalamic noradrenaline content was increased during the symptomatic phase and was paralleled by a gradual loss of noradrenergic fibers in the joints. The positive correlation between hypothalamic IL-1␤ expression and noradrenaline content in control groups was not observed in rats in which arthritis developed. Depletion of hypothalamic noradrenergic neurons when arthritis was established did not affect the course of the disease.Conclusion. The dissociation between hypothalamic cytokine gene expression and noradrenergic neuronal activity, the lack of sustained stimulation of the stress axes, and the loss of sympathetic signals in the joints indicate a disruption in communication between afferent immune messages to the central nervous system and 2 main efferent antiinflammatory pathways under control of the brain during collagen-induced arthritis.The inflammatory/autoimmune process observed during experimentally induced arthritis is paralleled by neuroendocrine alterations, particularly in the activity of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) (for review, see refs.

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Tumor necrosis factor–neutralizing therapies improve altered hormone axes: An alternative mode of antiinflammatory action

Cited by 49 publications

References 60 publications

Increased cortisol relative to adrenocorticotropic hormone predicts improvement during anti–tumor necrosis factor therapy in rheumatoid arthritis

Increased cortisol relative to adrenocorticotropic hormone predicts improvement during anti–tumor necrosis factor therapy in rheumatoid arthritis

Sex and rheumatoid arthritis: Mouse model versus human disease

Disrupted brain–immune system–joint communication during experimental arthritis

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