Inadequately low serum levels of steroid hormones in relation to interleukin‐6 and tumor necrosis factor in untreated patients with early rheumatoid arthritis and reactive arthritis

Straub, Rainer H.; Paimela, Leena; Peltomaa, Ritva; Schölmerich, Jürgen; Leirisalo‐Repo, Marjatta

doi:10.1002/art.10177

Cited by 180 publications

(134 citation statements)

References 43 publications

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“…The reduced glucocorticoid levels during the chronic phase of CII-induced arthritis correspond well to the decreased activity of the HPA axis that has been reported in patients with rheumatic diseases (30,31). Thus, CII-induced arthritis in DA rats appears to be a suitable model with which to analyze the mechanisms that interfere with the activation of the HPA axis during arthritis, a defect that is not observed during other experimentally induced inflammatory/autoimmune diseases, such as experimental autoimmune encephalomyelitis (28,32,33).…”

Section: Discussionsupporting

confidence: 76%

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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Section: Discussionsupporting

confidence: 76%

Disrupted brain–immune system–joint communication during experimental arthritis

Rey¹,

Wolff²,

Wildmann³

et al. 2008

Arthritis & Rheumatism

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“…186,187 Reduced glucocorticoid sensitivity due to GRb overexpression, 149 and a polymorphism of the GRb associated with the enhanced stability of the receptor, has also been described in patients with RA. 172 Adrenal steroid secretion is also inadequately low in relation to inflammation (IL-6) in patients with RA, 177,188 suggesting a relative adrenal insufficiency in the setting of a sustained inflammatory process. 42 Cytokines and their receptors are thought to play an important role in the development and maintenance of the inflammatory process in RA.…”

mentioning

confidence: 99%

Brain-immune interactions and disease susceptibility

2005

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Many studies have established the routes by which the immune and central nervous (CNS) systems communicate. This network of connections permits the CNS to regulate the immune system through both neuroendocrine and neuronal pathways. In turn, the immune system signals the CNS through neuronal and humoral routes, via immune mediators and cytokines. This regulatory system between the immune system and CNS plays an important role in susceptibility and resistance to autoimmune, inflammatory, infectious and allergic diseases. This review focuses on the regulation of the immune system via the neuroendocrine system, and underlines the link between neuroendocrine dysregulation and development of major depressive disorders, autoimmune diseases and osteoporosis.

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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).…”

Section: Discussionmentioning

confidence: 99%

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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Inadequately low serum levels of steroid hormones in relation to interleukin‐6 and tumor necrosis factor in untreated patients with early rheumatoid arthritis and reactive arthritis

Cited by 180 publications

References 43 publications

Disrupted brain–immune system–joint communication during experimental arthritis

Disrupted brain–immune system–joint communication during experimental arthritis

Brain-immune interactions and disease susceptibility

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

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