RA is a progressive inflammatory autoimmune disease with articular and systemic effects. Its exact cause is unknown, but genetic and environmental factors are contributory. T cells, B cells and the orchestrated interaction of pro-inflammatory cytokines play key roles in the pathophysiology of RA. Differentiation of naive T cells into Th 17 (T(H)17) cells results in the production of IL-17, a potent cytokine that promotes synovitis. B cells further the pathogenic process through antigen presentation and autoantibody and cytokine production. Joint damage begins at the synovial membrane, where the influx and/or local activation of mononuclear cells and the formation of new blood vessels cause synovitis. Pannus, the osteoclast-rich portion of the synovial membrane, destroys bone, whereas enzymes secreted by synoviocytes and chondrocytes degrade cartilage. Antigen-activated CD4(+) T cells amplify the immune response by stimulating other mononuclear cells, synovial fibroblasts, chondrocytes and osteoclasts. The release of cytokines, especially TNF-α, IL-6 and IL-1, causes synovial inflammation. In addition to their articular effects, pro-inflammatory cytokines promote the development of systemic effects, including production of acute-phase proteins (such as CRP), anaemia of chronic disease, cardiovascular disease and osteoporosis and affect the hypothalamic-pituitary-adrenal axis, resulting in fatigue and depression.

Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.20747

How psychological stress via hormones and nerve fibers may exacerbate rheumatoid arthritis

The investigation of the hypothalamicpituitary-adrenal (HPA) axis in chronic inflammation has demonstrated: 1) an anti-inflammatory influence of the HPA axis; 2) low serum levels of adrenal androgen; 3) equivocal results with respect to levels of adrenocorticotropic hormone and cortisol; 4) inadequately low secretion of adrenal hormones in relation to inflammation (the disproportion principle); 5) modulating role of TNF and IL-6 on the HPA axis; 6) disturbed cooperativity of HPA axis and sympathetic nervous system (uncoupling); 7) observable glucocorticoid resistance; 8) the circadian rhythmicity explains morning symptoms; 9) new medications based on malfunction of the HPA axis (e.g. adapted to the circadian rhythm of hormones and cytokines); and 10) the newly described role of the HPA axis in the context of misguided energy regulation in chronic inflammatory diseases. This review discusses items 1-6 and 10, while the other items are presented elsewhere in this Supplement. Evidence is presented that the basis for many alterations is in an adaptive program positively selected for short-lived inflammatory responses (energy appeal reaction), which becomes a disease-inherent pathogenetic factor, if it continues too long, that can drive systemic disease sequelae of chronic inflammatory diseases such as the metabolic syndrome.

Alterations of the hypothalamic-pituitary-adrenal axis in systemic immune diseases - a role for misguided energy regulation.

Prolactin and autoimmunity: The hormone as an inflammatory cytokine.

Chronic, in particular chronic psychosocial, stress is a burden of modern societies and known to be a risk factor for numerous somatic and affective disorders (in detail referenced below). However, based on the limited existence of appropriate, and clinically-relevant, animal models for studying the effects of chronic stress, the detailed behavioural, physiological, neuronal, and immunological mechanisms linking stress and such disorders are insufficiently understood. To date, most chronic stress studies in animals employ intermittent exposure to the same (homotypic) or to different (heterotypic) stressors of varying duration and intensity. Such models are only of limited value, since they do not adequately reflect the chronic, and continuous, situation that humans typically experience. Furthermore, application of different physical or psychological stimuli renders comparisons to the mainly psychosocial stressors faced by humans, as well as between the different stress studies almost impossible. In contrast, rodent models of chronic psychosocial stress represent situations more akin to those faced by humans and consequently seem to hold more clinical relevance. Our laboratory has developed a model in which mice are exposed to social stress for 19 continuous days, namely the chronic subordinate colony housing (CSC) paradigm, which bridges this gap. The main aim of the current review article is to provide a detailed summary of the behavioural, physiological, neuronal and immunological consequences of the CSC paradigm, and wherever possible relate the findings to other stress models and to those from human studies.

/pdf/chronic-subordinate-colony-housing-paradigm-a-mouse-model-to-e0dneh3q3x.pdf

Chronic subordinate colony housing paradigm: a mouse model to characterize the consequences of insufficient glucocorticoid signaling.

A defective hypothalamo–pituitary–adrenal axis response to inflammatory cytokines may contribute to the pathophysiology of rheumatoid arthritis (RA). The purpose of this study was to define further the mechanisms responsible for this dysregulation. Six normal individuals and seven patients with active RA were recruited and given an oral dose of dexamethasone at 2300 h the evening before the study. The next day, an i.v. catheter was fitted at 1300 h. Blood samples were collected between 1400 h and 1700 h before and after infusion (at 1500 h) of corticotrophin releasing factor (CRF). Plasma was separated and stored at20 C before radioimmunoassay for ACTH, cortisol and dihydroepiandrosterone (DHEA). Before the CRF challenge, ACTH and cortisol were significantly increased and DHEA significantly decreased in the patients with RA compared with the controls. Neither ACTH nor DHEA was significantly altered after CRF infusion. Control individuals did not mount a cortisol response to infusion of CRF. Similarly, four of the patients with RA did not respond to CRF. However, in contrast to the controls, three of the patients mounted an immediate and sustained cortisol response after receiving CRF. These data reveal that three of the seven patients with RA were able to escape from dexamethasone suppression and mount a cortisol response to CRF challenge. This suggests that there may be a subpopulation of patients with RA who have impaired glucocorticoid feedback. The implications of this alteration for disease progression remain to be determined.

/pdf/hypothalamo-pituitary-adrenal-axis-dysregulation-in-patients-rhyyujrngh.pdf

Hypothalamo-pituitary-adrenal axis dysregulation in patients with rheumatoid arthritis after the dexamethasone/corticotrophin releasing factor test.

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Hypothalamo-pituitary-adrenal axis dysregulation in patients with rheumatoid arthritis after the dexamethasone/corticotrophin releasing factor test.