Abstract

Neuroendocrine pathways link the central nervous system (CNS) with the periphery by means of hormones and nerve fibres. Neuroendocrine connections are important for integrating signals throughout the body. Hormones are soluble factors circulating in the blood and lymph, while nerve fibres are solid cables connecting brain centres with distinct anatomical sites in the periphery.

Several network connecting the NeuroEndocrine Immune (NEI) system are target for the treatment of chronic immune inflammatory diseases, including arthritis in RMD (1).

The hypothalamic–pituitary–adrenal (HPA) axis is the best studied connection between the CNS and peripheral sites of inflammation. The HPA axis hormones comprise CRH, adrenocorticotropic hormone (ACTH) and several steroid hormones of the adrenal gland, including cortisol and adrenal androgens such as dehydroepiandrosterone (DHEA), its biologically inactive degradation product DHEA sulfate (DHEAS), and androstenedione (ASD). The adrenal gland synthesises glucocorticoids (GCs) following a circadian rhythm and the exogenous administration of GCs in chronic arthritis should be regarded as a replacement therapy for adrenal gland hypofuntion (2).

The hypothalamic–pituitary–gonadal (HPG) axis has been linked to rheumatic diseases because we observe a female preponderance in the prevalence and incidence of rheumatic diseases, which is most probably linked to sex hormones. Hormones of the HPG axis comprise gonadotropin-releasing hormone, luteinising hormone/follicle-stimulating hormone and the two major bioactive steroid hormones of the gonadal glands, testosterone and oestrogens. Increased peripheral metabolism of sex hormones is seen in chronic arthritis (ie. synovial tissue).

The hypothalamic–pituitary–prolactin axis is important since Prolactin is thought to have proinflammatory effects in RMD. Blood levels rise sharply at the beginning of sleep so this hormone can be a regulatory element in the circadian rhythms of the immune system (1).

Similar condition for the melatonin pathway, that in addition is increased I rheumatoid arthritis patients. Blood levels rise sharply at the beginning of sleep and melatonin might, thus, be a regulatory element in the circadian rhythms of the immune system. Melatonin at normal concentrations has proinflammatory effects. Finally, the vitamin D endocrine system, which is one of the most complex and diffuse systems controlling bone mass and also the immune response in autoimmune rheumatic diseases. Vitamnin D deficiancy is common in chronic RMD and decreased in winter with related flares of RMD.

Finally, vitamin D, via its active hormonal metabolite 1,25(OH)2D3 (D hormone), regulates both innate and adaptive immunity, potentiating the innate response (monocytes/macrophages with antimicrobial activity and antigen presentation) but suppressing adaptive immunity (T and B lymphocyte functions). D hormone deficiency is a risk factor for autoimmunity and for infections and cancer.

By considering that all steroid hormones before mentioned, are also produced via intracrine synthesis by the inflammatory cells (ie. macrophages) at the site of arthritis, it is increasing in presence of localized inflammatory conditions the local treatment (ie injection of GCs in joints). On the other hands, the immune stimulating action of estrogens should noy suggest their use in pathological conditions. Same caution with the use of melatonin in presence of arthritis, whereas 1,25(OH)2D3 is considered an adhiuvant in immune system suppression at dosages over 2,000 IU/day.