Editorials and Opinion
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Neuroendocrine Immune Implications in Rheumatoid Arthritis and Polymyalgia Rheumatica: Past and Present Unresolved Issues and Optimising Glucocorticoid Treatment

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Rheumatoid Arthritis
Neuroendocrine-immune implications – arthritis

The dramatic effects of cortisone and pituitary adrenocortical hormone therapy on rheumatoid arthritis (RA) were discovered almost seven decades ago (1) and even longer for the significant disease amelioration during pregnancy as reported by Hench in 1938 (2).

However, major questions persist about the underlying adrenocortical and hypothalamic pituitary axis (HPA) predisposition to this disease and the optimal use of glucocorticoids (GCs) (3). A specific ongoing question is if GCs and other neuroendocrine immune (NEI) testing of individual RA patients can guide benefits to harms ratio in glucocorticoid therapy (3). Main considerations have been a constitutional insufficiency of the physiological adrenocortical and NEI system competency or response to stress or inflammation as discriminated from genetic or environmental activators of the immune and inflammatory pathways (3-5). As discussed in this Editorial, relative adrenal insufficiency in RA may contribute to systemic T helper (Th)1 shift and an amplification of the local pro-inflammatory activities in this condition (see Figure 1).

Figure 1 Neuroendocrine Immune Implications Rheumatoid Arthritis Polymyalgia Rheumatica
Figure 1. Adrenal insufficiency driving a T helper (Th)2 to Th1 shift and pro-inflammatory responses in rheumatoid arthritis (RA). In the pathogenesis of RA, a relative adrenal insufficiency could result in less systemic inhibition of the Th1 responses by glucocorticoids (GCs), and less potentiation of Th2 responses by gonadal deficiency, leading to Th1-mediated inflammation. Locally, pro-inflammatory factors including NE, CRH, SP and urocortin participate in persistence of chronic synovitis. Solid lines represent stimulation, while dashed lines inhibition. Abbreviations: APC, Antigen-presenting cell; CRH, Corticotropin-releasing hormone (peripheral); IL, interleukin; NE, norepinephrine; SP, substance P; TNF, tumor necrosis factor; Th, T helper lymphocyte; Th1, a type of effector T helper cell that promotes cell-mediated immune responses. Th2 cells exert mostly anti-inflammatory effects and counteract Th1 influences. Modified from: Calcagni E and I Elenkov, Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases, Ann N Y Acad Sci. 2006 Jun; 1069:62-76.

Immunogenetic mechanisms operating within the immune system influence cytokine profiles and may affect disease susceptibility (6). The neuroendocrine and immune pathways complexly interact, and the primary dysfunction is not known, nor are the individual benefits to risks responses to GCs (7). The role of the individual’s neurohormonal background in these processes remains undefined. Hormonal imbalances are documented in immune-related diseases, but it is unclear whether this represents a secondary phenomenon or a primary “defect” related to specific neurohormonal immune phenotype(s) (6). The accumulated data suggest a bi-directional crosstalk between the neuroendocrine, sympathetic nervous system (SNS), and products of the immune system. Greater understanding of the underlying physiology of individual NEI function may guide improved therapy of RA with respect to GCs, related adrenocortical or hormonal therapy, and anti-inflammatory compounds.

Due to the complexity and difficulty of clinical studies on adrenal and HPA physiology (5), a predominant focus on the NEI negative feedback loop emerged (Figures 1, 2). This perspective became a paradigm for studies in selected autoimmune diseases, including RA and polymyalgia rheumatica/giant cell arteritis (PMR/GCA), as reviewed in this Editorial (6, 8-12). In healthy subjects, early studies showed that subcutaneously administered cytokines, like IL-6, induced a dose-dependent increase in the basal metabolism and higher HPA axis activity, with higher cortisol or plasma adrenocorticotropic hormone (ACTH) blood levels (13,14).

Such data suggest hypothalamic mechanisms, including secretion of corticotrophin-releasing hormone (CRH), mediating the influence of inflammatory molecules on the organism’s function. Moreover, IL-6 also provokes growth hormone (GH) and prolactin (PRL) secretion and suppresses thyroid stimulating hormone (TSH) (13,14). The ameliorating effects of pregnancy on rheumatoid arthritis (RA) and its dramatic improvement with pharmacologic doses of cortisone support the role for the HPA axis in RA (1,2).

Other evidences of interrelation between inflammatory processes, cytokine secretion and endocrine functions were studied on a second axis, constituted by the hypothalamus, pituitary gland and gonads (HPG) (15). The role of IL-1α was demonstrated to inhibit reproductive functions through an action on central nervous system and gonads (16, 17). A dysfunctional neuroendocrine-immune interface may play a specific role in the pathogenesis of RA (Figure 2), associated with abnormalities of the ‘systemic anti-inflammatory feedback’ and/or ‘hyperactivity’ of the local pro-inflammatory factors. Better understanding of the neuroendocrine control of inflammation may provide critical insights into mechanisms underlying RA and certain other common human immune-related diseases (18).

Figure 2 Neuroendocrine Immune Implications Rheumatoid Arthritis Polymyalgia Rheumatica
Figure 2. Neuroendocrine-immune feedback loop. Activation of the hypothalamic-pituitary-adrenal (HPA) axis, represented by the green-coded pathway, is a key component of the stress response to various stressors. Adrenal glucocorticoids such as cortisol mediate their negative feed-back, represented by the red-coded pathway. This effect is on the HPA, regulating not only their own adrenal secretion and promoting metabolic effects, but also exerting their immunosuppressive effects in the peripheral tissues. From: Cornelia M Spies, Rainer H Straub, Maurizio Cutolo and Frank Buttgereit, Circadian rhythms in rheumatology – a glucocorticoid perspective, Arthritis Res Ther. 2014 Nov 13;16 Suppl 2:S3 (Open Access).
Hormones and immune system studies in RA

Disparities in sex hormone concentrations seem to contribute to gender differences in autoimmune disorders (19). The anti-inflammatory role of androgens is recognized, but estrogens seem to exercise pro- and anti-inflammatory activities (15). During pregnancy, particularly the 3rd trimester, the increase of estrogens and progesterone may facilitate, or accompanying high cortisol levels, a Th2 shift systemically.

In early postpartum, when these hormones return to normal or low normal levels, these changes may induce a rebound of IL-12 and TNF-α production and a Th1 shift. This may explain why Th1-related diseases such as RA and multiple sclerosis (MS) frequently remit during pregnancy, but exacerbate or have their onset in the postpartum period (18).

Physiological concentrations of estrogens boost immune and inflammatory activity, while progesterone (PG) and androgens, like testosterone and dehydroepiandrosterone (DHEA), have selective suppressive activity (20). In vitro, the adrenal androgen-like hormone, DHEA, inhibits IL-6 secretion in cultured human mononuclear cells (21).

Serum levels of anti-inflammatory androgens are low in RA. This finding was attributed to a cytokine-induced block of androgen production in adrenal and gonadal glands and an increased conversion of androgens to oestrogens in inflamed tissues (8, 9).

Additionally, melatonin, a hormone secreted during the night by the pineal gland, seems to activate the immune system at normal to slightly elevated levels, and to worsen inflammatory conditions like RA (22, 23). Melatonin secretion is associated with changes in light/darkness periods and consequently it seems to be implicated in the circadian and seasonal rhythms and might contribute to the inflammatory pathways of autoimmune diseases (23, 24).

Rheumatoid arthritis

In RA patients, the hypothesis of a “relative adrenal insufficiency” was formulated, following the observation of reduced cortisol and adrenal androgens secretion (4,5). In particular, the alterations in HPA axis function in RA have been recognized mainly at the adrenal than pituitary or hypothalamic levels (25, 26). Such interpretation is supported by consistent findings of lower levels of adrenal androgens, particularly DHEAS, in premenopausal onset RA patients (27).

Although, the findings likely reflect ongoing chronic inflammation, a role of neuroendocrine-related genetic factors such as SULT2A1 and HHEX genes in arthritis have been considered as well. Overall, effects of these DHEAS-related gene variants appear to be relatively small compared to other well-known factors such as age, complex interactions between DHEAS-associated genotypes and adrenal androgen hypofunction phenotype may exist in RA (28).

In support of the role of androgens in RA development, a recent study reported that an RA susceptibility gene polymorphism (rs1790834) encodes for a cofactor for 17, 20-lyase activity, cytochrome b5, on CYB5A gene, governing the decisive step of androgen synthesis (29). An association of RA with other adrenal androgen related genes, including ZKSCAN5 (rs11761528), SULT2A1 (rs2637125), HHEX (rs2497306), and ARPC1A (rs740160) were not confirmed in RA (30). In RA, increased oestrogen concentrations may produce activating effects on synovial cell proliferation, including macrophages and fibroblasts (31).

The cooperative anti-inflammatory coupling of sympathetic nervous system (SNS) and HPA axes functions may be deficient in RA. Low levels of cortisol in relation to SNS neurotransmitters may result in a pro-inflammatory predisposition (32) (Figure 2). In animals, SNS ameliorates collagen-induced arthritis (CIA) in the late phase of the disease, but can have a worsening effect in the pre-symptomatic phase.  One of the early phase effects of sympathetic nervous system activation may be the stimulation of CD4+CD25+ T cells (33,34).

In RA, cholinergic anti-inflammatory nerve fibres from the vagus nerve may have a role in reduction of inflammation. Their stimulation has an influence on disease activity score through inhibition of cytokine production (35,36). The reduced GC secretion, the circadian rhythmicity of symptoms and the release of pro-inflammatory cytokines have been better studied in RA than other diseases (37, 38) (Figure 3).

The European League Against Rheumatism (EULAR) and more recently the American College of Rheumatology (ACR) have recommended exogenous glucocorticoid administration from the time of diagnosis, because it could act as a “replacement therapy” (39), which needs further study.

Figure 3 Neuroendocrine Immune Implications Rheumatoid Arthritis Polymyalgia Rheumatica
Figure 3. Relationship between clinical symptoms of RA and hormonal circadian rhythms. In rheumatoid arthritis (RA), clinical symptoms of joint stiffness, pain, and functional disability are commonly most severe in the early morning at around 5-6 am. This clinical worsening of RA in early morning precedes cortisol and testosterone peaks and the melatonin cessation by approximately 2-4 hours. Symptoms subsequently improve in early afternoon hours reflecting effects of immunosuppressive steroids and dip in proinflammatory hormones such as melatonin or prolactin. Modified from: Cutolo M., Glucocorticoids and chronotherapy in rheumatoid arthritis, RMD Open, 2016;2: e000203. doi:10.1136/rmdopen-2015-000203.

The prevention of the circadian up-regulation of the immune-inflammatory mediators has been shown to be more efficient symptomatically, if exogenous glucocorticoids are administered with a night-time-release formulation (40). The concept of chronotherapy in RA is advocated (41). The prevention/treatment of the night up-regulation of the immune/inflammatory reaction has been shown more effective symptomatically in RA and other chronic inflammatory conditions, when exogenous glucocorticoid administration is managed with a night-time-release formulation (42).

The Nobel Prize for Medicine in 2017 was awarded to studies on circadian rhythms, adding a further blueprint for advancement in chronotherapy (43). Circadian rhythms regulate, under action of biological clocks located both at the level of central nervous system and inside peripheral cells. The rhythms control several daily activities, embracing sleep, feeding times, energy metabolism, endocrine and immune functions with related pathological conditions.

Polymyalgia rheumatica/giant cell arteritis

The typical old age incidence of polymyalgia rheumatica/giant cell arteritis (PMR/GCA) is associated with the natural decline of adrenal androgen concentration, like DHEA, DHEAS and androstenedione (ASD), which is also associated with an increase of pro-inflammatory cytokines, including TNF-α and IL-6 (immunosenescence) (44). Low levels of DHEAS were significantly correlated with disease activity (7).

Cortisol levels at time of PMR diagnosis did not significantly differ from healthy controls, but, remained insufficient compared to the inflammatory status (10). The relative clinical insufficiency of endogenous glucocorticoids is supported by the excellent therapeutic response to low-pharmacologic doses of exogenous glucocorticoids (12).  Both the process of aging and the higher TNF-α concentrations were reported to reduce P450 17, 20-lyase activity, with a following decrease of DHEAS production by adrenal glands (10). Regarding IL-6, its concentrations are typically high in PMR/GCA, which stimulates CRH secretion in the hypothalamus and ACTH from the pituitary gland and in the adrenal glands (13). It influences the activity of enzymes involved in steroidogenesis (45).

Some authors hypothesize that, for successful immunosuppression, exogenous glucocorticoid administration could be accompanied by supplementation with DHEA and/or androstendione (ASD) (7). In PMR, the circadian rhythms of pro-inflammatory cytokine release were reported (46). A recent multicentre randomised double-blind study demonstrated a favourable short-term symptomatic efficacy of modified-release versus immediate-release prednisone in early treatment of glucocorticoid naive patients affected by PMR (46).

Conclusions

The altered cortisol and adrenal androgen (i.e. DHEAS and ASD) secretion, observed in the recent decades in RA and more recently in PMR patients (before treatment with glucocorticoids), should be considered as a “relative adrenal insufficiency” in the setting of a sustained inflammatory process, as shown for example by high serum IL-6 levels (47). Future research on the epigenetic mechanisms that mediate glucocorticoid actions and its drug resistance promise to offer biomarkers to optimise individual dose therapy in long term treatment. Chronotherapy with low dose GCs for long term administration seems advantageous (48).

Critically-designed physiologic and prospective controlled studies are needed to determine the effectiveness and safety of individualized GC dosing and other therapies that could modulate the neuroendocrine and immune systems. Such studies promise to clarify optimal GC therapy as well as other endocrine and anti-inflammatory treatments of musculoskeletal and rheumatic diseases (49), and to advance progress in the field.

Authors Affiliations

Maurizio Cutolo – Research Laboratories and Academic Division of Rheumatology, Postgraduate School of Rheumatology, Department of Internal Medicine, University of Genova, IRCCS Polyclinic Hospital San Martino, Genova, Italy; Richard Imrich –  Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic; Rainer Straub – Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, University Hospital Regensburg, Germany. Ilia Elenkov – Brain Immune Media Ltd, Norwich, Norfolk, UK; Alfonse T. Masi – Division of Rheumatology, University of Illinois College of Medicine at Peoria, Peoria IL, USA.

Corresponding author, Maurizio Cutolo, email: mcutolo@unige.it

List of Non-Standard Abbreviations

ACTH, adrenocorticotropic hormone; CRH, Corticotropin-releasing hormone (peripheral); DHEA, dehydroepiandrosterone; GCs, glucocorticoids; GH, growth hormone; HPA, hypothalamic pituitary axis; IL, interleukin; NEI, neuroendocrine immune; PRL, prolactin (PRL), rheumatoid arthritis; PMR/GCA), rheumatica/giant cell arteritis;TNF, tumor necrosis factor; Th, T helper lymphocyte; TSF, thyroid stimulating hormone.

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