 |
|
|
 |
Editorial
The Neuroendocrine System and Rheumatoid Arthritis: Insights from
Anti-Tumor Necrosis Factor-a Therapy
ESTHER M. STERNBERG, MD,
National Institutes of Health, Rockville, Maryland; MARNI N. SILVERMAN, PhD, Prince of Wales National Center for Complementary and Alternative Midicine, Director's Fellow, Section on Neuroendocrine Immunology and Behavior, National Institutes of Health, Rockville, Maryland; GIOVANNI CIZZA, MD, Clinical Endocrinology Branch, National Institute of Diabetes, Digestive and Kidney Disorders, National Institutes of Health, Bethesda, Maryland, USA Supported in part by the Intramural Research Programs of the National Institute of Mental Health, the National Institute of Diabetes, Digestive and Kidney Diseases, the National Center for Complementary and Alternative Medicine, and the Warren Magnuson Clinical Center of the National Institutes of Health, Bethesda, Maryland. Address reprint requests to Dr. E. Sternberg, Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, 5625 Fishers Lane, Rm. 4N-13, MSC-9401, Rockville, MD 20852. E-mail: sternbee@mail.nih.gov The widespread use of tumor necrosis factor-a (TNF-a) inhibitors for treatment of rheumatoid arthritis (RA) provides a unique opportunity to dissect the complex relationships of hypothalamic-pituitary-adrenal (HPA) axis responses in the context of inflammation. The prospective study of neuroendocrine responses in RA in the course of anti-TNF-a therapy reported in this issue of The Journal1 provides important insights into these relationships and disease prognosis. The authors propose that inhibition of the key cytokine TNF-a, which also affects interleukin 6 (IL-6) and IL-1, would be expected to improve HPA axis function in RA. Proinflammatory cytokines such as TNF-a, IL-6, and IL-1 are potent activators of many aspects of central nervous system (CNS) function, including induction of a set of behaviors called sickness behavior, alteration of cognition, memory and mood, induction of sleep and fever, and activation of the brain's hormonal stress response2. In turn, the CNS regulates immune and inflammatory responses through the sympathetic, parasympathetic, and neuroendocrine stress systems. Under normal conditions, activation of these neural pathways by cytokines in the context of inflammation results in a negative feedback loop that shuts off inflammation and returns the host to homeostasis3. More specifically, proinflammatory cytokines activate the HPA axis by inducing secretion of corticotropin-releasing hormone (CRH) from hypothalamic secretory neurons, which in turn induces release of adrenocorticotropin (ACTH) from pituitary corticotrophs, finally stimulating secretion of antiinflammatory cortisol from the adrenal cortex. CNS regulatory pathways may be perturbed in RA in several ways. An inappropriately low HPA axis response, whether due to a blunted hypothalamic, pituitary, or adrenal response, or resistance at the level of the glucocorticoid receptor, predisposes to susceptibility to and/or exacerbates autoimmune/inflammatory disease, including RA3,4. While the latter association has been repeatedly established in animal models, the principle is more difficult to establish in humans with already diagnosed inflammatory disease, due to the activating effect of inflammation on the HPA axis5. Thus, RA patients have been shown to exhibit normal cortisol levels in the face of chronic inflammation, which in this context are inappropriately low6,7. Further, the chronic stress associated with the pain and disability of RA may itself compound and amplify HPA axis activation. Exposure to frequent or severe stress over a period of time (whether immunogenic or psychogenic) may lead to increased sensitization of the HPA axis, resulting in a pronounced stress response, or on the other hand may result in hypocortisolism or deficient glucocorticoid signaling8. Such insufficient glucocorticoid responses may contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism, and immune activation/ inflammation. Since glucocorticoids are often used for therapeutic purposes in these patients, separating the effects of the disease versus the medications on the HPA axis in RA becomes even more complicated. Other neural pathways also play a role in regulating the inflammatory/immune response, including the sympathetic nervous system (via the release of catecholamines and neuropeptides, such as neuropeptide Y)9, which has been shown to be dysregulated in RA10. The parasympathetic nervous system exerts antiinflammatory effects through cholinergic neurotransmitters and neuropeptides, such as vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP), released from the vagus nerve11. The peripheral nervous system regulates inflammation at local sites, including the synovium, through the release of neuropeptides from sensory peripheral nerves. These, including substance P and calcitonin gene-related peptide (CGRP), are generally proinflammatory3. Recent studies indicate that the adrenal gland is an important direct target of proinflammatory cytokines, including IL-6, that directly stimulate the adrenal gland during inflammation and infection5,12. Further, certain cytokines, such as TNF-a, may inhibit steroidogenesis in the adrenal cortex13, while stimulating central parts of the neuroendocrine axis. Taking into consideration that cytokines are also locally synthesized by the adrenal gland (TNF-a and IL-6 in the cortex; IL-1 in the medulla) and modify adrenal steroid synthesis and/or secretion, these cytokines could play a paracrine or autocrine role in the regulation of adrenal function14. In addition, cytokines may affect cortical steroidogenesis by modulating the synthesis and/or release of various neurotransmitters and neuropeptides (e.g., catecholamines, acetylcholine, serotonin, VIP, PACAP, CGRP, substance P, neuropeptide Y, opioids, galanin, CRH, ACTH) from adrenal nerve endings (e.g., splanchnic nerve) and/or medullary chromaffin cells15,16. Upon stimulation, the adrenal cortex releases not only cortisol but also the hormone dehydroepiandrosterone sulfate (DHEAS). DHEA, the major androgen secreted by the adrenal cortex, is transformed into its sulfuric acid ester, DHEAS (a compound with a half-life of several hours), and then converted again by the sulfatase enzyme to DHEA in target tissues such as brain, bone, breast, and adipose tissue. At the intracellular level, DHEA is further metabolized to various other steroids such as the androgens, androstenediol, testosterone, and dihydrotestosterone and the estrogens, estrone and 17-beta estradiol. In women, DHEA is the most important source of androgens. Therefore it is fair to say that in most cases, especially after the meno- and andropause, circulating androgen levels in women may be higher than those in men. DHEA is one of the most abundantly secreted steroids, whose physiological function in adult life is poorly understood. Recent studies have indicated that DHEAS levels in plasma are altered in several circumstances. DHEAS has been shown to have a role in adrenarche (early onset of puberty)17. In addition, DHEAS secretion declines steadily with age, one of the reasons why DHEAS levels have been linked to longevity, with low levels being "predictive" of mortality18. Interestingly, DHEA is a neurosteroid locally produced by the brain, where it exerts some neuroprotective action19. Moreover, as the authors point out, this hormone is also decreased in RA prior to disease onset and in HLA-identical siblings of patients with RA1. Unlike other major steroids, a receptor for DHEA(S) has not been isolated. The lack of a known receptor with the subsequent development of selective antagonists has limited our ability to understand the true physiological role of this hormone, beyond fetal life. Therefore, although this hormone is often used as an indicator of adrenal function, its true role remains to be determined. The study by Ernestam, et al has the major merit of being a longterm study (2-year duration) in a field typically characterized by shorter studies, as well as the merit of addressing an important question, the role of DHEA levels in RA. Their conclusions should, however, be taken with some caution for various reasons related to the design of this interesting study. First, the study was unblinded and not randomized. It is not clear how subjects were assigned to the 2 drugs, infliximab or etanercept, raising the question of selection bias in terms of disease severity and other factors in the 2 study groups. Second, studies of the neuroendocrine stress response in humans are fraught with potential methodological pitfalls because of various physiological and disease related confounding factors. These include the presence of inflammation, pretreatment with glucocorticoids, and the innate diurnal rhythms of these hormones. In this study, the characterization of the HPA axis was performed by means of single-timepoint determinations and over a wide window of time (8:00–13:00 h). However, HPA axis hormones fluctuate over 24 hours in a circadian fashion, and changes in cortisol levels over this time period could in part be related to circadian fluctuations. The characterization of the hypothalamic-pituitary-gonadal axis, similarly carried out by single-timepoint determinations, was further limited by the fact that it was performed only in a subgroup, 18 subjects, of the overall sample. In addition, the HPA axis is easily activated during experimental procedures including blood collection. The authors fail to mention the method of blood collection, which makes it difficult to determine whether the cortisol/ACTH levels reported are due to the stress of a needle stick, or accurately reflect the HPA axis status of the subjects. Further, the measurement of cortisol in patients receiving glucocorticoid treatment may not accurately reflect the status of HPA function. These confounding variables may explain why the data on DHEAS appear to correlate better with physical improvement than cortisol. That said, since most RA patients are or have been treated with glucocorticoids, it is almost impossible to perform a study in non-glucocorticoid-treated patients with RA. The study by Ernestam, et al informs the complex relationships between HPA axis function and inflammation by prospectively studying adrenal responses during the course of anti-TNF therapy. As predicted, DHEAS levels increased significantly after 1 and 2 years of treatment, and these levels also correlated with improved physical function. Interestingly, they did not correlate with clinical response or inflammatory markers. Other hormones measured, including cortisol, did not change over the period of the study. This suggests the intriguing possibility that the main beneficial effects of DHEAS may result from its general physiological effects rather than its antiinflammatory effects. There is a large body of literature claiming both improved energy levels and self-perceived well-being especially in elderly subjects in association with higher endogenous levels of DHEA(S) or in those receiving androgen replacement therapy for adrenal insufficiency20. However, apart from a few studies, solid evidence for a therapeutic role of DHEA is still lacking. Since the majority of these studies were uncontrolled in design and mostly observational in nature, it is difficult to draw any definitive conclusion from them. In conclusion, within the limitations listed above, the findings of Ernestam, et al, coupled with the stability of individual DHEAS measures, suggest that DHEAS may be a good marker for adrenal function in the context of active RA. Further, since in this study women with lower levels of DHEAS also showed a lower age of onset of RA, DHEAS may prove to be a prognostic indicator, if validated in larger studies. 2. Dantzer R, Kelley KW. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 2007;21:153-60. [MEDLINE] 3. Sternberg EM. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 2006;6:318-28. [MEDLINE] 4. Crofford LJ. The hypothalamic-pituitary-adrenal axis in the pathogenesis of rheumatic diseases. Endocrinol Metab Clin North Am 2002;31:1-13. [MEDLINE] 5. Silverman MN, Pearce BD, Biron CA, et al. Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol 2005;18:41-78. [MEDLINE] 6. Cutolo M, Sulli A, Pizzorni C, et al. Hypothalamic-pituitary-adrenocortical and gonadal functions in rheumatoid arthritis. Ann NY Acad Sci 2003;992:107-17. [MEDLINE] 7. Jessop DS, Harbuz MS. A defect in cortisol production in rheumatoid arthritis: why are we still looking? Rheumatology Oxford 2005;44:1097-100. [MEDLINE] 8. Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry 2003;160:1554-65. [MEDLINE] 9. Nance DM, Sanders VM. Autonomic innervation and regulation of the immune system (1987-2007). Brain Behav Immun 2007; April 26 E-pub ahead of print. 10. Straub RH, Harle P. Sympathetic neurotransmitters in joint inflammation. Rheum Dis Clin North Am 2005;31:43-59, viii. [MEDLINE] 11. Pavlov VA, Tracey KJ. The cholinergic anti-inflammatory pathway. Brain Behav Immun 2005;19:493-9. [MEDLINE] 12. Silverman MN, Miller AH, Biron CA, et al. Characterization of an interleukin-6- and adrenocorticotropin-dependent, immune-to-adrenal pathway during viral infection. Endocrinology 2004;145:3580-9. [MEDLINE] 13. Straub RH, Harle P, Sarzi-Puttini P, et al. Tumor necrosis factor-neutralizing therapies improve altered hormone axes: an alternative mode of antiinflammatory action. Arthritis Rheum 2006;54:2039-46. [MEDLINE] 14. Ehrhart-Bornstein M, Hinson JP, Bornstein SR, et al. Intraadrenal interactions in the regulation of adrenocortical steroidogenesis. Endocr Rev 1998;19:101-43. [MEDLINE] 15. Ait-Ali D, Turquier V, Grumolato L, et al. The proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1 stimulate neuropeptide gene transcription and secretion in adrenochromaffin cells via activation of extracellularly regulated kinase 1/2 and p38 protein kinases, and activator protein-1 transcription factors. Mol Endocrinol 2004;18:1721-39. [MEDLINE] 16. Ehrhart-Bornstein M, Bornstein SR, Scherbaum WA. Sympathoadrenal system and immune system in the regulation of adrenocortical function. Eur J Endocrinol 1996;135:19-26. [MEDLINE] 17. Cizza G, Dorn LD, Lotsikas A, et al. Circulating plasma leptin and IGF-1 levels in girls with premature adrenarche: potential implications of a preliminary study. Horm Metab Res 2001; 33:138-43. [MEDLINE] 18. Eskandari F, Cizza G. Cortisol, DHEA, the Holy Grail and the fountain of youth. J Endocrinol Invest 2002;25:753. [MEDLINE] 19. Charalampopoulos I, Alexaki VI, Tsatsanis C, et al. Neurosteroids as endogenous inhibitors of neuronal cell apoptosis in aging. Ann NY Acad Sci 2006;1088:139-52. [MEDLINE] 20. Arlt W, Callies F, Allolio B. DHEA replacement in women with adrenal insufficiency -- pharmacokinetics, bioconversion and clinical effects on well-being, sexuality and cognition. Endocr Res 2000;26:505-11. [MEDLINE]
|
