EDITORIAL - The neuroendocrine system and RA: insights from anti-TNF-alpha therapy

[Guest guest]

Journal of Rheumatology

July 2007

Editorial

--------------------------------------------------------------------------------

The Neuroendocrine System and Rheumatoid Arthritis: Insights from

Anti-Tumor Necrosis Factor-a Therapy

ESTHER M. STERNBERG, MD,

Chief, Section on Neuroendocrine Immunology and Behavior,

Integrative Neural Immune Program,

Director, National Institute of Mental Health,

National Institutes of Health,

Rockville, land;

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, land;

GIOVANNI CIZZA, MD,

Clinical Endocrinology Branch,

National Institute of Diabetes, Digestive and Kidney Disorders,

National Institutes of Health,

Bethesda, land, USA

--------------------------------------------------------------------------------

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.

***************************************************************

Read the entire editorial here:

http://www.jrheum.com/subscribers/07/07/1443.html

--

Not an MD