Neuroendocrine, immunologic, and microvascular systems interactions in rheumatoid arthritis: physiopathogenetic and therapeutic perspectives

Semin Arthritis Rheum. 1999 Oct;29(2):65-81. doi: 10.1016/s0049-0172(99)80039-0.


Objective: To review the "core" systems interactions in rheumatoid arthritis (RA): neuroendocrine, immunologic, and microvascular, and to interpret an integrated physiopathogenesis of the disease, beginning at a preclinical phase of risk factors to the later stages of manifest clinical inflammation.

Methods: Publications on stress reactions, serum hormonal levels, biological mediators of inflammation and vascular alterations in RA during its preclinical phase, course of active disease, including pregnancy, and hormonal therapy of active disease were retrieved. In addition, experimental reports on biological models of the disease were considered. Levels of adrenal and gonadal steroids (ie, glucocorticosteroids [GCS], dehydroepiandrosterone [DHEA], its sulfate [DHEAS], estradiol [E2], and testosterone [T]), as well as prolactin (PRL) and other hormones, biological mediators, vascular endothelial system (VES) interactions with hormones, and immunologic mediators of inflammation in RA, were reviewed and interpreted.

Results: Women with premenopausal onset of RA not previously treated with GCS had lower basal serum levels of adrenal androgens, that is, DHEA or DHEAS, both before and after onset of clinical disease, compared with controls. Risk factors, including hormonal, immunologic, and hereditary indicators, were found to be uniformly present many years before clinical onset in such younger women, as compared with a frequency of circa 15% in matched controls. Also, a history of heavy cigarette smoking significantly predicted the onset of RA in perimenopausal women, and in men, suggesting that vascular endothelial alterations predispose to the disease. In the same prospective study, 1 or more of 4 risk factors were present an average of 12 years before clinical onset of disease in 83% of male RA cases versus 26% in matched controls (ie, sensitivity of 83% and specificity of 74%). Early RA patients may have lower serum cortisol levels than normal controls, and less than expected for the degree of ongoing inflammation, as well as having upregulated PRL levels.

Conclusion: Among persons genetically prone to RA, the "core" systems are hypothesized to become "remodeled" during a long preclinical phase as a result of chronic imbalances in their interactive homeostasis. This hypothesis needs to be critically assessed in further studies of such physiological precursors of disease as well as stressors in the development and course of RA. Optimal hormonal management of biological mediators of RA is also a priority challenge for disease control in the future.

Relevance: Evidence indicates that men and women who are susceptible to premenopausal onset of RA can each be identified long before their clinical onsets of disease, and that productive research in primary prevention is an achievable objective. Disease prevention objectives are central in the public health strategy of the National Arthritis Action Plan and of the US Public Health Service "Healthy People 2000" (and 2010 proposed). Success in such prevention goals can be expected to significantly reduce the enormous burden of this common disease, which affects all segments of the population.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / physiopathology*
  • Arthritis, Rheumatoid / therapy*
  • Chronic Disease
  • Cytokines / physiology*
  • Endothelium, Vascular / physiology*
  • Female
  • Glucocorticoids / therapeutic use
  • Homeostasis / physiology
  • Hormones / physiology*
  • Humans
  • Male
  • Microcirculation / physiology
  • Neurosecretory Systems / physiology*
  • Pregnancy
  • Risk Factors


  • Cytokines
  • Glucocorticoids
  • Hormones