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Interleukin-6, an inflammatory cytokine, is characterized by pleiotropy and redundancy of action. Apart from its hematologic, immune, and hepatic effects, it has many endocrine and metabolic actions. Specifically, it is a potent stimulator of the hypothalamic-pituitary-adrenal axis and is under the tonic negative control of glucocorticoids. It acutely stimulates the secretion of growth hormone, inhibits thyroid-stimulating hormone secretion, and decreases serum lipid concentrations. Furthermore, it is secreted during stress and is positively controlled by catecholamines. Administration of interleukin-6 results in fever, anorexia, and fatigue. Elevated levels of circulating interleukin-6 have been seen in the steroid withdrawal syndrome and in the severe inflammatory, infectious, and traumatic states potentially associated with the inappropriate secretion of vasopressin. Levels of circulating interleukin-6 are also elevated in several inflammatory diseases, such as rheumatoid arthritis. Interleukin-6 is negatively controlled by estrogens and androgens, and it plays a central role in the pathogenesis of the osteoporosis seen in conditions characterized by increased bone resorption, such as sex-steroid deficiency and hyperparathyroidism. Overproduction of interleukin-6 may contribute to illness during aging and chronic stress. Finally, administration of recombinant human interleukin-6 may serve as a stimulation test for the integrity of the hypothalamic-pituitary-adrenal axis.

Glucocorticoids are pleiotropic hormones that at pharmacologic doses prevent or suppress inflammation and other immunologically mediated processes. At the molecular level, glucocorticoids form complexes with specific receptors that migrate to the nucleus where they interact with selective regulatory sites within DNA; this results in positive and negative modulation of several genes involved in inflammatory and immune responses. At the cellular level, glucocorticoids inhibit the access of leukocytes to inflammatory sites; interfere with the functions of leukocytes, endothelial cells, and fibroblasts; and suppress the production and the effects of humoral factors involved in the inflammatory response. Clinically, several modes of glucocorticoid administration are used, depending on the disease process, the organ involved, and the extent of involvement. High doses of daily glucocorticoids are usually required in patients with severe diseases involving major organs, whereas alternate-day regimens may be used in patients with less aggressive diseases. Intravenous glucocorticoids (pulse therapy) are frequently used to initiate therapy in patients with rapidly progressive, immunologically mediated diseases. The benefits of glucocorticoid therapy can easily be offset by severe side effects; even with the greatest care, side effects may occur. Moreover, for certain complications (for example, infection diathesis, peptic ulcer, osteoporosis, avascular necrosis, and atherosclerosis), other drug toxicities and pathogenic factors overlap with glucocorticoid effects. Minimizing the incidence and severity of glucocorticoid-related side effects requires carefully decreasing the dose; using adjunctive disease-modifying immunosuppressive and anti-inflammatory agents; and taking general preventive measures.

The molecular and biochemical bases for interactions between the immune and central nervous systems are described. Immune cytokines not only activate immune function but also recruit central stress-responsive neurotransmitter systems in the modulation of the immune response and in the activation of behaviors that may be adaptive during injury or inflammation. Peripherally generated cytokines, such as interleukin-1, signal hypothalamic corticotropin-releasing hormone (CRH) neurons to activate pituitary-adrenal counter-regulation of inflammation through the potent antiinflammatory effects of glucocorticoids. Corticotropin-releasing hormone not only activates the pituitary-adrenal axis but also sets in motion a coordinated series of behavioral and physiologic responses, suggesting that the central nervous system may coordinate both behavioral and immunologic adaptation during stressful situations. The pathophysiologic perturbation of this feedback loop, through various mechanisms, results in the development of inflammatory syndromes, such as rheumatoid arthritis, and behavioral syndromes, such as depression. Thus, diseases characterized by both inflammatory and emotional disturbances may derive from common alterations in specific central nervous system pathways (for example, the CRH system). In addition, disruptions of this communication by genetic, infectious, toxic, or pharmacologic means can influence the susceptibility to disorders associated with both behavioral and inflammatory components and potentially alter their natural history. These concepts suggest that neuropharmacologic agents that stimulate hypothalamic CRH might potentially be adjunctive therapy for illnesses traditionally viewed as inflammatory or autoimmune.

Study Objective: To assess the efficacy and toxicity of cyclosporin A in patients with severe, treatment-refractory rheumatoid arthritis., Design: Prospective randomized, double-blind 6-month trial., Patients: Thirty-one patients who had classic seropositive rheumatoid arthritis with active synovitis unresponsive to conventional therapy., Interventions: Patients were randomly assigned to high-dose (10 mg/kg body weight.d) or low-dose (1 mg/kg.d) cyclosporin A therapy. A reduction in the dose was permitted for adverse side effects. After 6 months of therapy, patients who showed clinically relevant improvement, defined as a 40% or greater reduction in their total joint activity score, were given the option to continue receiving the therapy for an additional 6 months., Measurements and Main Results: At 6 months, clinically relevant improvement occurred in 10 of 15 patients (95% CI, 38 to 88) receiving high-dose therapy and in 4 of 16 patients (CI, 7 to 52) receiving low-dose therapy (P = 0.02). Statistically significant improvements in individual measures were shown only in the high-dose group. Improvements were noted in the number of tender joints (-18.8; CI, -24.5 to -13.1) and swollen joints (-12.1; CI, -15.4 to -8.6), as well as in physician's global scores (-1.5; CI, -2.1 to -0.9) and patient's global scores (-1.1; CI, -1.9 to -0.5). Improvement in disease activity was maintained through 12 months in the high-dose group. The clinical responses to cyclosporin A were most evident in patients with depressed in-vitro proliferative responses of peripheral blood mononuclear lymphocytes to soluble recall antigens. Toxicities, such as fatigue, gastrointestinal and neurologic complaints, and hypertrichosis were frequent but often reversible with a reduction in the dose. Nephrotoxicity, with a 20% increase in the serum creatinine level, was seen in 27 of 31 patients (CI, 71 to 97)., Conclusions: Cyclosporin A is an effective therapy for severe, treatment-refractory rheumatoid arthritis. Side effects, particularly nephrotoxicity, are common.

Rheumatoid arthritis is a chronic inflammatory synovitis that primarily involves peripheral diarthrodial joints. Immunohistologic analysis of diseased synovium has shown a spectrum of abnormalities that resemble various stages of a cell-mediated, or delayed-type, immune reaction. The infiltrating mononuclear cells produce various factors that modulate adjacent tissues and appear to produce the characteristic destructive features of the disorder. Our understanding of the mechanisms of action of various therapeutic modes also indicates that the disease is primarily mediated by activated mononuclear cells. All effective therapies have been shown to affect either mononuclear cell function or the rates of production or elimination of these cells. The disorder likely represents the pathologic expression of a genetically controlled host immune response to an undefined causative stimulus. The stimulus could be an infectious agent(s), a product(s) derived from an infectious agent(s), a constituent(s) of synovial or connective tissue, or a combination of these.