Endogenous opioid tone in patients with rheumatoid arthritis.

We have previously shown that there is deficient hypothalamic-pituitary-adrenal (HPA) responsiveness in rheumatoid arthritis (RA) patients. The basis for this deficient response is not known. The purpose of the project was to investigate whether the defective HPA response in RA patients is the result of increased endogenous opioid tone secondary to chronic pain which can suppress corticotrophin-releasing hormone (CRH) production. We conducted a double-blind placebo-controlled cross-over trial to study the effect of the opiate antagonist, naloxone, on psychometric function together with plasma adrenocorticotrophic hormone (ACTH), cortisol and prolactin. Seven RA patients with active and established disease and eight healthy controls were studied. Each received either a bolus i.v. infusion of 20 mg naloxone or normal saline. After at least 72 h, they received naloxone if they had previously received normal saline or vice versa. The pain score was statistically significantly higher at baseline in the RA group compared with controls (5.7 +/- 3.25 vs 0.35 +/- 0.21, P < 0.001). No difference was found in the other psychometric assessments throughout the study. Patients receiving normal saline did not show any significant change in cortisol or ACTH. Cortisol and ACTH showed a sharp and significant rise after naloxone treatment in both RA and normal subjects (P < 0.001 and P < 0.01), but no difference was observed between the two groups. The mean prolactin level showed no significant change in both groups after any treatment. We conclude that endogenous opioid tone does not appear to be a major contributor to the HPA defect in RA. However, the number of patients studied was small and this result will require confirmation from larger trials

Anti-CD4 monoclonal antibody treatment in acute and early chronic antigen-induced arthritis: influence on T helper cell activation

To examine the effects of anti-CD4 mAb treatment in acute and chronic antigen-induced arthritis (AIA), C57BL/6 mice were treated intraperitoneally either with the depleting anti-CD4 mAb GK1·5 or with rat-IgG (control) on Days −1, 0, 1, 3, 5, and 7. Arthritis was monitored by assessment of joint swelling and histological evaluation in the acute (Day 3) and the chronic phase (Day 21) of AIA. To determine the effects on cellular immune responses, in vivo T-cell reactivity (delayed type hypersensitivity; DTH) was measured, as well as protein levels of T(H)1- (IL-2, IFN-γ) and T(H)2-cytokines (IL-4, IL-10) in joint extracts and supernatants of ex vivo stimulated spleen and lymph node cells. The humoral immune response was analysed by measuring serum antibodies against methylated bovine serum albumine (mBSA) and extracellular matrix proteins. Treatment with GK1·5 reduced swelling, inflammation, and destruction of the arthritic joint. Unexpectedly, the effects were even more pronounced in the acute than in the chronic phase. The anti-inflammatory effect was accompanied by a diminished DTH against the arthritogen mBSA and a decrease of T(H)1-cytokine production in spleen and pooled body lymph nodes, whereas the T(H)2-cytokine production in these organs was unchanged and the humoral immune response was only moderately reduced. There was a failure of depleting CD4(+) T-cells in the joint, reflected also by unchanged local cytokine levels. Therefore, systemic rather than local effects on the T(H)1/T(H)2 balance appear to underlie the therapeutic efficacy of anti-CD4 treatment in AIA

Increased activation-induced cell death in peripheral lymphocytes of rheumatoid arthritis patients: the mechanism of action

Recently, we have described a soluble survival signal for activated lymphocytes from CD14(+) cells. As a result of the importance of T lymphocytes in the pathogenesis of rheumatoid arthritis (RA), we speculate a possible role for CD14(+) cells in supporting the outgrowth of autoreactive lymphocytes in RA. To address this issue further, supernatants from activated CD14(+) cells (CD14 cocktails) in both normal controls and RA patients were collected. The relative strength of the CD14 cocktails from normal controls and RA patients was compared. The data showed that depletion of CD14(+) cells resulted in a much higher increase of activation-induced cell death (AICD) and a decrease of lymphocyte proliferation in the peripheral blood mononuclear cells of RA patients compared to normal controls. Interestingly, CD14 cocktails from RA patients provide much stronger protection against AICD compared to those from normal controls. The observed soluble survival signal from CD14(+) cells is a general phenomenon because CD14 cocktails prevent both phytohaemagglutinin A-p- and anti-CD3-induced AICD. Furthermore, supernatants collected from human dendritic cell cultures also prevent activated lymphocytes from undergoing AICD. The data implicate an important role of the CD14(+) cell and its secreted form of survival signal in the pathogenesis of RA