The effects of cytokines on suppression of lymphocyte proliferation by dexamethasone.

Treatment failure occurs in up to 30% of patients treated with steroids for inflammatory diseases. The aim of this study was to explore the potential role of 21 cytokines in steroid-resistant inflammatory disease and to develop methods to restore steroid sensitivity through cytokine manipulation. The dexamethasone inhibition of lymphocyte proliferation assay correlates with the outcome of steroid therapy in ulcerative colitis (UC) and other inflammatory diseases. Using this assay, PBMC production of 21 cytokines, assayed by cytokine bead array, was correlated with percentage of suppression of proliferation by 10(-6) M dexamethasone (Imax) in 26 healthy volunteers. Effects of the addition of exogenous cytokines to induce steroid resistance in PBMCs from healthy volunteers and cytokine blockade to improve steroid sensitivity in PBMCs from patients with steroid-resistant UC were then explored. Production of IL-1alpha, IL-10, IL-17, IFN-gamma, G-CSF, GM-CSF, TNF-alpha, and IFN-inducible protein 10 (IP-10) correlated significantly with in vitro steroid sensitivity; however, only IL-2 and TNF-alpha reduced steroid sensitivity when added exogenously. Addition of IL-10 enhanced steroid suppression. Immunoneutralization or receptor blockade of IL-2, but not TNF-alpha, IFN-gamma, IL-4, IL-17, or IP-10 increased steroid sensitivity in cells from steroid-resistant UC patients. Neutralization of IL-10 reduced steroid sensitivity. Of the large panel of cytokines studied, IL-2 appears to have the greatest antagonistic effect on the antiproliferative effect of steroids. These data suggest that IL-2 inhibition in vivo may improve the response to steroids in steroid-resistant individuals.

Patients over 45 years with iron deficiency require investigation.

BACKGROUND: Iron deficiency anaemia (IDA) that occurs in patients above the age of 45 years is often caused by gastrointestinal blood loss, and guidelines on the appropriate investigation of these patients have been published. There are few data regarding patients with iron deficiency who are not anaemic and it is not clear how these patients should be managed. OBJECTIVES: We set out to investigate the hypothesis that similar pathologies are likely to underlie iron deficiency and IDA, and to assess whether IDA was being investigated according to the guidelines published by the British Society of Gastroenterology (BSG). METHODS: The pathology computer identified 153 consecutive patients over the age of 45 years who had serum ferritin levels below 20 microg/dl (normal range 20-200 microg/dl) in a 2 month period (i.e., October and November 2000). Medical records were examined and we recorded all investigations, the diagnoses reached, and the investigating specialty. The results were compared using odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The study shows that the causes of iron deficiency and IDA are similar, but IDA is investigated more thoroughly than iron deficiency, OR 2.07 (CI 1.08-3.97). Ten patients with iron deficiency without anaemia were found to have coeliac disease, a significant result, OR 6.71 (CI 1.38-32.6). The majority of patients with IDA are not under the care of a gastroenterologist and this group are significantly less likely to be investigated according to the BSG guidelines, OR 0.15 (0.04-0.6). CONCLUSIONS: The study shows that the yield of investigation of iron deficiency is high and, hence, it should be investigated in all patients over the age of 45 years. Despite guidelines published by the BSG, IDA is investigated sub-optimally and measures other than the issuing of guidelines are needed to change practice.