Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytes

Abstract

Background-Up to 29% of patients with severe ulcerative colitis (UC) fail to respond to steroid treatment and require surgery. Previous studies have failed to show a clear correlation between failure of steroid treatment in severe UC and measures of disease severity. The reasons for treatment failure therefore remain unknown. Aim-To investigate the hypothesis that patients with severe UC who fail to respond to steroid treatment have steroid resistant T lymphocytes. Methods-Eighteen patients with severe UC were studied. After seven days' treatment with high dose intravenous steroids they were classified as complete responders (CR), incomplete responders (IR), or treatment failures (TF). Within 48 hours of admission blood was taken and the antiproliferative eVect of dexamethasone on phytohaemagglutinin stimulated peripheral blood T lymphocytes was measured. Maximum dexamethasone induced inhibition of proliferation (I max ) was measured. Results-In vitro T lymphocyte steroid sensitivity of TF and IR patients was significantly less than that of CR patients. Both TF and 3/5 IR patients had an I max of less than 60%; all CR patients had an I max of greater than 60%. No significant correlation was seen between response to treatment and disease severity on admission. When in vitro T lymphocyte steroid sensitivity was remeasured three months later, there was no diVerence between the groups. Conclusions-Results suggest that T lymphocyte steroid resistance is an important factor in determining response to steroid treatment in patients with severe UC and may be more predictive of outcome than disease severity. (Gut 1999;45:382-388)

Theophylline improves steroid sensitivity in acute alcoholic hepatitis

“…7 This implies that steroid resistance is unlikely to be overcome simply by increasing the steroid dose. The clinical marker of any fall in bilirubin by day 7 on treatment (ECBL) has been shown to identify patients who are clinically steroid responsive, with a 95% 6-month survival after treatment, as opposed to those with no fall in bilirubin Fig.…”

“…7,[14][15][16] Lymphocyte proliferative responses to liver-derived antigens are a feature of human alcoholic liver disease, 17 and steroid therapy is effective in a proportion of patients with AAH.…”

“…Proliferative response was plotted against dexamethasone concentration, a curve was fitted, and the maximum inhibition of proliferation (I max ) and the concentration of dexamethasone required to achieve 50% of maximal inhibition (IC 50 ) were calculated (Prism 4; Graph Pad, La Jolla CA). 7 Mean (6standard error) I max was compared between groups using the Mann-Witney U test (unpaired observations) and Wilcoxon signed-rank test (paired observations).…”

“…It has been well characterized in inflammatory skin diseases and ulcerative colitis, where it is evident as a reduced maximum inhibitory effect of dexamethasone on ex vivo phytohemagglutininstimulated lymphocyte proliferation. 7 Its prevalence is higher in chronic obstructive pulmonary disease (COPD), in which it has been shown to result from smoking-induced abnormalities in transcriptional regulation of pro-inflammatory genes (through reduced capacity of the glucocorticoid receptor to recruit histone deacetylases (HDACs) to actively transcribed proinflammatory genes because of the inhibitory effect of smoking-induced oxidative stress 8 ). The traditional bronchodilator theophylline was shown to counteract this effect, exerting an anti-inflammatory effect by improving HDAC recruitment to silence pro-inflammatory genes, 9 even at 10 À5 M, a concentration at which clinically useful bronchodilator effects do not occur.…”

CD4+CD25int T Cells in Inflammatory Diseases Refractory to Treatment with Glucocorticoids

“…Impaired in vitro responses to the synthetic GC dexamethasone (Dex) have been observed in PHA stimulated PBMCs from patients with steroid resistant (SR) asthma, SR UC, and SR rheumatoid arthritis, as well as SR renal transplant recipients (7)(8)(9)(10). There is now accumulating evidence that disparities in IL-2 responses to GCs are central to the SR phenotype.…”