Summary
Background : Steroid resistance represents a major clinical problem in the treatment of ulcerative colitis. In vitro, interleukin‐2 renders lymphocytes steroid resistant.
Aim : To explore the therapeutic potential of interleukin‐2 receptor blockade in steroid‐resistant ulcerative colitis with both in vitro measures and a pilot in vivo study.
Methods : Ten patients with steroid‐resistant ulcerative colitis received a single bolus of 40 mg of intravenous basiliximab plus steroid treatment in an open‐label, uncontrolled, 24‐week study. The outcome was assessed using the Ulcerative Colitis Symptom Score, rectal biopsy and Inflammatory Bowel Disease Questionnaire. Lymphocyte steroid sensitivity was measured in vitro in 39 subjects in the presence or absence of basiliximab.
Results : Nine of the 10 patients achieved clinical remission within 8 weeks. At 24 weeks, seven patients were in clinical remission. Marked improvement in the Ulcerative Colitis Symptom Score was seen by 1 week (P = 0.004) and on rectal biopsy and Inflammatory Bowel Disease Questionnaire by 2 weeks (both P < 0.05). Improvements persisted to 24 weeks (Ulcerative Colitis Symptom Score, Inflammatory Bowel Disease Questionnaire, both P < 0.005). Eight of the nine responders relapsed (median, 9 weeks), but remission was re‐achieved with further corticosteroids and the addition of azathioprine. At 24 weeks, seven patients were in full clinical remission, five off all steroid therapy. In vitro measurement of lymphocyte steroid sensitivity demonstrated steroid resistance in 22% of subjects. All were rendered steroid sensitive in the presence of basiliximab.
Conclusions : Basiliximab appears to be effective at inducing remission in steroid‐resistant ulcerative colitis. In vitro, basiliximab also produced a dramatic increase in lymphocyte steroid sensitivity in healthy subjects. Confirmation in randomized controlled studies is required.
Up to 30% of patients with autoimmune, allergic, and lymphoproliferative diseases are refractory to glucocorticoid therapy. The present study was undertaken to investigate whether such steroid resistance (SR) is limited to a subpopulation of CD4+ T cells and, as IL-2 is a putative driver of SR, whether T cell SR is associated with CD25 expression. We show that SR patients have a characteristic subgroup of activated CD4+ T cells that continue to proliferate despite exposure to high-dose Dexamethasone (Dex), demonstrate that CD4+CD25− cells are exquisitely sensitive to Dex whereas CD4+CD25int cells are highly SR, and further find that the combination of an anti-CD25 mAb with Dex enhances suppression of T cell proliferation compared with each agent alone. We therefore conclude that SR is not a general property of all lymphocytes but resides in T cell subpopulations, which are prevalent in SR patients and express intermediary levels of CD25. As a result, we propose a new paradigm for SR disease in which glucocorticoid therapy positively selects SR cells, generating a population of drug-resistant lymphocytes that perpetuate on-going inflammation.
Acute upper-gastrointestinal bleeding is a common indication for emergency admission to hospital. Risk-stratification scores have been devised to identify patients at risk of re-bleeding or death, but these have usually required both clinical and endoscopic assessment. Two recent studies have employed clinical criteria alone to identify low-risk patients that may not require admission or in-patient endoscopy. While each of these studies has individual merit, both are unable to answer the question of whether risk stratification improves health outcomes or resource use in acute gastrointestinal haemorrhage. They will nevertheless help the development of guidelines that enable patients to be managed more efficiently and outcomes to be compared more fairly.
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