Approaching the immunophysiology of steroid resistance

In the current issue of Arthritis Research & Therapy, Wang and colleagues provide functional immunologic data on a molecular pathway for glucocorticoid resistance in systemic lupus erythematosus (SLE) [1]. Glucocorticoids have broad and powerful effects on the immune response and, despite the advent of biologic therapies, remain the most important and frequently used immunosuppressive agents in clinical practice [2]. Indeed, if it were not for their dose-limiting toxicity, glucocorticoids in all other respects would be ideal anti-inflammatory agents: orally absorbed, rapidly acting, and highly effective at shutting down a multitude of tissue-damaging, inflammatory pathways. Despite the clinical success of disease-modifying agents, concomitant steroid use remains an integral part of effective therapy as well as an established means for controlling disease exacerbations.Among practitioners focused on inflammatory disorders, whether rheumatologic or nonrheumatologic, there has long been the observation that some patients respond poorly to steroids or require high doses and prolonged treatment for disease control. These patients expectedly suffer most from the treatment-related complications of glucose intolerance, hypertension, obesity, osteoporosis, and myopathy. Even among patients maintained on low doses, the therapeutic objective remains the absolute minimalization or discontinuation of glucocorticoids. This goal has gained additional prominence with the recognition that accelerated atherosclerosis is an attendant consequence of systemic inflammation and a major cause of morbidity and mortality in rheumatoid arthritis and SLE [3]. The contributing effects of steroid-induced glucose intolerance and dyslipidemia add to the pathophysiology of atherogenesis and prompt continued investigation into more effective steroid-sparing agents and safer approaches to immunosuppression.Wang and colleagues provide evidence of a specific pathway for steroid resistance in patients w