Approaching the immunophysiology of steroid resistance

Wang and colleagues provide functional immunologic data on a molecular pathway for glucocorticoid resistance in systemic lupus erythematosus (SLE) [1]. Gluco corti-coids have broad and powerful eff ects on the immune response and, despite the advent of biologic therapies, remain the most important and frequently used immuno-suppressive agents in clinical practice [2]. Indeed, if it were not for their dose-limiting toxicity, glucocorticoids in all other respects would be ideal anti-infl ammatory agents: orally absorbed, rapidly acting, and highly eff ec-tive at shutting down a multitude of tissue-damaging, infl ammatory pathways. Despite the clinical success of disease-modifying agents, concomitant steroid use remains an integral part of eff ective therapy as well as an established means for controlling disease exacerbations. Among practitioners focused on infl ammatory 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. Th ese patients expectedly suff er most from the treatment-related com-pli cations 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 gluco-corticoids. Th is goal has gained additional prominence with the recognition that accelerated atherosclerosis is an attendant consequence of systemic infl ammation and a major cause of morbidity and mortality in rheumatoid arthritis and SLE [3]. Th e contributing eff ects of steroid-induced glucose intolerance and dyslipidemia add to the pathophysiology of atherogenesis and prompt continued investigation into more eff ective steroid-sparing agents and safer approaches to immunosuppression. Wang and colleagues provide evidence of a specifi c pathway for steroid resistance in patients with treatment-unresponsive SLE [1]. Th e authors investigated the expression and function of the immunoregulatory cyto-kine macrophage migration inhibitory factor (MIF), which shares a unique regulatory relationship with gluco-corticoids, in the peripheral blood monocyte responses of steroid-resistant SLE patients. Experimental work had previously estab lished that MIF counter-regulates the immuno suppres sive action of glucocorticoids on pro-infl ammatory cyto kine expression [4]. In human subjects, MIF circu lates in a diurnal rhythm in phase with corticosteroids, but it is rapidly upregulated by stress or infl ammatory stimuli [5]. Indeed, murine MIF was fi rst cloned from activated anterior pituitary cells [6] and a model soon emerged by which MIF, whether released from the neuroendocrine system or the immune system, acts in concert with circulating glucocorticoids to regulate …