This study is intriguing to rheumatologists for a number of reasons. First, it demonstrated the benefit of a vaccination strategy in an established human autoimmune disease. Most often, these trials show efficacy in animal models of human disease but fail when adapted to patients with established disease. Second, the BCG vaccine stimulated the release of an adequate concentration of TNF to generate the desired effect on the innate immune system. In the past, controlling the scope of TNF release using experimental therapies has been very challenging, limiting its use as an experimental therapy. Third, perhaps these results should make us think about what effect, if any, our use of the anti-TNF therapies may have on the course of type I diabetes. Just thinking, slowly.
Can Stress Promote Cancer Metastases?
This is an intriguing question that a group of researchers at Vanderbilt University in Nashville recently attempted to answer. Using a mouse model of breast cancer bone metastasis, they demonstrated that activation of sympathetic nerves, which is typical in chronic stress or depression, promoted the colonization and establishment of metastatic cancer cells within the bone marrow, resulting in an increase in bone osteolytic lesions.8 This effect was mediated via a β-adrenergic receptor–dependent response of the host bone marrow stroma to catecholamines, which are released upon sympathetic activation, and via the promigratory activity of RANKL, a cytokine that is known to promote bone resorption.
Interestingly, blocking sympathetic activation with a β-blocker, or blocking RANKL signaling in cancer cells, inhibited the stimulatory effect of sympathetic activation on bone metastasis in this mouse model. It may come as a bit of a surprise to learn that the sympathetic nervous system (SNS) can play an important role in determining the development of metastases. Since the SNS pathways extend to the bone marrow and the bone cortex, they may provide the mechanistic link between stress and the spread of cancer. A number of preliminary clinical studies have confirmed a potential role for beta blockade as an adjuvant therapy for the prevention of metastases in patients with breast, ovarian, and hepatocellular cancers.9
Seeing Things Differently
We are just beginning to understand some of the ways our bodies work in health and disease. As we attempt to make further progress in unraveling the vexing illnesses that constitute the field of rheumatology, we need to “think slow and think different.” I believe that, as a discipline, we are already thinking this way. This approach has been transformative; after it failed as a treatment for septic shock, who would have predicted that anti-TNF therapy would have such a profound impact on the management of RA? Without this way of thinking, would researchers have discovered that the inflammasome serves as a key activator of inflammation in diseases as diverse as Crohn’s disease and gout? Who would have cared about the citrullination of the amino acid arginine and why this chemical reaction matters in the pathogenesis of RA? (For a more detailed discussion of this topic, please read the “Rheum with a View” article by Richard Panush, MD, in the September 2012 issue of The Rheumatologist, p. 40.)
