Precision medicine has attracted great attention in oncology, and rightly so. Sophisticated research studies have defined the errors in chemical pathways that transform healthy cells to tumor cells, driving the discovery of targeted therapies that, in some cases, have resulted in dramatic cures. Advances in treating patients with the chronic autoimmune and inflammatory diseases that our rheumatologists see at Hospital for Special Surgery (HSS), however, have come more slowly. But the daily interactions among our clinicians and researchers, along with the dedication of our highly engaged patients, have provided an ideal environment for gaining new knowledge about the biology of these challenging diseases, and this distinctive integrated approach plays a critical role in progress toward important scientific discoveries. Research is now underway to define the relevant molecular pathways that confer distinct clinical features in each patient, and we are collaborating with experts in drug development to translate knowledge gained from our studies into more targeted treatment for patients.
Rheumatologists at HSS have a long history of partnering with patients to study their diseases and improve the lives of future generations of patients. Rheumatoid arthritis (RA) and systemic lupus erythematosus (lupus) are two relatively common, severe autoimmune diseases that are a focus of care and research at our institution. RA and lupus are chronic and life-altering conditions – they cause severe disability, affect one’s quality of life, and are associated with increased risk of early death. These disorders entail distinct flaws in the function and regulation of the immune system, leading to inflammation that damages tissues. In addition, the course of both diseases is difficult to predict and, particularly in patients with lupus, the disease manifests differently from patient to patient. The heterogeneity of disease features suggests that knowledge of an individual’s biology will ultimately offer precision approaches to patient management.
At HSS, physician scientists and rheumatologists work together to identify patients for participation in our research studies and to collect long-term clinical and biologic data as the disease activity waxes and wanes. This information will help us to better predict the course of disease, and identify biomarkers of disease activity and new therapeutic targets. Our ultimate goal is to use this knowledge to predict and prevent disease flares, or even to identify those at risk of disease in order to prevent its development. The trick is to understand the underlying genetics and biology of the individual patient, as genetics, environmental triggers and chance conspire to alter the immune system in a slightly different manner in every patient with RA or lupus. If we are successful in unravelling the underlying biology in individuals or groups of patients with similar disease mechanisms, we can apply this knowledge to treat each patient with the most appropriate and effective medications.
In 2014, HSS was named a participating center in the National Institutes of Health Accelerating Medicines Partnership Program, a public-private partnership developed to transform the current model for identifying and validating the most promising biological targets for the development of new drugs and diagnostics. Our investigators have made important contributions to understanding how inflammatory mediators contribute to disease through the so-called Jak-STAT molecular pathway. The knowledge generated from this research has provided support for development of oral Jak inhibitors that are now approved for treatment of patients with RA. (Jak is an acronym for “Janus kinases”, or small proteins involved in intracellular signaling that trigger inflammatory immune system responses).
Lupus research at HSS also has relevance to understanding and improving treatments for many other diseases. The clinical features of lupus affect nearly all organ systems, and virtually all components of the immune system behave abnormally. In general, patients with lupus develop many features consistent with what is seen in chronic viral infections, although no virus has been identified as an etiologic agent. Our longitudinal patient data registries and detailed molecular studies have identified the type I interferon pathway as central to the disease and the complement pathway as a key mechanism that contributes to tissue damage and the poor pregnancy outcomes that lupus patients can experience. Additional molecular pathways active in some patients have been identified, and it is the unique combination of pathways implicated in a given patient that informs our thinking about optimal approaches for treatment of each individual. HSS laboratory studies are providing the groundwork for our pharmaceutical industry partners to extend our observations toward new drug development.
Precision medical management of RA and lupus are still in the future, but we believe the approach being taken by HSS rheumatologists will lead the way to availability of more effective therapies and more rational targeting of available therapies based on an individual patient’s biology. We are excited to be participants in providing that future for our patients.Mary K. Crow, M.D., is Physician-in-Chief and Chair of the Department of Medicine at Hospital for Special Surgery and is Chief of the Division of Rheumatology at HSS and NewYork-Presbyterian/Weill Cornell Medical Center.