Lupus is a complicated illness in which the immune system becomes disorganized and over-stimulated. Advances in science have made it possible to understand several ways in which tiny proteins and interacting immune cells become out of balance. We now understand that the exact way this happens may differ from patient to patient. Because of this, it has been difficult to test new treatments for lupus, which may work on only a subset of patients and may require different doses for each patient. To make things more difficult, most clinical trials of new treatments are adding them on to various background medications, and it is not always safe for the patients to just take these away.

Most standard treatments, including those used as background treatments in clinical trials, are not approved for lupus by the FDA and thus are not as precisely studied as treatments that have succeeded in going through a rigorous drug approval process. We know how these medications are supposed to work, and we know something about their impact on the other diseases we borrow them from, but the details of how this plays out in the special immune disorder of lupus are poorly understood.

The DoD has called for grant applications that focus on the variability of lupus. This particular project is looking at an aspect of "precision" medicine, improving the ability to pick out and optimize treatments for individuals who may not be identical to all other lupus patients. The goal is to begin the important work of better understanding the common, standard drugs used for lupus, how to determine who the drugs will work best for, and defining how the drugs work for those individuals. We will use blood samples donated by lupus patients who were participating in clinical trials during the past few years. We will compare the exact ways in which methotrexate and other immune-regulating treatments work in subsets of lupus, using new insights in how to sort these types of patients based on the manner in which their immune systems are activated. One of the trials we will obtain materials from is actually a clinical trial of methotrexate in which patients have donated samples we can use to track, over time, the immune system changes that occur in people who do or do not respond to the treatment.

We are applying new scientific approaches to study drugs that have been around for a long time and that can now be better understood. By doing so, we can help people with lupus in two key ways: (1) we can design more successful clinical trials by picking the right background treatment that will not be likely to interfere with the new treatment being studied; and (2) we can help clinics to choose available standard treatments that would more likely help a given individual. This leads to a little less trial and error in how we prescribe medicine. To this end, we expect to obtain preliminary data on several drugs and complete a more focused study of methotrexate within three years.