12:30 PM

What Drives Lupus and What are Potential Treatment Approaches?

Systemic lupus erythematosus (known as lupus) is a chronic disease in which the body generates an immune response to its own cells. This causes inflammation that can affect tissues such as the skin, the joints, and many different organs such as the kidneys, heart, and brain. In my recent review article in the Annals of the Rheumatic Diseases, called “Pathogenesis of Systemic Lupus Erythematosus: Risks, Mechanisms, and Therapeutic Targets,” I discuss recent insights into the causes and drivers of lupus as well as treatment approaches.

 For roughly 50 years, lupus has been recognized as a disease that involves the immune system. In the 1960s, investigators made important discoveries about the autoantibodies that are hallmarks of the disease, how they function, and what they react to. Further studies of the immune system in general added understanding of changes in certain immune cells that contribute to lupus. For example, research on the function of immune cells such as T cells and B cells allowed for understanding how autoantibodies are produced and contribute to lupus.

 Over the last several decades, researchers have discovered that cytokines, a type of protein, are key components in the body’s response to infection. They provide chemical signals to immune system cells that help them eliminate other cells infected with bacteria or viruses, but in rheumatic diseases, cytokines can play a role in inflammation. For example, in rheumatoid arthritis, cytokines were found to activate cells in the lining of joints, resulting in joint swelling and damage to healthy tissues like cartilage.

 In the early 2000s, researchers including myself discovered that cytokines called interferons are significant players in lupus. Normally, interferons orchestrate a response to virus infection. But in people with lupus, interferon levels are elevated and cause inflammation in many parts of the body. In a healthy situation, a virus infection will stimulate rapid production of interferons, then go back to normal in several days; however, in most lupus patients, interferon levels remain elevated for months and years. Researchers have also identified many lupus-associated genetic changes that affect molecular pathways involved in the development of lupus, including the interferon pathway. Any one of these common genetic variants has a modest effect on risk of disease, but when multiple variants occur in an individual, risk of disease is significantly increased.

 Based on what has been learned about the mechanisms involved in lupus over the last 20 years, researchers have made great efforts to develop new drugs to more effectively treat the disease. Roughly ten years ago, the FDA approved belimumab, which blocks the activity of a molecule called BAFF (B-cell activating factor) that drives B cells to become active and contributes to their ability to make damaging autoantibodies. A year and a half ago, the FDA approved anifrolumab, an antibody that blocks the cell surface receptor for the type I interferons that are particularly elevated in lupus patients.

 Lupus research is conducted by investigators around the world, with many opportunities for progress being pursued. Sunlight, for example, can trigger flares of lupus, but we don’t really understand why. One possibility is that the ultraviolet rays of sunlight could damage DNA. Studies have supported an association between herpes virus, particularly Epstein-Barr virus, and lupus, and researchers have been working out the mechanisms. My laboratory has investigated the possibility that virus-like sequences in DNA, called genomic retroelements, can sometimes result in production of interferon in patients with lupus. There are currently many ongoing studies aimed at understanding why the interferon pathway is activated in lupus patients or why the body produces autoantibodies.

 Clinical drug development studies have exploded in recent years, with candidate drugs focused on many immune components involved in the disease. Rituximab, for example, which is approved for other uses, is sometimes used for lupus patients. Rituximab depletes B lymphocytes, which are the cells that make autoantibodies. Future drugs will aim to achieve optimal B cell depletion or reduce the function of interferon-producing cells. Other drugs that inhibit cellular signaling pathways involved in lupus are being developed, some of which may be administered as a pill rather than as an injection. I believe that multiple components of the immune response represent rational therapeutic targets for treatment of patients with lupus, and in the end, it may be necessary to target several parts of the immune system to achieve long-lasting responses or even cure. One approach of great current interest is administration of CD19-CAR T cells, a novel therapy that involves modification of a patient’s T cells followed by injection of those cells back into the body. A study of a small number of patients with lupus nephritis, a form of disease that involves the kidneys, has shown impressive responses that last as long as a year. Longer studies are necessary to fully assess the efficacy of the CAR T cell approach. Furthermore, some research is focused on why some patients develop disease of the vasculature, kidneys, heart, spleen, skin, and brain while others do not, drawing attention to alterations in cells outside of the immune system that impact the vulnerability of those organs for developing chronic damage.  

 Lupus is very variable in how an individual person will react to having the disease, even given the same degree of immune system activation. Though people do better with lupus now than they did 50 years ago, they can be quite damaged by the disease, and experience severe organ involvement, such as kidney failure or cardiovascular disease. Even those patients who do not experience organ damage can report life-altering symptoms such as fatigue and what they describe as “brain fog”.

 Because so much of the immune system is involved in lupus, studying lupus patients has taught us a lot about the immune system that can be applicable to many other diseases that rheumatologists treat, as well as about how the immune system responds in the setting of infection or cancer. An example of that is COVID-19; there was a lot of study of the immune system in people who got sick with COVID. This created an opportunity to relate that data on how the immune system was behaving to what we have been studying in lupus.

 My research efforts are focused on better understanding the underlying biology that results in the development of lupus and its complications. This includes the contributions of genetic risk factors, understanding what activates the immune system and results in the autoimmunity characteristic of lupus, and how patients can be characterized based on their unique immune response and disease symptoms. The overall objective is to gain enough new information that we can propose targets for more effective therapies, ultimately improving the lives of patients. More specifically, our current research is defining differences between those patients who maintain high levels of interferon chronically and those patients who only increase their interferon levels at times of disease flare. Other current projects include defining the immune mechanisms that are associated with different specificities of autoantibodies, understanding the molecular pathways that trigger flares of lupus nephritis, and understanding genetic risks for chronic inflammation in lupus.

 Despite all we’ve learned, we still have a lot of work to do to understand what drives lupus, what activates the immune system, and what causes organ vulnerabilities. If we understand the mechanisms of the disease, the whys and what’s of the immune system becoming altered in its behavior, then we will have relevant ideas of what would be good approaches for development of novel therapies. There are many points of attack for this disease that are being considered and tested in clinical trials, so there is a lot of optimism that some of these will pan out as effective and relatively safe.

 — Mary Crow, MD, physician-in-chief emerita and senior scientist at the HSS Research Institute