Chances are, you either know someone or are someone who suffers from an autoimmune condition. In the US, an estimated 15 million people have one, and nearly 70 percent of that group are women. Autoimmune disease is not a single condition but hundreds of chronic disorders that can arise at any age and affect almost every organ in the body. All autoimmune diseases exist on a spectrum of severity, and some can be managed effectively with relatively benign medications. But many require powerful immunosuppression — and even then, some patients face the risk of permanent organ damage and, in some cases, death. Within this broad and complex category are diseases such as lupus, myositis, and scleroderma, which are often severe, difficult to manage, and potentially fatal.
While autoimmunity is relatively common, many individual diseases still have no cure, largely because there’s still quite a bit of mystery surrounding their cause. According to Vivek Nagaraja, M.B.B.S., M.D. and Chair for the Division of Rheumatology at Mayo Clinic in Phoenix, Arizona, autoimmune diseases occur when the body mistakenly attacks its own cells, either targeting a single organ, or in cases of rheumatic or systemic autoimmune diseases, attacking multiple organs.
“We know that autoimmune diseases are much more prevalent in women, but the why is still a mystery,” said Dr. Nagaraja. “Could it be hormones? Chromosomal impact? Is it related to menstruation or menopause? The immune system is an incredibly complex network, and we just don’t have answers to a lot of these questions. With no uniform screening test for these diseases, we often have to rely on information we get from patients.”
As a rheumatologist, Dr. Nagaraja treats patients with some of the most severe autoimmune diseases, with a special interest in scleroderma and myositis. He directs the Scleroderma Program at Mayo Clinic Arizona.
In patients with scleroderma the body overproduces collagen, resulting in a hardening of the skin and, at times, the internal organs, blood vessels, and connective tissue. Myositis causes muscle inflammation that can lead to skeletal muscle damage and, in some cases, affect the heart or lungs.
Dr. Nagaraja also treats patients with lupus, a particularly debilitating condition in which the immune system attacks one or more systems in the body, including the joints, skin, kidneys, heart, lungs, blood cells, or brain. It’s often referred to as "the great imitator," because the most common symptoms — like fatigue, joint pain, and brain fog — overlap with a host of other conditions. Patients with severe autoimmune conditions often experience alternating periods of flare-ups and remission, which Dr. Nagaraja says can be triggered by anything from environmental factors to stress.
Because there is no cure for the underlying disease, treatment has focused on decreasing the activity of the immune system, commonly with powerful immunosuppressive drugs. Unfortunately, says Dr. Nagaraja, some of those treatments come with severe side effects: “There’s always a risk-benefit analysis, because while treatments like immunosuppressive therapy, including corticosteroids, can reduce symptoms and prevent long-term organ damage, they also increase infection risk and require constant monitoring. So, we’re always reevaluating the consequences of short- and long-term treatment on overall quality of life.”
Another challenge in managing autoimmune disease is that the treatments that once worked well can lose effectiveness over time, placing significant stress on patients — particularly when their condition is itself exacerbated by stress. But after decades of trial and error, patients with severe chronic rheumatic autoimmune disease have a reason to be cautiously optimistic: A new clinical trial using a treatment known as Chimeric Antigen Receptor T-cell therapy (CAR T) aims to reprogram and reset the immune system to treat autoimmune disease at its source.
CAR T therapy, which has been successfully used to treat various blood cancers, works by genetically modifying T-cells to seek out and eliminate cancer cells, or in this case, the cells attacking the immune system. While CAR T was first developed by modifying a patient’s own cells (known as autologous CAR T), the trial Dr. Nagaraja is working on, known as the RESOLUTION trial, uses an “off-the-shelf” (or allogeneic) CAR T, meaning the modified immune cells come from a healthy donor rather than the patients themselves. “The donor T cells are genetically engineered to survive longer in the body, potentially increasing their effectiveness,” he explains, “and they don’t require the patient to wait for their own cells to be extracted, re-engineered in a lab and re-infused.”
While allogeneic CAR T treatment remains experimental for autoimmune diseases, the introduction of an “off-the-shelf” approach could dramatically expand treatment access. Patients would no longer have to wait weeks for their own cells to be manufactured, a long, rigorous process that’s often available only to patients with access to a major teaching hospital. Unlike autologous CAR T, an “off-the-shelf” CAR T product, if successful in treating rheumatic autoimmune disease, has the future potential to be administered at a local hospital in the outpatient setting, saving patients time and money and significantly narrowing the access gap.
Before CAR T treatment, patients are given a brief course of low-dose chemotherapy referred to as lymphodepletion. Rather than targeting the disease itself, this step helps prepare the immune system to accept and support the engineered cells. Chemotherapy drugs act on rapidly dividing cells, including those involved in reproductive function. For women of reproductive age, the decision to undergo treatment with CAR T and related chemotherapy may be a major disruption to future family planning.
In addition to its impact on fertility, Dr. Nagaraja notes that lymphodepletion chemotherapy given before CAR T therapy typically requires patients to receive between two and three days of chemotherapy followed by close monitoring after infusion, often requiring hospitalization for approximately five to ten days. In the first phase of the RESOLUTION trial, Dr. Nagaraja and his team are testing whether an “off-the-shelf” allogeneic CAR T can be used either with reduced lymphodepletion or without it entirely. “To me, this is the most exciting part of the study,” he says. “If we can administer a one-time, ready-to-use product in an outpatient setting, such as an infusion center, with minimal or no chemotherapy, patients could potentially avoid chemotherapy side effects, including prolonged low blood counts, increased infection risk, and weeks of hospitalization. They can return home soon afterward and continue care through outpatient follow-ups. Think about how this could change the patient experience in the future: It would mean no anxiety about hospitalization and everything that comes with it. It would mean accessibility for people who otherwise wouldn’t be able to travel to a major hospital and spend a week or more being monitored.” Reducing or eliminating the need for chemotherapy could also ease the significant physical and emotional burden that fertility concerns place on women of reproductive age.
For people living with severe autoimmune disease — many of whom have spent years cycling through treatments, managing flare-ups, and weighing trade-offs between relief and risk — the possibility of a therapy that resets the immune system rather than broadly and chronically suppressing it represents a profound shift. While the use of allogeneic CAR T for autoimmune conditions is still in its very early stages, it's possible that the immune system itself could be reprogrammed safely, efficiently, and potentially without long-term hospitalization. That possibility offers something that may often feel out of reach for patients with these chronic diseases: Hope.
