The case study involved just one patient: a 20-year-old woman with severe systemic lupus erythematosus (SLE). But the study’s results were so dramatic that they appeared in 2021 in the New England Journal of Medicine.
The woman received a type of cell therapy called CAR-T, which in the past has been used primarily to treat cancer. CAR-T cell therapy involves altering a patient’s immune cells so that they identify and attack problems or pathogens. In people with cancer, that attack is aimed at the diseased cells. But in the NEJM case study, the therapy was directed at the woman’s own B cells, which are thought to be a primary cause of inflammation and damage in patients with lupus. The results were astonishing. “Within one month, nearly all of her symptoms had calmed down,” says Dr. Michelle Petri, a professor of medicine and director of the Johns Hopkins University Lupus Center, who was not involved with the case study.
Soon after that initial case study appeared, the same group of researchers showed that CAR-T therapy led to dramatic and lasting improvements in five additional patients with SLE. Even when the patients’ B cells returned, they did not initially display their old pattern of harmful activity. “They didn’t come back as bad lupus B cells,” Petri says.
While these early CAR-T results have created a lot of excitement, Petri notes that a lot more work is needed before the therapy could conceivably be rolled out to more patients. Right now, CAR-T is prohibitively expensive. (It costs roughly $400,000 per patient, she says.) CAR-T therapy is also associated with risks, including severe and systemic toxicity, which in some cases can result in coma or infection. “We need to see if the treatment is durable, which means its benefits persist for at least five years,” she says. “If the lupus comes back too soon, then we’ve spent a lot of money and exposed people to major potential for toxicity without a durable benefit.”
The latest CAR-T work is arguably the most exciting breakthrough in the treatment of SLE. (It also holds promise for the treatment of other autoimmune conditions that feature B-cell involvement, such as Type 1 diabetes and rheumatoid arthritis.) But it’s far from the only new advancement in the treatment of lupus. In recent years, several new lupus medications have received U.S. Food and Drug Administration (FDA) approval. Many others have demonstrated benefits in early clinical trials, and there’s hope that more approvals will follow soon.
Here’s a rundown of the latest intriguing advancements in the lupus space. From new monoclonal antibody therapies to advancements in how the disease’s activity is monitored in patients’ urine, medical science is quickly revolutionizing lupus treatment and care.
New and more effective drug treatments
Lupus is a disease of immune system overactivation. “The immune system attacks the body’s own tissues, and that attack can lead to damage in many different parts of the body,” says Dr. Joseph Craft, a professor of medicine and immunobiology at the Yale School of Medicine. Craft directs a lab devoted to the study of systemic lupus erythematosus. He explains that, in some patients, lupus attacks the skin or joints. It also frequently attacks the kidneys. “That doesn’t happen in every patient, but it does happen in a significant proportion, and it can lead to kidney disease and failure,” he says. Historically, lupus has been treated with medicines that broadly suppress the immune system, such as steroids like prednisone. “Those therapies work, but they have a lot of side effects, so we don’t like to use those for long periods of time,” Craft says. (Weight gain, poor bone health, and increased risks for infections are some of the most common side effects.)
A lot of time and resources have been directed at the development of new lupus therapies that act more narrowly, meaning they affect only a minor element of the immune system’s operation. These so-called targeted medicines have arrived, and they’ve made a big difference. One of them is an intravenous drug called belimumab, which blocks or kills the B cells that cause tissue damage in people with lupus. “B cells produce antibodies, which are proteins that float in the blood and act against infection,” Craft explains. “In patients with lupus, the B cells are abnormally regulated, and they make antibodies that bind to self-tissues—the kidneys for example—and cause autoreactivity.” Belimumab is now FDA-approved for lupus patients with or without kidney involvement.
Another new drug in lupus treatment is an oral medicine called voclosporin, which is a type of calcineurin inhibitor. “Calcineurin inhibitors have been used in transplant medicine in the past, and voclosporin was approved in 2021 for lupus nephritis,” says Dr. Elena Massarotti, a lupus specialist and associate professor of rheumatology at Harvard Medical School. Calcineurin inhibitors interfere with the action of a protein (calcineurin) that contributes to certain types of immune system overactivity, Massarotti explains. Voclosporin is normally given along with mycophenolate (an older immunosuppressant drug) in people who have lupus with kidney involvement, and trials have shown that it significantly outperforms standard care.
Like all lupus medications, voclosporin is associated with risks and side-effects. A 2021 phase-three trial found that roughly 1 in 5 people on voclosporin experienced “serious” adverse events, the most common of which was pneumonia. However, that side-effect profile was on par with the risks posed by standard treatments, and the leaders of the trial determined that voclosporin has a “comparable safety profile” to the older drugs.
Yet another drug, anifrolumab, targets a specific type of protein receptor. “It attaches to interferon alpha receptors, which are thought to play a major role in the pathogenesis of lupus,” Massarotti says. This drug may turn out to be most helpful for people who have systemic lupus that does not feature kidney involvement, she adds.
More drugs in the trial pipeline
Apart from the FDA-approved treatments mentioned above, there are a handful of new drugs that have performed well in clinical trials (though they have not yet been formally approved for the treatment of lupus).
One of these is a therapy called obinutuzumab. This is a monoclonal antibody treatment that works by depleting the blood’s B cells. Some research has found that it can help people with systemic lupus who have not responded well to other medications.
Several other monoclonal antibody therapies—treatments that use specially engineered antibodies to shift the activity of the immune system—have likewise looked promising in early trials. A drug called obexelimab was found to help extend symptom remission among lupus patients who had previously taken other immunosuppressant drugs. Another new medication, daratumumab, targets long-lived white blood cells that are thought to contribute to lupus-related immune overactivity. Research has found that daratumumab may provide an advantage over existing drugs in certain patient subgroups. “However, studies with meaningfully larger groups of SLE patients are necessary to determine the efficacy and safety of daratumumab in lupus,” wrote the authors of a 2021 research review in the journal Frontiers in Medicine.
There’s a lot more going on in this space. Many drugs—either novel medicines or treatments that have proven effective against other conditions—are now under investigation. “We have several new agents in clinical trials, and there’s active interest by academicians as well as biotech and pharmaceutical companies to develop new treatments,” Craft says. “Some of these are now moving into clinical trials.”
Advancements in measuring lupus activity
In order to know if a drug is working, medical scientists and providers need dependable ways to measure the disease’s activity. Among people with forms of lupus that involve the kidneys, experts often rely on urine protein levels to assess disease activity or medication efficacy. But there’s evidence that this method is unreliable. “We use urine protein to see how active kidney lupus is, but this method may be misinforming us about 30% of the time,” says Petri.
Petri says that she and some of her colleagues at Johns Hopkins—namely Dr. Andrea Fava—are now focused on enhancing the science of urine proteomics, or the ways that lupus may affect the chemical composition of a patient’s urine. Already, that work has identified multiple urine proteins, including a compound called IL-16, that may be better indicators of kidney inflammation in people with systemic lupus. “Before, no one knew that interleukin-16 was a player in kidney inflammation,” Petri says. “In the future, I think we’re going to be so much better at tracking lupus, which is a dynamic process, rather than relying just on the urine protein that, some of the time, is misleading us.”
While new or repurposed medicines are a major focus of lupus research, there’s also a lot of work being done on combination therapies. Lupus is often referred to as a multifactorial disease, meaning it’s driven by more than one underlying issue. An old saying among lupus doctors is that “no two lupus patients are identical,” and personalized approaches to care and treatment are necessary. For some people—perhaps even a majority with systemic lupus—a single drug may not be sufficient to address the heterogeneous nature of the condition, and a lot of work is now looking at how combinations of existing drugs may help patients with specific subtypes of SLE.
Meanwhile, so-called big-data approaches to disease mapping are also helping lupus specialists better differentiate the disease’s different subtypes in ways that may improve outcomes. Using gene-wide association studies and “gene expression profiling”—techniques that have been employed to good effect in work on other autoimmune conditions, such as Crohn’s disease—researchers are developing a clearer picture of the many faces of lupus. “Disease activity waxes and wanes, confounding attempts to determine the cause of lupus and develop effective treatments for the disease,” wrote the authors of a 2020 study in the Journal of Autoimmunity. “In the past 20 years, new technology collectively referred to as ‘Big Data’ has allowed thousands of data points to be assessed in individual patients and compared to healthy controls.” They express hope that these new analytical methods will help inform treatment models in ways that reduce side-effects and improve responses.
According to the U.S. Centers for Disease Control and Prevention (CDC), hundreds of thousands of Americans are living with SLE. Most are women, and the disease disproportionately affects people of color, the CDC reports. Hopefully, breakthrough cell-based treatments—such as the CAR-T therapy that recent case studies linked to radical remission—will turn out to be a true gamechanger. But even if CAR-T doesn’t pan out, many other new therapies are under investigation, and several are now improving the lives of people with SLE. For people with lupus and those who care for them, there’s a lot of reason for optimism.Leave a comment