Federal budget cuts slow pace of breakthrough autoimmune therapies

It sounds like alchemy: doctors treating rheumatoid arthritis with the beloved base metal gold. Popularized in the 1920s by French physician Jacques Forestier, injecting gold compounds became a mainstay of treating individuals with rheumatoid arthritis, an autoimmune disorder that causes joint pain and swelling, plus other symptoms that can range from brain fog and low energy to breathing difficulty and vision loss.

"Gold therapy persisted for decades but was discontinued because of its toxicity and potential for organ damage," says rheumatologist Maximilian Konig, an assistant professor of medicine in the Division of Rheumatology at Johns Hopkins University's School of Medicine. Today, Konig and other physicians refer to this time as "the dark ages of rheumatology," owing to the lack of understanding what drives autoimmune diseases and how to effectively treat them. They now fear they're facing the dawn of another dark age—one fueled not by a lack of scientific evidence and know-how but by the federal government's budget cuts to medical research that can improve or save lives.

"The federal cuts have had a chilling effect on the medical community and research," says Konig, who is spearheading the Johns Hopkins Cellular Therapy Program for Autoimmunity—an initiative that borrows from and adapts advancements in oncology to treat systemic autoimmune diseases like lupus, myositis, scleroderma, and rheumatoid arthritis. These occur when the immune system mistakenly attacks its own tissues and organs, "resulting not just in localized pain but also systemic [effects] that make people feel crummy because inflammation is everywhere in the body," he says.

Rheumatic autoimmune diseases currently affect more than 58.5 million adults and hundreds of thousands of children in the U.S. As many as 80% of those affected are female, whether owing to molecular differences on the X chromosome, to the influence of sex hormones, or to something else, medical researchers postulate. On top of that, the number of people worldwide with a diagnosed autoimmune disease is rising at an alarming rate. One study estimates a 19.1% global increase every year, but experts agree that the number is hard to pinpoint because of the dearth of data—and the difficulty in quantifying conditions that are routinely overlooked or missed in the clinic.

For Konig and his colleagues, cuts to the National Institutes of Health come at precisely the wrong time, given the prevalence of autoimmune diseases and the heavy burden they place on those who live with (and die from) them. His research was surging full steam ahead—"until suddenly, there is tremendous uncertainty about what next year will bring and how we will advance the development of next-generation therapies."

Konig says his team has become conservative in figuring out what they can take on. "We're looking at what's practical and wondering whether we can even [afford to] train additional graduate students," he says. The predicament, he explains, will affect an entire generation of students who want to pursue medical research as a career. This, in turn, will have a trickle-down effect on society, with fewer medical advances and breakthroughs available to those who suffer daily—and whose ability to function depends on them, he says.

Difficult diagnoses

As a physician-scientist, Konig spends time not only in the lab but also the hospital, where he sees what patients go through firsthand. Diagnosis, he says, can take years and serve as a huge source of frustration. "Autoimmune diseases often start slowly, and immune abnormalities can go unnoticed for five to 15 years before the onset of symptoms," he explains. "Then symptoms and signs like joint pain and swelling may come and go. If patients are evaluated in these early stages, doctors may have no way of making a definitive diagnosis or determining, for instance, whether a patient with joint pain has psoriatic arthritis, rheumatoid arthritis, or a completely different disease that causes joint inflammation."

Lab tests can help pinpoint a portion of these conditions. Some look for autoantibodies, maladapted proteins of the immune system that attack the body, rather than warding off foreign invaders such as bacteria and viruses, as they normally do. But for many systemic autoimmune diseases—including psoriatic arthritis, ankylosing spondylitis, reactive arthritis, and many more—no such autoantibody has been conclusively identified. Diagnosis, then, becomes a timely process plagued with uncertainty—of monitoring a patient's evolving clinical presentation and symptoms, ruling out other conditions, and trying out various therapies to zero in on an underlying cause.

In Konig's lab, however, his team is developing novel ways to use molecular diagnostics, an approach that involves analyzing DNA and RNA, the unique genetic code found in human cells, to accelerate diagnosis. The goal is to identify two types of cells that can cause autoimmune diseases: rogue T lymphocytes (known as T cells), which can directly attack other cells, and B lymphocytes (or B cells), which make harmful antibodies. When these "bad actors" emerge among T cells and B cells, they attack the body's own tissues and can lead to a range of systemic autoimmune conditions, from lupus and Sjögren's disease to ankylosing spondylitis and psoriatic arthritis. By figuring out which specific T- and B-cells are associated with each condition, and learning to identify them reliably by using their unique disease-causing receptors as barcodes, doctors could determine a diagnosis early with a blood test, potentially saving years before suitable treatments are initiated.

"With molecular diagnostics, we could soon be able to identify whether a patient who presents with joint pain has disease X or Y at their first visit," Konig says. "That would be huge." Following these rogue cells over time may also provide new tools to monitor treatment responses, particularly when applying precision therapies—next-generation treatments going after these bad actors—that are on the horizon.

Revolutionizing treatment

Rheumatic disease therapies have vastly improved since the era of gold injections, having become much more effective and, in some ways, safer, Konig says. But every treatment option available today still suppresses the entire immune system and puts patients at risk of infection and cancer. Through his laboratory research and Johns Hopkins' new Cellular Therapy Program for Autoimmunity, however, Konig and his team are advancing new treatments that use the body's natural defense mechanisms to fix the root cause—a faulty immune system—instead of merely tamping down symptoms.

Many of the treatments borrow and repurpose immunotherapies used by oncologists to fight cancer, including chimeric antigen receptor (CAR)-T cell therapy—a success story against blood cancers such as lymphoma and leukemia driven by "rogue" B cells. Konig uses CAR-T cell therapy to treat B-cell driven rheumatic diseases. T cells, one of the body's own killer cells, are engineered in a lab to make CAR-T cells that are infused into the patient. There, they "deplete all [of the patient's] B cells, not just the 'bad actors' but every single one of them," Konig says.

While this approach can lead to complete remission in some people, who can go off their medications for extended periods, it doesn't work for everyone. The main problem: "Approaches like this weaken the entire immune system, commonly leading to severe infections, rather than zeroing in on the small part malfunctioning," Konig says.

Even still, these treatments can provide substantial relief and represent a huge breakthrough—one that Konig and his team are building on to create better solutions. "We're seeking to merge the strength of these powerful new therapies with an unprecedented way of targeting the precise cause of the disease," he says. "This way, we hope to enact profound disease control early in the disease process—all without lowering a patient's ability to fight infection."

It's a matter of "leveraging the immune system itself as a living drug to go after the drivers of the disease," Konig says. To do so, his team targets the molecules on rogue B- and T cells that initiate the disease process in the first place. Often, a small number of specific B cells are the culprit. "Each B cell has a unique receptor on the cell surface that can recognize, bind to, and get activated by one thing … such as a protein of SARS-CoV-2, [the virus that causes] COVID-19," Konig says. "When such B cells get activated, they develop into cells that secrete large amounts of antibodies that protect us by neutralizing the virus." But when B cells that bind self-proteins get activated and are not kept in check, they can produce antibodies that cause inflammation or direct damage to tissues, the beginning of an autoimmune disease.

One of the novel cellular therapies (CATCR-T cells) Konig's team developed eliminates the specific B cells that cause blood clots and fetal losses in patients with antiphospholipid syndrome and lupus, while keeping beneficial B cells intact. In other work, his team is developing therapies that can precisely eliminate T cells that cause ankylosing spondylitis, known to involve crippling inflammation and pain in the spine. "These precision therapies coming out of Johns Hopkins are now being developed in a startup, with plans to implement the first-in-human trials in the next few years," he says. "This is a moment of unprecedented promise for patients."

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The impact of funding cuts

Without research—and the federal support that makes it possible—scientific breakthroughs suffer, and the lifesaving treatments of tomorrow are at risk.

But progress could come to a standstill if funding freezes and budget cuts continue, Konig stresses. In fact, "there's no viable way to sustain our research momentum long-term without support from funding agencies like the NIH," he says.

Konig says he's already seeing physician-scientists across the country put aside their research to take on more clinical responsibilities or careers in industry—"all to protect their livelihoods in what has become a climate of uncertainty and anxiety," he explains. Previously, Konig received weekly emails from "some of the world's brightest and most ambitious students, inquiring about research opportunities in our lab or elsewhere at Hopkins or in the U.S.," he says. "But these emails have become sparse."

Originally from Germany, Konig himself moved to the U.S. to join what he considered the cutting edge of medical research. Now he worries about the future of science across the country—and the millions of people with autoimmune diseases who will suffer the biggest consequences.