The National Institutes of Health has launched its first agencywide Strategic Plan for Autoimmune Disease Research, a five-year initiative aimed at accelerating research into diseases that affect an estimated 50 million Americans and cost more than $100 billion annually.

Autoimmune disorders occur when the immune system, designed to protect the body from viruses, bacteria and other threats, mistakenly attacks healthy tissues. Nearly every part of the body can be affected, including the skin, joints, heart, lungs and nervous system.

The result is often chronic and debilitating illness as most autoimmune diseases have no permanent cure and require lifelong management. While treatments continue to improve, many patients still rely on the long-term use of immunosuppressive therapies to manage their disease.

One of the key features of autoimmune diseases is that they disproportionately affect women, who account for more than 70% of patients worldwide, a distinction the NIH initiative will explore.

At Cedars-Sinai, scientists and clinicians with the Kao Autoimmunity Institute are working to understand how biological sex influences immune responses and disease risk. In lupus, for example, 90% of the patients are women and investigators are trying to understand what factors drive that enormous disparity and what could improve treatment.

Autoimmune disease and lupus investigator Caroline Jefferies, PhD, scientific director of the Center for Research in Women’s Health Science at Cedars-Sinai, and rheumatologist Mariko Ishimori, MD, associate director of the Clinical and Translational Research Center, sat down with the Cedars-Sinai Newsroom to discuss how sex differences can shape lupus risk, symptoms and patient care.

Why do autoimmune diseases affect women more often than men?

Jefferies: Differences in sex chromosomes, hormones and environmental exposures all influence the immune system. Some genes involved in regulating immune responses are located on the X chromosome. Although females typically have two X chromosomes, one is usually switched off in each cell. Certain immune-related genes, however, can escape that inactivation process and remain active, which may contribute to a heightened immune response and help explain why autoimmune diseases are more common in women.

How does the immune system function differently in women compared to men?

Jefferies: Women generally mount stronger immune responses than men, resulting in faster responses to viruses and better responses to vaccines. This was especially evident during the COVID-19 pandemic, when men experienced higher mortality and more severe disease. But that significant antiviral advantage also may contribute to the higher rates of inflammatory and autoimmune diseases seen in women, including lupus.

Why is lupus a key example of sex differences in autoimmune disease?

Jefferies: About 9 out of 10 lupus patients are women, and lupus was one of the first autoimmune diseases linked to overactivation of antiviral immunity. Decades ago, researchers discovered that interferons—proteins released when the body detects viruses—were elevated in lupus patients. Interferons drive immune cell activation, antibody production and cell death, all of which can contribute to the development of autoimmunity and illness.

Does lupus present differently in women and men, and can those differences affect diagnosis or treatment?

Ishimori: Women are far more likely to develop lupus, especially during their reproductive years, when the ratio of women to men with the disease is about 9 to 1.

Lupus symptoms can vary widely, but women commonly experience fatigue, joint pain, swelling, rashes and oral ulcers. Men may be more likely to develop inflammation around the heart or lungs, or organ-threatening disease affecting the kidneys or heart. Because there is no definitive blood test, or single symptom, that confirm lupus, delays in diagnosis can occur. Men may face additional delays because lupus is generally considered more common in women and may be less likely to be considered in the differential diagnosis in men.

Are there stages in a woman’s life when autoimmune symptoms may change or become more noticeable?

Ishimori: During pregnancy, the immune system adapts to tolerate a growing fetus while continuing to protect the mother. Some women with autoimmune disease experience flares during pregnancy, while others do not. Patients with known autoimmune disease are generally encouraged to achieve good disease control before conception because well-controlled disease is associated with fewer pregnancy complications. Several weeks after delivery, there may be an increased risk of disease flare or even a first presentation of autoimmune disease as the immune system readjusts.

Around menopause, some autoimmune symptoms can overlap with changes naturally associated with that stage of life, which can sometimes complicate diagnosis of a specific disorder.

What should women do if they think they may have an autoimmune disease?

Ishimori: Autoimmune symptoms often persist over time, although they may come and go. Because infections and other illnesses can sometimes cause similar symptoms, it’s important to look at the bigger picture. Keeping track of symptoms—such as fevers, rashes or patterns of joint pain—can help patients have more informed conversations with their doctors. Patients should feel comfortable asking what conditions are being considered, what tests are being ordered and whether autoimmune disease could be a possible explanation for their symptoms.

How could a better understanding of sex differences change autoimmune disease treatment?

Jefferies: One of the biggest gaps in our knowledge is understanding how sex chromosomes and sex hormones influence the immune system across different tissues and organs. A better understanding of those mechanisms could eventually help researchers develop more targeted treatments for organ-specific complications of lupus, including heart and lung disease. Ultimately, that is why we do this work—to help patients, many of them women, live healthier lives.

Read more from Cedars-Sinai Stories and Insights: Cultivated Care for Autoimmune Diseases

But that all changed about four years ago when the 43-year-old father of two suddenly began losing weight, having migraines and trouble breathing, and experiencing debilitating bouts of major fatigue. He said he even became too weak to lift up his young children.

“I didn’t know what was wrong with me,” Raden said. “I saw my primary care doctor, an infectious disease specialist, a pulmonologist and a gastroenterologist. My liver enzymes were off the chart, suggesting liver damage,  and one of the many CT scans I had revealed nodules all over my lungs. One doctor was convinced I had tuberculosis.”

But Raden says despite those physicians’ best intentions, no one had the answer or understood why he was getting sicker.

“I didn’t know if I was dying. I didn’t know if I needed to prepare a will and an estate for these little kids and my wife. It was brutal,” Raden said. “One day I finally ended up at Cedars-Sinai’s Emergency Department after having severe breathing problems. I was seen by Dr. Akhavan and that changed everything.”

A Complex Disease

Bobak Akhavan, MD, is a pulmonologist and director of Pulmonary Sarcoidosis in the Sarcoidosis Program at Cedars-Sinai.

“Unfortunately, Jake’s experience reflects a common challenge for patients with sarcoidosis,” Akhavan said. “It’s a rare and often misunderstood inflammatory disease that can affect multiple organs, most often the lungs, and can mimic other conditions.”

Sarcoidosis occurs when the immune system mistakenly forms clusters of inflammatory cells—called granulomas—in healthy tissue. These clusters can cause lasting damage and affect the lungs, heart, liver, brain and other organs.

“I often hear from patients convinced they have advanced cancer because there was no clear explanation for all of their symptoms,” Akhavan said. “The fear and worry that come with not knowing where to turn can be as much of a burden as feeling so unwell.”

Under normal circumstances, the body fights some kinds of infections by forming granulomas, said Elizabeth Frame, MD, one of Raden’s Cedars-Sinai physicians and director of the Sarcoidosis Clinic in the Division of Rheumatology.

"However, in sarcoidosis, those granulomas start forming healthy tissues, where there is no infection, and the resulting inflammation damages the affected organs,” Frame said.

Approximately 200,000 people in the U.S. are living with sarcoidosis, according to the Foundation for Sarcoidosis Research. While the rare disease can range from mild to severe—and in rare cases may require organ transplantation—specialized care can significantly improve outcomes.

Cedars-Sinai is a founding member of the Foundation for Sarcoidosis Research Global Sarcoidosis Clinic Alliance (FSR-GSCA), which is committed to finding a cure and offering evidence-based, patient-centric care for those living with sarcoidosis

Treatment Plan: It Takes a Village

At Cedars-Sinai, specialists across pulmonology, rheumatology, cardiology, neurology and other fields work together to evaluate patients with sarcoidosis, ensuring that all organs are assessed and treated.

“Because Jake’s case was complex and involved multiple organs, our specialists worked together closely—reviewing his tests and sharing their perspectives in real time—to confirm the diagnosis and create a treatment plan,” Akhavan said.

The multidisciplinary, evidence-based, approach to diagnosing and treating this rare disease is among the reasons Cedars-Sinai is designated a Center of Excellence in Rare Neuroimmune Disorders, including neurosarcoidosis, as well as recognized as a "Sarcoidosis Clinic of Excellence" by the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG).

“Most of the diseases that rheumatologists take care of affect multiple organs,” Frame said. “We’re accustomed to organizing lots of disparate information and integrating it into a complete picture so everyone can get a comprehensive understanding of the patient as a whole.”

The Road to Recovery

With a diagnosis and treatment plan in hand, Raden received high-dose steroids and other therapies aimed at reducing inflammation and preventing further organ damage. Within weeks, his strength began to return. Lung function and blood tests, as well as CT scans, confirmed Raden’s condition was improving.

“The art of treating sarcoidosis has to do with finding the doses and combinations of medicines that are best for a specific patient,” Frame said. “The goal of treatment is always to help a patient live the healthiest, fullest, happiest life possible.”

Today, Raden is in remission and back to the life he feared he might lose.

“I can breathe again and I have energy,” Raden said. “I can exercise, I run around with my kids, and I can be of real help to my wife. Work is good. It’s not an exaggeration to say that finding these experts and this special sarcoidosis program saved my life.”

Read More on Stories and Insights: When Superfoods and Inflammatory Diseases Are a Recipe for Trouble

Although rheumatoid arthritis is an autoimmune disease with no cure, a tailored, multidisciplinary treatment approach at Cedars-Sinai’s Inflammatory Arthritis Clinical Center helps patients get back to the activities they enjoy.

“It may take trying different medications and a bit of time, but I tell patients that we will work together with a goal to get back to their work, their family life and all the things that they like to do, with no limitations,” said rheumatologist Jon Giles, MD, MPH, director of the Inflammatory Arthritis Clinical Center in the Division of Rheumatology and the Department of Medicine at Cedars-Sinai.

Giles, an associate professor of Medicine, joined Cedars-Sinai from Columbia University in 2024 to establish the Inflammatory Arthritis Clinical Center, which also treats people with all other types of inflammatory arthritis, such as psoriatic arthritis and related spondyloarthropathies; and crystal arthritis, such as gout and calcium pyrophosphate deposition disease. Giles also leads research into the causes of autoimmune diseases.  

Rheumatoid arthritis affects more than 3 million people in the U.S. and is more common in women than men. It causes inflammation, swelling and stiffness in the joints—prominently in the hands and feet but also in larger joints. Rheumatoid arthritis can also be associated with other potentially severe health conditions, including interstitial lung disease, accelerated cardiovascular disease, and an increased risk of certain malignancies and osteoporosis.

As co-director of the Rheumatoid Arthritis Translational Research Program in the Kao Autoimmunity Institute at Cedars-Sinai, Giles co-leads a comprehensive research program focusing on screening, diagnosis and management of these common but often overlooked—and sometimes deadly—complications.

In recognition of National Arthritis Awareness Month in May, the Cedars-Sinai Newsroom spoke with Giles about the latest treatment and research advances.

When does rheumatoid arthritis typically develop?

Some people think of rheumatoid arthritis as a disease that only older people get, but we treat adults of all ages. While women and men tend to develop the disease around 50, there also is a peak for women during childbearing years.

How are rheumatoid arthritis and osteoarthritis different?

Osteoarthritis can affect some of the same joints as rheumatoid arthritis, but it’s caused by non-inflammatory damage to cartilage and underlying bone. It tends to bother people toward the end of the day or when they use their joints. With rheumatoid arthritis and most forms of inflammatory arthritis, joint stiffness is at its worst in the morning and tends to improve with activity. Also, unlike osteoarthritis, it is caused by a complex and not completely understood dysregulation of the immune system, leading to elevated inflammation and immune activation in the joints and throughout the body.

How effective are treatments for rheumatoid arthritis?

Today I can confidently tell patients there are many resources to treat this disease, and that very few patients do not respond to any of the available treatments. Twenty years ago, that was not the case. Sometimes, our trainees don’t consider rheumatoid arthritis a severe disease because they see mostly people who have been diagnosed early and treated aggressively, who don't have advanced deformity and destruction in their joints and all the accompanying health conditions we once saw.

That said, if not treated effectively, rheumatoid arthritis can be quite severe. At Cedars-Sinai we “treat to target,” meaning if a patient is not in low disease activity or remission—usually no or only a few swollen and/or tender joints—we adjust their therapy. We don’t let active inflammation fester. Studies have shown this to be very effective at improving quality of life by reducing inflammation, symptoms and joint damage.

How often should patients with rheumatoid arthritis be evaluated by their doctor?

We recommend seeing a rheumatologist and getting screening blood work done every three to four months. We don’t use a “set it and forget it” treatment approach. Sometimes patients stop responding to a medication, so both the patient and the physician must be willing to make changes. There may be complexities and subtleties in treatment—such as combination therapies with an injected medication and oral medications, each taken at different times—but with all the available medications today, patients generally do very well.

Why is multidisciplinary care important with this disease?

We take a multidisciplinary approach in treating rheumatoid arthritis-associated interstitial lung diseases, which can be very severe and lead to lung transplant, or sometimes even death. We collaborate with our Women’s Guild Lung Institute to determine the best treatments for these patients because some of the medications to treat their lungs might not be the medication that we would use to treat their joints, and vice versa.

What research is underway?

At the Kao Autoimmunity Institute, along with our Lung Institute colleagues, lung transplant physicians and lung pathology specialists, we’re focused on understanding how rheumatoid arthritis and interstitial lung diseases develop and how to treat them. As we've been treating rheumatoid arthritis more aggressively over the years, most of the very severe organ-threatening manifestations outside of the joints have declined—except for interstitial lung diseases. We also study the mechanisms behind accelerated atherosclerosis in people with rheumatoid arthritis, and how to best screen for and treat it. We are interested in the way inflammation affects muscle and fat tissue in the body and how this contributes to poor outcomes. In addition, we are starting clinical trials of new treatments that may be more effective than current therapies.

What do you most enjoy about your work?

It’s rewarding to be able to say to someone starting treatment, “How you feel right now is not how you are going to feel in the future.” Rheumatoid arthritis is a long-term disease that requires ongoing care, giving rheumatologists time to build strong relationships with their patients. I was fortunate to have many of those in my 13 years at Columbia University and now I’m doing the same at Cedars-Sinai.

Read more on the Cedars-Sinai Blog: Why Is Arthritis Worse in the Winter?

An estimated 100,000 people in the U.S. are living with scleroderma, and there are about 7,000 to 8,000 new cases every year. In advanced stages of systemic sclerosis, which disproportionately affects women, the chronic symptoms can lead to irreversible organ damage and death. There is no cure.  

“Scleroderma is the epitome of complex autoimmune rheumatic disorders because it can affect any organ in the body. Scleroderma is a chronic illness that can place an incredible burden on patients and their families for a long period of time,” said Francesco Boin, MD, the chair of Rheumatology and director of the Scleroderma Program in the Kao Autoimmunity Institute at Cedars-Sinai.

Research That Benefits Patients

Cutting edge research is the best care we can offer scleroderma patients, said Boin, and leading that effort at Cedars-Sinai is Nunzio Bottini, MD, PhD, the director of the Kao Autoimmunity Institute.

“Our research priorities at the Kao Autoimmunity Institute are twofold: first, how to prevent, and hopefully reverse, the progression of fibrosis in patients with scleroderma, and secondly, we want to identify risk factors for the development of interstitial lung disease, a major complication of scleroderma, that can lead to an early death,” said Bottini.

A Super-Family of Enzymes

Groundbreaking research on the role a group of enzymes Bottini calls a “super-family,” protein tyrosine phosphatases (PTPs), has been a key focus of his work investigating the development of rheumatic diseases.

“PTPs have recently emerged as important drug targets for a multitude of diseases. For scleroderma, we want to better understand precisely how this family of enzymes regulates the progression of fibrosis, the production of excessive collagen that can scar and thicken tissue, a hallmark of scleroderma,” said Bottini, who has been continuously funded by the National Institutes of Health for autoimmune disease research since 2007.

Spatial Biology: Location Matters

Cells in the body exist in relationship to one another, they are not islands. Spatial biology explores how the neighborhood, the location of one cell within tissue relative to another, could affect cellular activity.

“The fibroblast cell’s behavior is affected by different types of cells, including immune cells, that are located near it. Spatial biology has the potential to help us understand pathology in a new way. How might the behavior of the fibroblast be influenced by specific factors in the immune cells or by its location in the skin or the lungs? In autoimmune disorders, like scleroderma, that information could be a game changer,” said Bottini.

“All that we do at the Kao Institute is geared toward helping patients. That is the end goal.  We study specimens graciously donated by our patients and we make our hypotheses about targets for potential therapies. Then we test the hypotheses and based on the results of the experiments, develop therapies tailored to patients with scleroderma. We want to enable personalized care.”

Autoimmune disorders affect 24 million adults and children in the U.S., according to the National Institutes of Health. 

“Autoimmune diseases are a leading cause of death and disability. At the Kao Autoimmunity Institute, we want to bring top investigators and clinicians together and leverage the culture of scientific excellence and collaboration here. Our goal is to promote personalized medicine by developing  novel, evidence-based therapies that can help patients,” said Bottini.

Read More on the Cedars-Sinai Blog: Lifelong Journey: A Scleroderma Patient and Her Doctor