Untangling the Web of Autoimmune Diseases

Seven years ago, Fatiha began to experience joint pain and swelling of her hands. A doctor diagnosed her with Sjögren’s syndrome, an autoimmune disease.

Three years later, the joint pain flared up and was accompanied by a severe rash and sudden hair loss. Fatiha, 32, who asked for her last name to be withheld, could barely walk. The diagnosis was lupus, another autoimmune disease.

Lupus causes inflammation in the skin, joints, and kidneys. Symptoms include fatigue, joint pain, skin rashes, leg swelling, and chest discomfort.

Still later, she received yet another diagnosis: rheumatoid arthritis.

Rheumatoid arthritis occurs when the body’s immune system attacks the lining of its joints, causing pain, inflammation, and eventually, cartilage and bone damage. This autoimmune disorder can also harm the body’s internal organs such as the heart, lungs, and nervous system.

In spite of her illnesses, the Trumbull, Conn., resident works at a restaurant and is studying computer science at the University of Bridgeport. “I was never sick before in my life. Then one day everything changed,” she said.

Autoimmunity occurs when the immune system loses tolerance of the body’s own tissues and behaves as if they are infected with a pathogen. In addition, some researchers believe autoimmunity may occur when the immune system overreacts to a pathogen that has entered the body and attacks healthy tissues.

Autoimmune diseases are typically caused by mutations in multiple genes, but they can be triggered by environmental factors and stress. Inflammation is closely associated with autoimmune disorders. Most often, it’s a symptom of the disorders, but sometimes it’s a trigger. “Immune diseases are very complex. You can have the wrong genes, but need also the wrong microbiome, diet, or environmental factors,” said Martin Kriegel, MD, PhD, associate professor adjunct of immunobiology.

As is the case with Fatiha,it is not unusual for people who develop one autoimmune disorder to experience one or more additional ones. Figuring out why this happens is challenging for clinicians and medical scientists. It’s a tangled web of causes and effects.

In 2015, a Yale School of Medicine study found that many autoimmune diseases are caused by changes in enhancer elements of the DNA that can regulate several immune genes. Many of the affected genes overlap between diseases.

Researchers believe that a malfunctioning thymus may cause some people to have multiple diseases, said Kriegel. The thymus is instrumental in the maturation of T lymphocytes (T cells), which are essential for fighting pathogens throughout the body. Sometimes, because of genetic defects, the T cells aren’t taught how to distinguish between pathogens and normal cells.

In other cases, researchers suspect that checkpoints in the lymph nodes and spleen, where immune responses are typically launched, are faulty, leading to patients having more than one disorder.

Experts in the field believe that the knowledge they gain from treating such patients combined with advances in laboratory research will not only bring relief to countless people around the globe but will also help scientists better understand the fundamental mechanisms of inflammation and the immune system.

The prevalence of autoimmunity is on the rise in the United States. Researchers have found a 44% increase in ANA, the autoantibody (antibodies that target self) in lupus, in the last 25 years, with 41 million people affected.

These autoantibodies presage autoimmune diseases such as rheumatoid arthritis, which is the most common type of autoimmune arthritis, and systemic lupus erythematosus (SLE) in about 30% of individuals over a 5-10 year period, said Richard Bucala, MD, PhD, Waldemar Von Zedtwitz Professor of Medicine (Rheumatology) and Professor of Pathology and of Epidemiology (Microbial Diseases) and the chief of the Section of Rheumatology, Allergy & Immunology at Yale School of Medicine.

“The good news is that high-risk individuals can be identified, and treatment may prevent disease progression,” Bucala said.

Typically, autoimmune diseases are treated with therapies that depress the immune system—an approach that leaves patients vulnerable to viruses, bacteria, and other pathogens. “The immune system can be protective or pathogenic. It’s the classic metaphor—the double-edged sword,” said Jordan Pober, MD’77, PhD ’77,professor of immunobiology, the Bayer Professor of Translational Medicine and pathology and dermatology.

Tumor necrosis factor (TNF) blockers are being used successfully to treat rheumatoid arthritis and other autoimmune diseases, including psoriatic arthritis, ulcerative colitis, and Crohn’s disease. However, lupus and some
other diseases are not as well understood. People with lupus seem to be particularly susceptible to developing additional diseases.

The causes and manifestations of autoimmune diseases are so complex that researchers struggle to find the best ways to discuss them. Insoo Kang, MD, associate professor of medicine (rheumatology) at Yale School of Medicine, describes a “rainbow spectrum” of disorders in which causes and effects overlap. Often, several gene mutations are shared by multiple disorders.

Meanwhile, Andrew Wang, MD, PhD, assistant professor of medicine (rheumatology) and of immunobiology, refers to “constellations” of disease. “If we’re honest with ourselves, we recognize that patients with complicated inflammatory diseases can’t all be lumped together and all treated the same,” he said.

One of his patients, Lois Walters, a retired postal worker in Hamden, Conn., was diagnosed with lupus more than a decade ago, yet her symptoms, including fatigue, joint pain, and skin rashes, didn’t respond well to traditional therapies for lupus.

After Wang became her doctor four years ago, he tried a different strategy. He recognized that Walters essentially suffered from her own personal version of lupus, so he broke from conventional therapies and treated each of her symptoms separately. It’s working. “This is the best I’ve felt in a long time,” said Walters.

Wang believes that a new approach will be required to address the complexities of autoimmune disorders. Today, many of the successful therapies target immune mediators, the signals that immune cells make to tell the body there’s a problem. He believes that an alternative approach is to target the metabolic programs that support the immune cells.

Wang said research breakthroughs will be essential in dealing with these complex illnesses, but so will old-fashioned doctoring: “It’s important to be mindful of the particular constellation that your patient might have, and it’s
important to listen to the patient because they’ll tell you what’s wrong with them.”

While tremendous progress has been made in treating some autoimmune disorders, doctors are frustrated by the slow progress in treating other disorders and in cases where multiple disorders or unusual clusters of symptoms occur. For example, a patient diagnosed with a rare chronic autoimmune condition called antisynthetase syndrome can require care in multiple specialties from immunology to pulmonary to oncology, and more.

“We have to understand the mechanisms, especially the immune mechanisms. But we also have to understand deeply what’s going on with an individual patient. It’s a form of precision medicine,” said Kang. “This is what we hope to accomplish over the next five to 10 years.”

Originally published Winter 2020; updated May 16, 2022.