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.
Still later, she was diagnosed with rheumatoid arthritis. 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.
But 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.
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. “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 Insoo Kang, MD, an associate professor of medicine (rheumatology) at Yale School of Medicine, who is now treating Fatiha. “This is what we hope to accomplish over the next five to 10 years.”
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.
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, FW ’78, professor of immunobiology, the Bayer Professor of Translational Medicine and pathology and dermatology.
Some of the more common autoimmune diseases include rheumatoid arthritis, which attacks the joints; lupus, which affects skin, joints, and kidneys; multiple sclerosis, which attacks the nervous system; and inflammatory bowel disease.
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, FW ’06, an associate professor adjunct of immunobiology.
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.
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.
The causes and manifestations of autoimmune diseases are so complex that researchers struggle to find the best ways to discuss them. Kang 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, HS ’13, FW ’17, 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 clinician 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.”