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.
What Causes Autoimmune Disease?
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.
Finding Commonalities Between Multiple Autoimmune Diseases
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.
Common Autoimmune Diseases on the Rise
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.
How Are Autoimmune Diseases Treated?
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
A Need for Precision Medicine to Treat Autoimmune 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
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.
Wednesday, April 8, 2020
Autoimmunity, a condition in which the body’s immune system reacts with components of its own cells, appears to be increasing in the United States, according to scientists at the National Institutes of Health and their collaborators.
In a study published April 8 in Arthritis and Rheumatology, the researchers found that the prevalence of antinuclear antibodies (ANA), the most common biomarker of autoimmunity, was significantly increasing in the United States overall and particularly in certain groups. These groups include males, non-Hispanic whites, adults 50 years and older, and adolescents. The study is the first to evaluate ANA changes over time in a representative sampling of the U.S. population.
"The reasons for the increases in ANA are not clear, but they are concerning and may suggest a possible increase in future autoimmune disease," said corresponding and senior author Frederick Miller, M.D., Ph.D., deputy chief of the Clinical Research Branch at the National Institute of Environmental Health Sciences (NIEHS), part of NIH. "These findings could help us understand more about the causes of these immune abnormalities and possibly learn what drives development of autoimmune diseases and how to prevent them."
The study included 14,211 participants, 12 years and older, in the U.S. National Health and Nutrition Examination Survey (NHANES). The scientists used immunofluorescence, a technique that uses fluorescent dye to visualize antibodies, to examine the frequencies of ANAs in subjects from three time periods. They found that ANA prevalence for 1988-1991 was 11.0%, while for 1999-2004 it was 11.5%, and for 2011-2012 it was 15.9%. These percentages corresponded to 22, 27, and 41 million affected individuals, respectively.
Of the four demographic groups that displayed considerable ANA increases, findings in the adolescent group were the most worrisome to the research team. Young people, ages 12-19, had the largest ANA increases in the study, going from a two-fold to a three-fold increase over the three timeframes.
The researchers want to know why they are seeing these changes in autoimmunity in each of the groups, but especially in teenagers. Since people have not changed much genetically during the past 30 years, the scientists suggest that changes in lifestyle or the environment may be involved in ANA increases.
"These new findings may have important public health implications and will help us design studies to better understand why some people develop autoimmune diseases," said Christine Parks, Ph.D., co-author and staff scientist in the NIEHS Epidemiology Branch. She added that autoimmune diseases are a group of more than 100 chronic, debilitating conditions.
Determining whether autoimmune diseases, like lupus or myositis, are increasing in prevalence requires a clinical evaluation, which was not performed in this study. Nevertheless, ANA are commonly seen in patients with these conditions and similar autoimmune disorders. Co-author and NIEHS Scientific Director Darryl Zeldin, M.D., said other studies have suggested there is an increase in autoimmune disease prevalence, but the findings are based on incomplete data. He and Miller hope that a national registry of autoimmune diseases will be established so that they can examine changes over time, define geographic hotspots, and eventually understand what is causing them.
"Hopefully, this important study will stimulate further research on the environmental factors related to the apparent increased prevalence of autoimmune diseases," Zeldin said.
About the National Institute of Environmental Health Sciences (NIEHS): NIEHS supports research to understand the effects of the environment on human health and is part of the National Institutes of Health. For more information on NIEHS or environmental health topics, visit www.niehs.nih.gov or subscribe to a news list.
Grant Numbers: Z01ES025041, Z01ES101074
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