Changing environments, extraordinary stress, and the autoimmunity epidemic
Stacy Verdick Case was ill with a host of disparate symptoms. She suffered from joint pain, heart palpitations, and severe fatigue. Doctors tried to address her symptoms, prescribing her the anti-anxiety drug Xanax, attending to her acid reflux, or telling her to exercise. But no one could figure out the root of her underlying health problems.
“Every time they’d look for the cause, there was no cause,” Case says. “Being treated has been a nightmare.”
It took nearly three years and dozens of doctors before Case got a diagnosis: Hashimoto’s disease, an autoimmune disorder that causes inflammation of the thyroid and a number of associated problems, like fatigue and weight fluctuation.
While Case’s disease is rare, autoimmune diseases are not — and neither is the difficulty of her journey to reach a diagnosis. It can take a person an average of five years and five doctors to get diagnosed with an autoimmune disorder, according to the American Autoimmune Related Diseases Association (AARDA) — despite the fact that some 50 million Americans suffer from one. Autoimmunity is now one of the most common disease categories, ahead of cancer and heart disease. And while rates of the latter are falling, autoimmune diseases are being diagnosed with such frequency that some medical experts are calling it an epidemic.
“There’s still a lot of mystery associated with autoimmune disease,” says Kathleen Gilbert, an immunologist and retired professor at the University of Arkansas for Medical Sciences.
Autoimmune diseases occur when the immune system turns on itself and attacks the body’s own cells and tissues. Beyond that, however, there’s little consensus on why this happens, what can be done to stop it, or even what diseases can be classified as autoimmune.
Researchers largely assume that the cause of the rise can be pinpointed to changes in our environment, which in turn are causing changes in our bodies. Over the past 100 years, humanity has drastically altered the way we lived for the majority of existence. And while advancements in technology and living conditions lead us to believe we should be healthier than ever — after all, the majority of Western civilization now has access to better medicine, clean water, and abundant food — doctors are beginning to understand some of the unintended consequences of these changes. With better medicine, for instance, comes the overuse of antibiotics and the rise of superbugs; with industrialized farming comes the rise of chemicals and processed foods — all of which could have something to do with the onset of autoimmunity.
As such, autoimmune diseases could be the product of our own success as an industrialized species. This vexes researchers, because autoimmunity is not only one of the most prevalent disease categories but also fiendishly complex, a tangle of factors that scientists have yet to fully understand.
One of the central problems in understanding the rise of autoimmunity is that the classification of autoimmune disorders as a singular disease category is still relatively new. Until recently, each illness was viewed as a unique and rare affliction, and doctors today still do not agree on the criteria of what constitutes the broader definition. Even the number of diseases that AARDA recognizes as autoimmune — currently 100, including lupus, Type 1 diabetes, celiac, multiple sclerosis, Crohn’s disease, rheumatoid arthritis, and many more — is up for debate.
“Defining something as an autoimmune disease is still quite difficult,” says Noel Rose, MD, PhD, founding director of the Johns Hopkins Autoimmune Disease Research Center. “And depending on how you define the disease, the number will change. I think most people reasonably say 100 is a pretty conservative number.”
Rose is known in the field as the father of autoimmunology for his pioneering work in the field, including a breakthrough discovery of thyroid autoimmunity in 1956. Johns Hopkins University in Baltimore — the lab Rose retired from several years ago — is still one of the few labs that research autoimmune diseases as a whole. That’s another problem facing the autoimmune field — each disease within the category is still studied, treated, and researched independently.
For this reason, experts struggle to calculate precisely just how much autoimmune disease has risen and where. Unlike cancer, autoimmune diseases do not need to be reported to the U.S. Centers for Disease Control and Prevention (CDC) or the National Institutes of Health (NIH), which means there’s no database to help researchers understand how many people are affected, where cases are occurring, and how quickly incidences of certain diseases are rising — all key data points for scientists trying to understand what’s happening.
Without hard data on autoimmune disorders in general, researchers track incidences of individual diseases. Type 1 diabetes diagnoses, for instance, rose 23% between 2001 and 2009 in the United States, according to the American Diabetes Association. In the U.K., diagnoses of Crohn’s disease grew more than 300% between 1994 and 2014, according to the Health and Social Care Information Centre. Canada saw cases of pediatric inflammatory bowel disease increase 7.2% every year between 1999 and 2010, according to a 2017 study.
In a broader view, a 2015 study from Israel looked at 30 individual studies to determine which types of autoimmune diseases were increasing the fastest. They found that global instances of rheumatologic diseases rose an average of 7.1% per year over 30 years, endocrine diseases 6.3%, gastrointestinal diseases 6.2%, and neurological diseases 3.7%.
“We think of cancer collectively or infectious disease collectively because we’ve known about them for many years,” says Frederick Miller, MD, PhD, senior investigator for the Environmental Autoimmunity Group, which works to identify the environmental factors contributing to autoimmune disease. “And so we collect figures every year on the amount of cancer. We don’t collect figures every year on the totality of autoimmune disease in the United States, because that’s not just the way most physicians and most investigators think about it.”
Miller is among many in the field who have spent decades pushing — without success — for an autoimmune disease database. That failure means illnesses like Case’s remain medical mysteries until the right combination of clinical science, symptoms, tests, pathologies, or just plain luck come together to help doctors develop a diagnosis.
At the same time, autoimmune diseases are often difficult to diagnose with standard tests, especially when they’re administered by doctors who may be unfamiliar with the specific disease a person is suffering from. On top of that, doctors often dismiss a patient’s symptoms as psychogenic and refer them to a psychiatrist. For Case, it was her gynecologist who finally solved the puzzle and suggested she get tested for a thyroid-related disease. That was after she says many doctors dismissed her symptoms as related to depression.
“Autoimmune diseases, like many diseases, are a combination of genetic susceptibility on one hand and some exposure on the other.”
It’s possible that the apparent increase in autoimmune diseases may be chiefly the result of more reporting and more sensitive diagnoses, but most researchers in the field believe these factors alone cannot account for the rise in cases of autoimmunity. Something else must be at play.
Genetics explain a good portion of autoimmune disease prevalence. Scientists know that these diseases tend to cluster in families. When one family member has an autoimmune condition, other family members are at an increased risk of autoimmunity — though not necessarily of the same disease. It’s not uncommon for someone with rheumatoid arthritis to have an aunt with, say, ulcerative colitis or any number of seemingly unrelated autoimmune conditions. What this means is that one of the main factors contributing to autoimmune susceptibility more generally is likely genetic.
Scientists also know that autoimmune diseases affect women at a disproportionately higher rate than men. By some estimates, women account for 75% of the U.S. population affected by autoimmunity, or some 30 million people. Some research suggests that the fact that women have two X chromosomes could be a factor. The X chromosome is home to tiny pieces of genetic material called microRNAs, which are thought to be involved in immune system function. While this is one reason women live longer, it could also make their immune system more susceptible to turning on itself.
It’s not so much our cleanliness but our increasingly industrial lifestyle that is blocking the intake of these important microorganisms.
Still, the rate at which autoimmune conditions are rising far outpaces the rate at which genes can pass them on, Rose says. “Autoimmune diseases, like many diseases, are a combination of genetic susceptibility on one hand and some exposure on the other,” he says. “We’re talking about an increase over 20, 25, 30 years. Genetics don’t change that rapidly, so it must be something environmental.”
Scientists began noticing a steep uptick in cases of autoimmune disease and allergies in the 1980s and 1990s, while cases of infectious diseases such as mumps, measles, and tuberculosis were falling, largely due to the widespread use of vaccines and antibiotics. Researchers theorized that these trends were related: Perhaps the absence of infection — the very thing our immune systems were designed to protect us from — was causing those systems to malfunction.
This observation was the genesis of the so-called hygiene hypothesis, the theory that sterile modern environments leave children vulnerable in unanticipated ways. Researchers thought children should be introduced to more pathogens at a young age to build up the immune system. Scientists have since refined this theory. According to Graham Rook, emeritus professor of medical microbiology at University College London, the immune system needs early and regular exposure to common and harmless microbes — bacteria, essentially — in order to learn how to react to threats.
“Epidemiologically, the point is confirmed that if you don’t have the right organisms in your gut at a certain critical point in your development, then there are defects in the immune system,” Rook says.
These much-needed microorganisms come primarily from the natural environment and what’s known as the maternal microbiome — the healthy bacteria we get from our mother in utero, through the vaginal canal, and even through breast milk. These sources have been compromised in developed nations due to less exposure to green spaces, a less varied diet, the overuse of antibiotics, and falling rates of breastfeeding and natural birth, Rook argues. People are exposed to a far less diverse range of microbes (or, in the case of antibiotics, those microbes are killed off), and that means our immune systems are less equipped to deal with the bacteria — good or bad — that comes our way. It’s not so much our cleanliness but our increasingly industrial lifestyle that is blocking the intake of these important microorganisms.
“The greater diversity of organisms in our gut, the healthier we seem to be,” Rook says.
People who live in developed countries have higher rates of autoimmune diseases than people living in the least developed countries, and people living in rapidly modernizing nations are more susceptible to autoimmune disease as their countries modernize. Studies show that developed nations have less microbially diverse environments than undeveloped ones, according to Rook, suggesting a strong link between the onset of autoimmunity and a lack of exposure to diverse microbes.
Rook and other researchers recommend that people try to get more exposure to nature by spending time outside, use antibiotics more judiciously — especially pregnant or breastfeeding women — and eat a healthy, holistic diet. They also acknowledge that there’s a limit to how much individuals can do to steel themselves against autoimmunity.
“There is almost universal agreement among scientists and physicians that the environmental toxins and chemicals to which we are increasingly exposed are interfering with the immune system’s ability to distinguish self from non-self,” writes Douglas Kerr, MD, PhD, associate professor of neurology, molecular microbiology, and immunology at the Johns Hopkins University School of Medicine.
There are some 80,000 chemicals approved for commercial use in the United States that have not been adequately studied to determine their effects on autoimmunity, according to Miller of the Environmental Autoimmunity Group, and some 5,000 are added every year.
A 2003 study tested for the presence of 210 chemicals in Americans’ blood and urine, including industrial compounds, pollutants, insecticides, dioxins, and mercury, and found that the study subjects tested positive for an average of 91 of them. Another study from 2005 looked at the fetal cord blood of 10 newborns from different locations around the United States and found the presence of 287 industrial chemicals, all of which were transmitted to the infants by their mothers before and during pregnancy.
There is some evidence that certain chemicals may set off an autoimmune response. Trichloroethylene, for instance, is a solvent used in refrigerators that has been detected in the U.S. water supply and has been found to triggeran autoimmune response and compromise the gut microbiome. Mercury has been found to trigger lupus, and certain pesticides have been found to causelupus and rheumatoid arthritis, to name just a few.
“The list of chemicals that have been indicted is a very long list,” Rose says. “The list of chemicals that have been shown to be able to induce an autoimmune disease, even in genetically prepared individuals, is a very short list.”
Vitamin D deficiency has also been linked to autoimmunity. More than a billion people on the planet are vitamin D deficient, according to theInternational Journal of Health Sciences. A chronic deficit of vitamin D has been linked to such autoimmune diseases as mellitus, rheumatoid arthritis, lupus, multiple sclerosis, and others.
Still other environmental factors could be at play. Smoking is shown to potentially trigger rheumatoid arthritis, lupus, multiple sclerosis, and more (though some studies have been inconclusive). Miller says that even meteorological components, such as ultraviolet radiation, temperature, and humidity, could be triggering autoimmunity.
The rise in out-of-whack immune systems may also be tied to internal stressors, specifically our increasingly stressed-out minds. Every year, Americans are reporting higher levels of stress and anxiety than the year before, according to the American Psychological Association (APA), citing everything from work and home life to technology to the political state of the country as reasons for their worry.
This has led to what many are calling an epidemic of stress — according to a 2017 report from the APA, 75% of Americans experienced at least one stress symptom in the past month. Forty-five percent report lying awake at night, 36% report feeling anxious, and 34% report stress-induced fatigue.
A 2018 study found that people with previously diagnosed stress-related disorders are far more susceptible to autoimmune diseases than those without. What the researchers found was threefold: The stressed-out individuals were more likely to be diagnosed with an autoimmune disease, more likely to develop multiple autoimmune diseases, and tended to develop autoimmune diseases earlier in life. The study also found that people with PTSD who were being treated with an SSRI antidepressant had lower chances of developing an autoimmune disease.
While all of these correlations are compelling, the bottom line is that they don’t reveal exactly why internal and external stressors contribute to the onset of autoimmune disease.
It’s likely a combination of all of these environmental exposures colliding on our immune systems at once. In fact, part of the difficulty of determining whether any one of these triggers is more important than the others is that humans are increasingly mobile, which means our exposure to agents is not isolated. Autoimmune symptoms take time to show up, making it difficult to know exactly what caused the problem in the first place.
“Every time I would go to a doctor, they would say, ‘There’s nothing wrong with you.’”
For Case, and millions of others, this has made the path to a diagnosis all the more frustrating. While her broad range of symptoms are all associated with Hashimoto’s, the disease doesn’t show up the same in everyone, leading to a long line of misdiagnoses.
“Every time I would go to a doctor, they would say, ‘There’s nothing wrong with you,’” Case says. “They were looking for arthritis, and I didn’t have it. When they did the X-rays looking for heart problems, I didn’t have heart problems. It was just a relief when it was finally diagnosed.”
Of course, figuring out how to better diagnose autoimmune disorders is an important element to better serving people like Case. But as Gilbert of the University of Arkansas put it, figuring out what’s causing the diseases is what will ultimately change the game.
“Combating an autoimmune disease, once you already have one, is extraordinarily difficult, as many people know,” Gilbert says. “The more we work on trying to figure out the triggers for autoimmune diseases, the more likely we will be able to start avoiding them—and avoiding the toll they take on patients.”
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