Source of surging autoimmunity may lie in ‘a thousand cuts’
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The common consensus for some time has been that the prevalence of autoimmunity and autoimmune diseases has been on the rise.
Decidedly less common, however, is a widely accepted explanation of why this is occurring.
Source: Andrew Wang, MD, PhD
Although solid figures remain elusive, estimates place the number of Americans with autoimmune diseases at approximately 24 million. According to a December 2023 opinion piece in Scientific American coauthored by Frederick W. Miller, MD, PhD, scientist emeritus in the Clinical Research Branch of the National Institute of Environmental Health Sciences at the NIH, there are at least 8 million people in the United States with psoriasis, as well as 4 million with Sjogren’s disease and 3 million with inflammatory bowel disease.
Meanwhile, a study published in The Lancet last December by Conrad and colleagues found that autoimmune disease impacts approximately one in 10 people in the United Kingdom.
Perhaps even more alarming are recent data from Miller and colleagues that the prevalence of antinuclear antibodies throughout the United States has increased nearly 50% in less than 30 years.
And although rheumatologists have their suspicions as to why, definite answers remain out of reach. Current evidence seems to implicate relatively recent changes in mass-produced foods, xenobiotics, air pollution, infections, personal lifestyles, stress, and climate change. However, this is far from consensus.
“We are not sure of their true causal roles or mechanisms or how much each might contribute, and that contribution will likely vary in any particular individual,” Miller told Healio Rheumatology. “In most cases, autoimmune illnesses develop in genetically susceptible individuals after multiple exposures to environmental risk factors over many years.”
To further complicate matters, the timing of these environmental influences may also be significant, according to Miller.
“Some exposures may be most influential at critical times during development to result in molecular changes in the body that then allow for future, other exposures to have their effects,” he said. “In some ways, this process could be considered disease by a thousand cuts.”
Because there are so many possible pathways to autoimmune disease development, it is nearly impossible to establish causality, according to Cassandra Calabrese, DO, of the department of Rheumatologic and Immunologic Disease at the Cleveland Clinic.
“The etiology of most autoimmune diseases is unknown,” she said, echoing Miller’s “thousand cuts” with the suggestion that a “multi-hit hypothesis” — genetic susceptibility plus stress and poor dietary habits, for example — drives understanding of how autoimmunity develops.
However, whether the mechanisms are understood or not, clinicians are forced to deal with the consequences. Until the genetics are more clearly described in the literature, rheumatologists must use available best practices and set their patients on a path that minimizes exposure to those triggers.
“We do terrible things to our bodies,” Calabrese said. “Terrible things are happening to our bodies. Poor physical and mental health habits are so common in this country, and we see it in our patients every day.”
That said, proper sleeping and eating habits can only go so far. There are also larger factors like the environment that lie beyond any individual’s control.
“You can’t avoid living in the modern world,” Andrew Wang, MD PhD, a rheumatologist and associate professor of medicine in rheumatology and immunobiology at the Yale School of Medicine, told Healio Rheumatology. “But we have to think about holistic care in rheumatology. Of course, we should advocate for our patients to eat healthier, exercise, get sufficient sleep, and watch their weight, but there could also be greater attention placed on managing mental health.”
To this end, education is essential, according to Wang.
“Just because we do not quite understand the associations does not mean we should avoid it with our patients,” he said. “We should educate our patients that there is an underlying biology connecting their habits to their disease.”
On a broader level, public policy targeting everything from climate change to food additives could be beneficial in minimizing the increasing rates of autoimmune disease in the world’s population. However, with so many competing priorities in health care public policy, regulating food coloring usage to reduce incidence of a niche condition like lupus, for example, often slips far down the priority list.
As rheumatologists and researchers grapple with these issues, defining the nature and prevalence of autoantibodies may be a useful place to begin.
Not a ‘Smoking Gun’
In a paper published in Arthritis & Rheumatology, Dinse and colleagues assessed data from the National Health and Nutrition Examination Survey to determine whether the prevalence of antinuclear antibodies (ANA) had changed between 1988 to 1991, 1999 to 2004, and 2011 to 2012. Results showed that the presence of ANA increased from 11% in the first time period to 16.1% in the last period. Moreover, the data showed a substantial increase in ANA among adolescents aged 12 to 19 years. Compared with the first time period, for individuals in that age range, the increases were observed in both the 1999 to 2004 group (OR = 2.07; 95% CI, 1.18-3.64) and the 2011 to 2012 group (OR = 2.77; 95% CI, 1.56-4.91).
Concurrent trends in overweight and obesity, smoking exposure or alcohol consumption failed to explain the increases in ANA, the researchers wrote.
These findings raise at least two important questions. One is why this increase occurred. Another is whether the increase in ANA correlates to true increases in autoimmune disease.
“It is possible that increased screening and detection protocols may lead to an apparent increase in the prevalence of autoimmune diseases and autoantibodies,” Miller, who was one of the authors of the paper, said. “That is why we need registries in the United States so we can fully assess the magnitude of the problem here, and if there are any hot spots where autoimmune diseases seem to concentrate.”
Miller additionally noted, however, that the ANA findings were not based on any screening protocols.
“So, these findings represent true increases in ANA in the United States,” he said.
Despite this observable trend, Calabrese argued that increases in autoantibodies do not necessarily correlate to increases in autoimmune disease.
“This has become increasingly true after COVID,” she said. “We are seeing so many more patients tested for various types of antibodies and referred to rheumatology as a result. As rheumatologists, we have to consider whether we should interpret those results in the context of the pandemic, or whether they are actually clinically significant and represent true increases in autoimmune disease.”
COVID-19 autoantibodies can be present for as long as a year, Calabrese added.
“As rheumatologists, we are the keepers of the people with vague symptoms and unusual lab results,” she said. “Primary care providers are seeing all of these patients with non-specific pain or fatigue, so they are sending them off for a whole series of labs and tests. Of course, some of them will naturally be positive for ANA, so they are referring them to us.”
However, as every rheumatologist knows, vague symptoms and positive ANA tests do not necessarily — or even often — lead to a diagnosis.
“Autoimmunity as measured merely by the presence of autoimmune laboratory phenomenon is not necessarily the smoking gun for the causality of long COVID,” Calabrese said.
The broader lesson is that the prevalence of autoantibodies in the wake of the pandemic may force public health officials to make more concerted efforts to understand these trends. However, at the moment, that work remains in its infancy.
“Whose job is it to standardize the testing and reporting protocols for autoantibodies?” Calabrese said. “That is a good question.”
That said, it may be possible to extend current U.S. data assessing the changing rates of ANA to eventually improve the understanding of autoimmunity, according to Miller.
“We are not completely sure of the magnitude of the prevalence of autoimmune diseases given the lack of registries and no coordinated health care system in the United States,” he said. “But using NHANES data and samples, we have measured the changing rates of ANA over time, and it is possible to extend this work to measure additional autoantibodies so we can have a more complete picture of autoimmunity in the United States.”
In the meantime, rheumatologists are faced with managing patients as best they can. That often means assessing, and improving, wellness behaviors.
Stressful Interactions
Rheumatologists see the impacts of stress on their patients every day.
“The idea that stress could induce some kind of autoimmunity has been percolating in the field for some time,” Wang said.
Many of the patients who are experiencing a flare of their disease have had “a major acute stressor” somewhere in their lives, according to Wang.
“Most of the physiology we attribute to this is like the fight or flight response, where there is a release of hormones and mediators,” he said. “But cortisol and adrenaline, which are released in normal fight or flight responses, are usually immune suppressors. It does not make sense why stress would induce this type of autoimmune response.”
In response to this conundrum, Qing and colleagues, including Wang, conducted a study on the origin and function of stress-induced interleukin-6.
“Acute psychological stress has long been known to decrease host fitness to inflammation in a wide variety of diseases, but how this occurs is incompletely understood,” they wrote.
In the murine study, the results of which were published in Cell, IL-6 was observed to be the dominant cytokine that could be induced by stress alone.
“These findings provide a mechanistic understanding of the ontogeny and adaptive purpose of IL-6 as a bona fide stress hormone coordinating systemic immunometabolic reprogramming,” the researchers wrote. “This brain-brown fat-liver axis might provide new insights into brown adipose tissue as a stress-responsive endocrine organ, and mechanistic insight into targeting this axis in the treatment of inflammatory and neuropsychiatric diseases.”
Importantly, IL-6 is also associated with anxiety and depression, which may explain its presence in stressful situations such as a death or illness in the family, according to Wang.
“This is one example where we can mechanistically show how psychological stress can promote inflammatory responses,” he said.
This interaction can also combine with a patient’s underlying genetics to impact the development of an autoimmune disease, Wang added.
“You can imagine that if you have a 40% chance of developing an autoimmune disease because of your genetic makeup, and then you have a stressful event in your life, it can tip you over,” he said. “We can see both the adaptive purpose of making the cytokine and how it can become maladaptive.”
With this biology as a backdrop, Case and colleagues investigated possible associations between post-traumatic stress disorder and systemic lupus erythematosus, in a paper published in Arthritis Care & Research. The cohort included 10,942 incident SLE cases and 109,420 controls. Results showed that the prevalence of PTSD was 10.74 cases per 1,000 person-years in the SLE group (95% CI 9.37–12.31), compared with just 7.83 cases per 1,000 person-years (95% CI 7.42–8.27) among controls.
These findings can be applied more broadly in other autoimmune diseases.
In a 2020 paper published in BMC Psychiatry, Bookwalter and colleagues investigated associations between PTSD and several conditions, including rheumatoid arthritis, SLE, irritable bowel disease and multiple sclerosis, among active-duty U.S. military service members. Results showed that in individuals with a history of PTSD, the risk for autoimmune disease was 58% higher vs. those who had no such history (HR = 1.58; 95% CI, 1.25-2.01).
“Increasing evidence suggests a link between PTSD and physical health,” Anca D. Askanase, MD, MPH, director of the Columbia University Lupus Center, and professor of medicine in the division of rheumatology at the Columbia University College of Physicians & Surgeons, told Healio Rheumatology. “Stress disorders may lead to impairment of the immune system and subsequent autoimmune disease.”
Despite these findings, few rheumatologists would suggest that stress is the sole contributor to autoimmunity. Investigation into other factors may also add to the “thousand cuts” hypothesis.
Keeping a Circadian Rhythm
“Sleep deprivation occurs due to lifestyle, work and environmental factors,” Askanase said. “Sleep disorders and other chronic medical conditions can also cause sleep deprivation.”
Given that rheumatology is rife with chronic conditions, the bidirectional relationship between sleep and autoimmunity is well documented.
Jeffrey C. Hall, MS, PhD, Michael Rosbash, MD, PhD, and Michael W. Young, PhD, won the 2017 Nobel Prize in Physiology or Medicine for their work in the molecular mechanisms controlling the circadian rhythm. Cutolo and colleagues published a paper in Joint Bone Spine based on that research examining sleep and autoimmunity more specifically.
“Circadian rhythms regulate, at the level of central nervous system and inside cells, daily activities like sleep, feeding times, energy metabolism, endocrine and immune functions, including inflammation,” Cutolo and colleagues wrote. “The circadian rhythms are responsible for the night synthesis and release of pro-inflammatory (cytokines and chemokines, cell migration to inflamed tissues, phagocytosis, proliferative cell response and all are peaking late night) and anti-inflammatory endogenous cortisol.”
Askanase explained how this underlying biology can play out in an individual patient.
“Arthritis interferes with sleep,” she said. “Additionally, people with arthritis can have comorbid fibromyalgia, depression, anxiety and sleep apnea, which can interfere with sleep quality.”
According to Askanase, it is important to understand how sleep can impact individuals even before their autoimmune disease develops.
“Pain sensitivity and markers of inflammation increase when sleep is disrupted, even in people without arthritis,” Askanase said. “During sleep the body produces growth hormone, endorphins, serotonin and dopamine, which help with mood, wellbeing and coping. Not being well rested is a stress on the body, and as such increases the risks for flares.”
With so many potential biological consequences, it is easy to see how poor sleep can serve as one of the triggers to an underlying genetic predisposition to autoimmunity.
That said, understanding the chemical processes of how stress and sleep can lead to autoimmunity is only part of the equation. The toxins and chemicals in our food, air and water must also be considered.
A Potentially Dangerous Environment
In another murine paper published in Cell Metabolism, He and colleagues investigated associations between azo dyes Red 40 and Yellow 6 — the two most common food colorants in the world — and inflammatory bowel disease. Results showed that these two dyes were associated with the expression of IL-23, which, in turn, is part of the signaling pathway for inflammatory bowel disease.
“Increased IL-23 expression led to generation of activated CD4+ T cells that expressed interferon- and transferred disease to mice exposed to Red 40,” the researchers wrote, later adding that food colorants may represent a “novel risk factor” for colitis development.
Wang, who was not associated with the paper, noted that it is important to look not only at foods that have been purported to exacerbate inflammation, but the ingredients in those products.
“Instead of thinking about food, we are looking at the preservatives we add to them to see if they could be adjuvants that lead to autoimmunity against self,” he said.
According to Wang, it is important to understand that the potential effects of products like Red 40 and Yellow 6 are not only “dose-dependent and time-dependent,” but also dependent on the gut microbiome and genetic background.
“The cards have to align to cause disease,” he said. “But in a susceptible individual, it is possible that these products may increase the risk for disease onset.”
Although Americans are often viewed as paragons of unhealthy eating habits, the worldwide availability of such food additives makes them unavoidable for almost anyone living in the developed world.
Another unavoidable reality for most individuals is air pollution. According to Askanase, data have linked pollution to conditions ranging from asthma to SLE.
Specifically, a recent review paper by Gilcrease and colleagues published in the European Journal of Rheumatology demonstrated that variations in air pollution may influence disease activity in patients with SLE.
“They propose that understanding the increased burden of SLE and its complications, as it related to exposure to pollutants, should have implications for resource allocation and access to subspecialty care,” Askanase said.
Again, research into such factors is limited, according to Wang.
“We tell our patients that the environment can be a big factor in their disease but, unfortunately, we do not know exactly what in the environment matters or the magnitude of that impact,” he said. “Our environment has a lot of potential ways to change our immune system functions.”
As experts continue to understand etiological factors, experts like Miller called on the rheumatology community to begin moving toward solutions to the rise in autoimmune disease seen in the United States and across the globe.
‘Stop It Before It Starts’
“Autoimmune diseases have a major impact on the individuals and families they affect, as well as on our society and health care costs, and current projections suggest they may soon take their place among the predominant medical disorders,” Miller wrote a February 2023 editorial published in Current Opinions in Rheumatology. “This necessitates that we increase the scope and scale of our efforts, and coordinate our resources and studies, to understand autoimmune disease risk factors and pathogeneses and improve our diagnostic, therapeutic, and preventive approaches, as the costs of inaction will be profound and far greater without such investments.”
According to Miller, there are a few simple starting points for rheumatologists to consider when counseling patients on reducing their individual risk for autoimmune disease.
“There are adequate data now to suggest that physicians can advise their patients that altering their lifestyle activities can have an impact on decreasing the risks for autoimmune and other diseases,” he said. “Do not smoke and do not drink alcohol excessively; eat in more healthy ways, along the lines of the Mediterranean diet, with less salt, fat, sugar and processed foods; get regular and adequate sleep; maintain a healthy body weight; exercise regularly; avoid exposures to toxic fumes and chemicals as much as possible; and practice stress reduction.”
However, for Calabrese, constantly repeating all the things patients should or should not do can sometimes cause them to tune out.
“We also should look at the themes and common denominators on a broader level,” she said. “There are populations around the world who consistently live longer and healthier lives than others. Understanding their habits and lifestyle may help us minimize the autoimmunity we are seeing here.”
Similar to Wang, Miller also championed education as another potential component to the battle against autoimmunity.
“We need a comprehensive education program to inform people about the problem and preventatives,” Miller said. “Our health care system has been stretched very thin by many pressures, including the recent pandemic, and improved funding to allow for more access, screening and treatment programs for autoimmune diseases would be helpful.”
Education can also extend to health care providers, according to Askanase.
“Educating primary care providers to better identify autoimmune diseases, and thereby improve referrals, will mitigate the anxiety associated with the unnecessary work-up and decrease the burden on the health care system,” she said.
Meanwhile, at the government and public health level, additional laws, controls and inspections to improve air, water, soil and food quality are essential, according to Miller.
“Decreasing chemical use and pollution would be useful in preventing the development of more diseases of many types, including autoimmune diseases,” he said.
Although such solutions would surely be difficult to enact — depending on the jurisdiction — Wang stressed the urgency of the situation.
“Once autoimmunity is established, it is very rare that it can be reversed,” he said. “It becomes a chronic disease that requires chronic treatment, often for the rest of the patient’s life. It would be hugely beneficial to find ways to stop it before it starts.”
- References:
- Bookwalter DB, et al. BMC Psych. 2020;doi:10.1186/s12888-020-2432-9.
- Conrad N, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)00457-9.
- Case SM, et al. Arth Care & Res. 2021;doi:10.1002/acr.24758.
- Cutolo M. Joint Bone Spine. 2019;doi:10.1016/j.jbspin.2018.09.003.
- Dinse GE, et al. Arthritis Rheumatol. 2022;doi:10.1002/art.42330.
- Gilcrease GW et al. Eur J Rheumatol. 2020;doi:10.5152/eurjrheum.2019.19141.
- He Z, et al. Cell Metab. 2021;doi:10.1016/j.cmet.2021.04.015.
- Miller FW. Curr Opin Immunol. 2023;doi:10.1016/j.coi.2022.102266.
- Qing H, et al. Cell. 2020;doi:10.1016/j.cell.2020.05.054.
- For more information:
- Anca D. Askanase, MD, MPH, can be reached at 161 Fort Washington Ave., New York, NY 10032; email: ada20@cumc.columbia.edu.
- Cassandra Calabrese, DO, can be reached at 9500 Euclid Ave., Cleveland, Ohio 44195; email: calabrc@ccf.org.
- Frederick W. Miller, MD, PhD, can be reached at Bldg. 101, Mail Drop A2-03, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709; email: millerf@mail.nih.gov.
- Andrew Wang, MD, PhD, can be reached at Anylan Center S520, 300 Cedar St., New Haven, CT 06519; email: andrew.wang@yale.edu; colleen.moriarty@yale.edu.
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