Summary: Researchers consider why those with autoimmune diseases are more likely to have a previous diagnosis of stress-related disorders.
A new study has raised the possibility that stress may cause autoimmune disease, such as lupus or rheumatoid arthritis, because it found a higher incidence of autoimmune diseases among people who were previously diagnosed with stress-related disorders.
I have patients who heard about this research and are saying, “I knew it!”
But before we accept a potential link between stress and autoimmune disease, let’s look at some details of the study and consider how we define the terms “autoimmune disease,” “stress,” and “stress-related disorder.”
What is autoimmune disease?
These are fascinating and mysterious conditions in which the body’s immune system “misfires” and attacks its own tissues. There are scores of autoimmune diseases out there. Some of the most well-known are rheumatoid arthritis, psoriasis, multiple sclerosis, and type 1 diabetes.
In some cases, a condition is labeled “autoimmune” based on conventional wisdom or expert consensus rather than hard science. And I’ve seen the term “autoimmune” used loosely to apply to any condition of unknown cause in which inflammation is present or the immune system appears to be active. But an infection could do the same thing. So perhaps some of these conditions now considered to be autoimmune will turn out to be chronic infections by an organism we’ve not yet identified.
What is stress?
A common definition of “stress” is any experience that causes tension, whether physical, psychological, or emotional, especially if it sets off the “fight or flight” response (during which the adrenal gland releases adrenaline, leading to rapid pulse and breathing, and increased blood pressure). This serves us well if chased by a lion. But it’s theorized that persistent stress (such as worry about finances, mental or physical health, or interpersonal relationships) could lead to chronic disease such as high blood pressure or autoimmune disease.
What causes stress for a person is highly individual. A common example is having to speak in public. Some people find it easy to give a speech in front of a crowd; for others, however, the exact same situation may feel nothing short of dreadful and causes worry for weeks in advance. A stressful experience can also be something quite positive, like getting married, or walking into a room on your birthday where friends and family are hiding. Surprise!
What is a stress-related disorder?
There is a big difference between stress and having a “stress-related disorder,” in which a particular, well-defined condition or disease develops following a specific and intensely stressful event. A dramatic example is post-traumatic stress disorder (PTSD), in which a serious physical or psychological injury leads to a host of problems including distressing, intrusive memories of the traumatic event; memory problems; apathy; and irritability.
Exploring the connection between stress and autoimmune disease
In this new study, researchers analyzed more than 100,000 people diagnosed with stress-related disorders and compared their tendency to develop autoimmune disease at least one year later with 126,000 of their siblings, and another million people who did not have stress-related disorders.
The study found that individuals diagnosed with a stress-related disorder
- were more likely to be diagnosed with an autoimmune disease (about nine per 1,000 patient-years* who had stress-related disorders, but only about six per 1,000 patient-years among those without stress-related disorders)
- were more likely to develop multiple autoimmune diseases
- had a higher rate of autoimmune disease if younger.
*Patient-years is an expression that combines how many and for how long people are assessed in a study. If the frequency of a condition is 9 per 1,000 patient-years, that means 9 people would develop the disease among, 1000 patients monitored for 1 year, or among 500 patients monitored for 2 years, and so on).
A particularly important observation was that, for those with PTSD who were being treated with an SSRI (a type of antidepressant), the increased rate of autoimmune disease was less dramatic. While these observations are intriguing, they don’t tell us why or how a stress-related disorder might provoke or cause autoimmune disease.
The usual caveats about observational studies
It’s important to emphasize that a study of this type (called an observational study) cannot conclude that stress-related disorders actually cause autoimmune disease. There could be other explanations for the findings. For example, it is often impossible to identify a precise date that an autoimmune disease or a stress-related disorder began. So, despite the researchers’ requirement that the autoimmune disease be diagnosed well after the stress-related disorder, it’s possible that the autoimmune condition was already present before the stress-related disorder was diagnosed. If that was the case, the stress-related disorder could not have caused the autoimmune disease.
In addition, it’s possible that something other than the stress-related disorder was to blame for the higher rate of autoimmune disease. For example, people who have been through severely stressful circumstances may be more likely to smoke, and smoking has been linked to an increased risk of certain autoimmune diseases, including rheumatoid arthritis and multiple sclerosis.
One more point: this study appears to have included type 2 diabetes among the 41 autoimmune diseases it considered. Although this is the most common type of diabetes (accounting for more than 90% of all cases), it is not considered an autoimmune disease. Different results might have been noted if stricter definitions of autoimmune disease had been applied.
The mystery of autoimmune illness continues
Whether stress or stress-related disorders play an important role remains speculative. Even more important is the question of whether any particular treatment of these stress-induced psychological illnesses can prevent autoimmune disease. I look forward to a clinical trial that examines this fascinating possibility.
Robert H. Shmerling, MD – Harvard
The image is in the public domain.
Original Research: Open access
“Association of Stress-Related Disorders With Subsequent Autoimmune Disease”. Huan Song, MD, PhD et al.
Association of Stress-Related Disorders With Subsequent Autoimmune Disease
Psychiatric reactions to life stressors are common in the general population and may result in immune dysfunction. Whether such reactions contribute to the risk of autoimmune disease remains unclear.
To determine whether there is an association between stress-related disorders and subsequent autoimmune disease.
Design, Setting, and Participants
Population- and sibling-matched retrospective cohort study conducted in Sweden from January 1, 1981, to December 31, 2013. The cohort included 106 464 exposed patients with stress-related disorders, with 1 064 640 matched unexposed persons and 126 652 full siblings of these patients.
Diagnosis of stress-related disorders, ie, posttraumatic stress disorder, acute stress reaction, adjustment disorder, and other stress reactions.
Main Outcomes and Measures
Stress-related disorder and autoimmune diseases were identified through the National Patient Register. The Cox model was used to estimate hazard ratios (HRs) with 95% CIs of 41 autoimmune diseases beyond 1 year after the diagnosis of stress-related disorders, controlling for multiple risk factors.
The median age at diagnosis of stress-related disorders was 41 years (interquartile range, 33-50 years) and 40% of the exposed patients were male. During a mean follow-up of 10 years, the incidence rate of autoimmune diseases was 9.1, 6.0, and 6.5 per 1000 person-years among the exposed, matched unexposed, and sibling cohorts, respectively (absolute rate difference, 3.12 [95% CI, 2.99-3.25] and 2.49 [95% CI, 2.23-2.76] per 1000 person-years compared with the population- and sibling-based reference groups, respectively). Compared with the unexposed population, patients with stress-related disorders were at increased risk of autoimmune disease (HR, 1.36 [95% CI, 1.33-1.40]). The HRs for patients with posttraumatic stress disorder were 1.46 (95% CI, 1.32-1.61) for any and 2.29 (95% CI, 1.72-3.04) for multiple (≥3) autoimmune diseases. These associations were consistent in the sibling-based comparison. Relative risk elevations were more pronounced among younger patients (HR, 1.48 [95% CI, 1.42-1.55]; 1.41 [95% CI, 1.33-1.48]; 1.31 [95% CI, 1.24-1.37]; and 1.23 [95% CI, 1.17-1.30] for age at ≤33, 34-41, 42-50, and ≥51 years, respectively; P for interaction < .001). Persistent use of selective serotonin reuptake inhibitors during the first year of posttraumatic stress disorder diagnosis was associated with attenuated relative risk of autoimmune disease (HR, 3.64 [95% CI, 2.00-6.62]; 2.65 [95% CI, 1.57-4.45]; and 1.82 [95% CI, 1.09-3.02] for duration ≤179, 180-319, and ≥320 days, respectively; P for trend = .03).
Conclusions and Relevance
In this Swedish cohort, exposure to a stress-related disorder was significantly associated with increased risk of subsequent autoimmune disease, compared with matched unexposed individuals and with full siblings. Further studies are needed to better understand the underlying mechanisms.