Among U.S. veterans with antibody-positive rheumatoid arthritis (RA), concomitant post-traumatic stress disorder (PTSD) was associated with notably elevated serum concentration of inflammatory cytokines, suggesting that the systemic inflammation underlying RA may be exacerbated in the context of this psychiatric comorbidity.
Patients with RA who were positive for anti-cyclic citrullinated peptide (CCP) and had been diagnosed with PTSD had higher cytokine scores (β = 0.179, P=0.018) than those without psychological comorbidities or with other forms of anxiety or depression, according to Ted R. Mikuls, MD, of the University of Nebraska Medical Center in Omaha, and colleagues.
They also had a higher number of positive inflammatory cytokines (β = 0.339, P<0.001), they reported online in Seminars in Arthritis & Rheumatism.
It has become clear that psychosocial stress can increase the risk for the development of autoimmune disease, presumably because of contributory factors such as low-grade systemic inflammation, but whether such stress can also influence the course of autoimmune disease once established has not been fully examined.
“This is a clinically relevant question, as evidence linking the two would suggest that treatments aimed at reducing levels of psychosocial stress could yield meaningful benefits in the management of autoimmune disease,” Mikuls and colleagues stated.
Therefore, to consider whether high levels of inflammatory mediators and cytokines are present in RA patients with PTSD, the researchers analyzed data from 1,460 patients enrolled in the Veterans Affairs Rheumatoid Arthritis registry. Participants were classified according to their medical records as having PTSD with or without concomitant depression or anxiety, depression or anxiety without PTSD, or neither.
Concentrations of 17 cytokines considered relevant to RA inflammation were measured, and were considered positive if the value was at least two standard deviations above the mean in the overall population. Cytokine scores reflecting overall inflammation levels were then calculated from the individual analytes, including interleukin (IL)-1β, IL-2, IL-4, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein (MCP)-1, interferon-γ, and tumor necrosis factor-α.
Additional factors included in the analysis were sex, age, race, comorbidities, and seropositivity.
Participants’ mean age was 64, and most were white (78%) and men (91%). A total of 11.6% had one or more ICD-9 codes for PTSD, most of whom also had diagnoses of anxiety and/or depression; 23.7% had been diagnosed with forms of anxiety and/or depression other than PTSD; and 64.7% had neither diagnosis.
Those with PTSD or another form of anxiety or depression had more comorbidities, worse function, and higher disease activity scores.
The higher cytokine scores and greater number of individual positive cytokines seen in the PTSD group were not found in the group of patients with non-PTSD anxiety or depression. Nor were they observed in anti-CCP-negative patients, who tend to have less severe disease.
In analyses that adjusted for age, sex, race, and smoking, PTSD was significantly associated with serum concentrations of these cytokines:
- IL-1β (β = 0.252, P=0.010)
- GM-CSF (β = 0.239, P=0.039)
- MCP-1 (β = 0.156, P=0.024)
Trends also were seen for higher concentrations of other cytokines such as IL-6, IL-10, and interferon-γ.
And among PTSD patients who were anti-CCP positive, significantly higher serum concentrations were seen for 13 of the 17 cytokines measured. It’s possible that the influence of PTSD on inflammation acts through pathways that are dependent on anti-CCP positivity, the authors noted.
The findings of this study — that the cytokine profiles of RA patients with PTSD were significantly different from those without anxiety or depression diagnoses and also from those with other forms of anxiety or depression — “suggest that along the spectrum of different anxiety and mood disorders, PTSD appears to be unique in its capacity of promoting heightened inflammatory responses and thus may be more likely to adversely influence the natural course of disorders characterized by systemic inflammation,” they wrote.
Another important observation was that certain of the cytokines found in high concentrations in the PTSD group, such as IL-1β and IL-6, they have been implicated in RA pathogenesis, and whether therapies targeting these markers could be of particular benefit in these patients is unknown but could be considered.
“Additional insight into the complex mechanisms that underpin the relationship of PTSD with measures of systemic inflammation will be needed to optimize future interventions in this population,” the researchers concluded.
A limitation of the study was the predominance in the VA population of older white men.
The authors disclosed support from the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Alcohol Abuse and Alcoholism, the National Institute of General Medical Sciences, the Veterans Affairs Office of Research and Development, Bristol-Myers Squibb, Ironwood Pharmaceuticals, and the Department of Veterans Affairs. One co-author is now an AbbVie employee.