Volume 69, Issue 11 p. 2162-2169
Original Article
Free Access

Association of Trauma and Posttraumatic Stress Disorder With Incident Systemic Lupus Erythematosus in a Longitudinal Cohort of Women

Andrea L. Roberts PhD

Corresponding Author

Andrea L. Roberts PhD

Harvard T. H. Chan School of Public Health, Boston, Massachusetts

Address correspondence to Andrea L. Roberts, PhD, Harvard Chan School, 401 Park Drive, Boston, MA 02115. E-mail: [email protected].Search for more papers by this author
Susan Malspeis MS

Susan Malspeis MS

Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

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Laura D. Kubzansky PhD

Laura D. Kubzansky PhD

Harvard T. H. Chan School of Public Health, Boston, Massachusetts

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Candace H. Feldman MD

Candace H. Feldman MD

Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

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Shun-Chiao Chang ScD

Shun-Chiao Chang ScD

Brigham and Women's Hospital, Boston, Massachusetts

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Karestan C. Koenen PhD

Karestan C. Koenen PhD

Harvard T. H. Chan School of Public Health and Massachusetts General Hospital, Boston, Massachusetts

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Karen H. Costenbader MD, MPH

Karen H. Costenbader MD, MPH

Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

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First published: 20 September 2017
Citations: 70
Supported by NIH grants R01-AR-057327 and K24-AR-066109 to Dr. Costenbader. The Nurses’ Health Study II is supported by NIH grant UM1-CA-176726.

Abstract

Objective

To conduct the first longitudinal study examining whether trauma exposure and posttraumatic stress disorder (PTSD) are associated with increased risk of incident systemic lupus erythematosus (SLE) in a civilian cohort.

Methods

We examined the association of trauma exposure and PTSD symptoms with SLE incidence over 24 years of follow-up in a US longitudinal cohort of women (n = 54,763). Incident SLE in women meeting ≥4 American College of Rheumatology criteria was ascertained by self-report and confirmed by medical record review. PTSD and trauma exposure were assessed with the Short Screening Scale for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition PTSD and the Brief Trauma Questionnaire, respectively. Women were categorized as having no trauma, trauma and no PTSD symptoms, subclinical PTSD (1–3 symptoms), or probable PTSD (4–7 symptoms). We examined whether longitudinally assessed health risk factors (e.g., smoking, body mass index [BMI], oral contraceptive use) accounted for increased SLE risk among women with trauma exposure and PTSD versus those without.

Results

During follow-up, 73 cases of SLE occurred. Compared to women with no trauma, probable PTSD was associated with increased SLE risk (for 4–7 symptoms, hazard ratio [HR] 2.94 [95% confidence interval {95% CI} 1.19–7.26], P < 0.05). Subclinical PTSD was associated with increased SLE risk, although this did not reach statistical significance (for 1–3 symptoms, HR 1.83 [95% CI 0.74–4.56], P = 0.19). Smoking, BMI, and oral contraceptive use slightly attenuated the associations (e.g., for 4–7 symptoms, adjusted HR 2.62 [95% CI 1.09–6.48], P < 0.05). Trauma exposure, regardless of PTSD symptoms, was strongly associated with incident SLE (HR 2.83 [95% CI 1.29–6.21], P < 0.01).

Conclusion

This study contributes to growing evidence that psychosocial trauma and associated stress responses may lead to autoimmune disease.

Exposure to psychosocial stress may alter immune function, and exposure to severe stressors and high levels of subsequent distress have been implicated in autoimmune disease pathogenesis 1-3 and have been associated with subsequent development of autoimmune disease 4, 5. Posttraumatic stress disorder (PTSD) is the sentinel stress-related disorder and indicates severe psychological distress occurring in response to a traumatic stressor. Epidemiologic research has suggested that PTSD may increase the risk of autoimmune disease 6, 7, including rheumatoid arthritis 7-10, autoimmune thyroiditis 9, 10, inflammatory bowel disease, multiple sclerosis 9, and psoriasis 10. Thus, PTSD may also be associated with increased risk of systemic lupus erythematosus (SLE).

SLE is an autoimmune disorder associated with renal failure 11, myocardial infarction 12, 13, fatal infection 14, 15, and premature mortality (standardized mortality ratio 2.4) 14, the incidence of which is 3–13-fold higher among women than among men 16. High prevalences of anxiety and psychological distress are well documented among individuals with SLE 17-19, and stress and emotional distress are often implicated by SLE patients as triggers of their disease flares 20. However, evidence is sparse regarding whether traumatic experiences, stress, or PTSD increase SLE risk, as just 1 study comprising predominantly male military veterans has specifically examined the association of PTSD with risk of SLE. In a study using computerized medical records of individuals enrolled in the Department of Veterans Affairs health care system, war veterans diagnosed as having PTSD had a significantly higher risk of subsequently being diagnosed as having SLE (adjusted relative risk 1.85) 9 than those without a diagnosis of a psychiatric disorder over a median of 4 years of follow-up. Moreover, the association of PTSD with SLE (as well as with other autoimmune diseases) was stronger than those of other psychiatric disorders. This sample was 88% male, and the median duration between psychiatric diagnosis and immune disorder diagnosis was slightly >7 months (220 days), raising concerns about potential confounding or reverse causation due to undetected autoimmune disease.

No longitudinal studies have been conducted among civilians regarding risk of SLE in association with PTSD or traumatic events. Additionally, no studies have examined whether trauma exposure alone, irrespective of psychological sequelae, is associated with increased risk of SLE. Finally, lifestyle factors that are more common in persons with PTSD have been identified as possible risk factors for increased systemic inflammation and autoimmune disease, including smoking, obesity, and oral contraceptive use 16, 21-26. These behavioral factors may partially account for the relationship between trauma, PTSD, and autoimmune disease, yet their role has not been examined.

In the present study, we tested the hypothesis that trauma and PTSD are associated with increased risk of incident SLE in a large longitudinal cohort of civilian women. We further examined whether a higher prevalence of health risk behaviors, namely, smoking, sedentary lifestyle, obesity, alcohol use, and oral contraceptive use, might account for possible increased risk of SLE in women with PTSD and trauma exposure versus those without. Finally, as depression has been associated with SLE 18 and is frequently comorbid with PTSD 27, we ascertained the association of PTSD with SLE independently of depression.

Patients and Methods

Participants. The Nurses’ Health Study II (NHSII) is an ongoing cohort of 116,430 female nurses initially enrolled in 1989 and followed up with biennial questionnaires. The present study included follow-up through 2013. This study included women who returned a supplementary 2008 questionnaire on trauma exposure and PTSD symptoms (n = 54,763). This questionnaire was sent to a subsample of participants (n = 60,804; response rate 90.1%). To retain participation in the ongoing longitudinal cohort, only women who have already returned their biennial questionnaire are sent supplementary questionnaires. Women missing data on trauma or PTSD symptoms (n = 3,930) were excluded. This study was approved by the Institutional Review Board of Brigham and Women's Hospital. Return of the questionnaire via US mail constitutes implied consent.

Case ascertainment. Methods for SLE case identification and validation according to the American College of Rheumatology (ACR) revised criteria for SLE 28 as updated in 1997 29 have been reported 30, 31. Nurses were asked to report all new physician-diagnosed SLE on each questionnaire. Women who self-reported new cases were then asked to complete the Connective Tissue Disease (CTD) Screening Questionnaire 30, to provide the name and address of the health care provider who had diagnosed SLE, and to sign a medical records release. For all women who scored positive for symptoms of SLE on the CTD Screening Questionnaire, we attempted to obtain medical records from the time of diagnosis. These records were independently reviewed by 2 board-certified rheumatologists for all ACR criteria for SLE and other features consistent with SLE.

We excluded participants who reported an existing diagnosis of SLE at baseline and censored those who self-reported CTD at follow-up without SLE confirmation with ≥4 ACR criteria by medical record review (n = 531). The sensitivity and specificity of this 2-stage screening procedure have been shown to be high 32.

PTSD and trauma ascertainment. Trauma exposure and PTSD symptoms were assessed on a supplementary 2008 questionnaire. The 16-item Brief Trauma Questionnaire queried lifetime exposure to 15 types of traumatic events (e.g., serious car accident, sexual assault), and an additional item queried any traumatic event not covered in the other questions 33. Respondents were asked to identify which trauma was their worst or most distressing; they were then asked their age at this worst trauma as well as their age at their first trauma. PTSD symptoms were assessed in relation to their worst trauma with the 7-item Short Screening Scale for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition PTSD 34. Four or more symptoms on this scale have been associated with PTSD diagnosis (sensitivity 80%, specificity 97%, positive predictive value 71%, negative predictive value 98%) 34.

For each year of follow-up, participants were characterized as trauma unexposed, trauma exposed/no PTSD symptoms, trauma/1–3 PTSD symptoms (subclinical PTSD), or trauma/4–7 PTSD symptoms (probable PTSD). Trauma and PTSD status were time-updated over the follow-up period, with date of onset of trauma and PTSD symptoms determined as follows. A respondent was considered trauma unexposed for each year of follow-up before her age at first trauma. For each year of follow-up after her age at first trauma, she was considered trauma exposed/no PTSD symptoms. For each year of follow-up after her age at worst trauma, she was characterized as having no symptoms, 1–3 symptoms, or 4–7 PTSD symptoms based on her responses to the PTSD screen. If a woman reported only 1 trauma, her age at first trauma and age at worst trauma were considered the same. For example, a woman who reported experiencing her first trauma at age 40, her worst trauma at age 50, and 6 PTSD symptoms in relation to this worst trauma would be coded as trauma unexposed before age 40, trauma exposed with no PTSD symptoms after age 40, and trauma exposed with 4–7 PTSD symptoms after age 50. To mitigate concerns about reverse causality, women who reported illness as their worst trauma were excluded from analyses of PTSD and SLE to avoid including women whose SLE could have induced PTSD symptoms (n = 2,129; 18 cases of SLE).

For analyses of the association of any lifetime trauma with SLE risk (irrespective of PTSD symptoms), we coded trauma exposure according to a woman's age at her first trauma. For each year of follow-up, a woman was considered trauma exposed if she was older than her reported age at first trauma and was considered trauma unexposed if she was younger than her age at first trauma or reported never experiencing a traumatic event. Women whose first trauma was illness were excluded (n = 408; 4 cases of SLE).

Health risk behaviors and demographic covariates. We selected covariates that have been related to either PTSD or SLE or both 16, 21-23, 25, 26, 31, 35. Covariates were time-updated, such that for each year of follow-up the most recent report was used (further information is available upon request from the corresponding author). Oral contraceptive use, current smoking status, and weight were queried on each biennial questionnaire, from 1989 to 2013. Body mass index (BMI) was calculated in kg/m2 based on weight reported on the biennial questionnaires and self-reported height as reported on the baseline questionnaire (1989). Self-reported weight was highly reliable (r = 0.97) in a validation study 36. Physical activity was queried in 7 waves (1989–2013) and was characterized as 0–9 or ≥10 metabolic equivalents/week. Alcohol use was queried in 1989, 1995, 2005, and 2009. Lifetime history of depression was assessed in 2001. Indicators of socioeconomic status included US Census tract median household income obtained from geocoded home addresses and highest level of parents’ education when respondents were infants, reported in 2005 as high school or less, some college, or college or more. Self-reported race was coded as white or nonwhite. As race has been strongly associated with SLE risk 16, we included race in all models.

Statistical analysis. We examined prevalence of all covariates by trauma/PTSD status at baseline in 1989. To ascertain the association of trauma exposure and PTSD with incident SLE, we calculated hazard ratios (HRs) with 95% confidence intervals (95% CIs) for each level of trauma/PTSD symptoms using Cox proportional hazards regression with age in months as the measure of time (time metameter), with trauma unexposed as the referent. We additionally examined the association of PTSD symptoms, coded as a continuous variable (from 0 to 7), with SLE incidence.

We evaluated census tract median income and parents’ education in respondents’ infancy as possible demographic covariates; since we found that they were not associated with SLE and did not alter the association of trauma or PTSD with SLE, we did not include them in models. We separately examined the association of each health risk factor (e.g., smoking, sedentary behavior, obesity, alcohol use, and oral contraceptive use) with SLE incidence using Cox proportional hazards models. To ascertain the extent to which higher prevalence of health risk factors in women with PTSD could account for any observed elevated risk of SLE, we calculated HRs for SLE for each level of trauma/PTSD symptoms in models including as covariates all health factors associated with SLE, using Cox models.

We did not conduct formal mediation analyses, as the health risk factors we examined could be either confounders, to the extent that they were present prior to trauma or PTSD onset, or mediators, to the extent that they increased following onset of trauma or PTSD. Given the rarity of SLE and that these health risk factors typically initiate prior to the age of most women at our study enrollment, we did not have sufficient power to distinguish confounding from mediation. Thus, these analyses address the question “Does potentially higher prevalence of health risk factors in women with trauma/PTSD account for any observed elevated risk of SLE?” without distinguishing whether the factors are confounders or mediators of the PTSD–SLE relationship. To examine whether trauma exposure per se confers increased risk of SLE, regardless of whether women subsequently developed PTSD, we calculated hazard of incident SLE in relation to any lifetime trauma exposure using Cox models with age in months as the measure of time, with trauma unexposed as the referent.

Although we established the date of onset of PTSD, because PTSD assessment was in 2008, we conducted careful tests of the possibility of reverse causality in the relationship between PTSD and SLE. That is, we assessed the likelihood that prediagnosis SLE symptoms might either elicit PTSD symptoms or increase the likelihood of reporting PTSD symptoms, in 3 sensitivity analyses. First, we conducted analyses excluding any SLE cases occurring within 2 years of PTSD onset/trauma. Next, we examined the association of PTSD status at cohort enrollment in 1989 (i.e., without updating PTSD status over time) in relation to incident SLE over follow-up, to ensure that PTSD likely occurred well before SLE onset, given that women who reported SLE at cohort enrollment were excluded. Finally, we tested whether SLE incidence was associated with increased subsequent risk of PTSD; for this analysis we excluded women with PTSD symptom onset prior to developing SLE or prior to cohort enrollment and conducted Cox models with age as the time measure, adjusted for race. In these models, women were considered SLE unexposed before their SLE diagnosis or if they did not report SLE and SLE exposed in the year of their confirmed SLE diagnosis and for subsequent years. To ascertain whether PTSD was associated with SLE independently of depression, we conducted analyses excluding women with depression prior to PTSD onset. Thus, we conducted sensitivity analyses including only women who 1) reported no depression prior to 2001, when lifetime history of depression was assessed, and 2) had their worst trauma prior to 2001 or did not experience a traumatic event.

Results

Compared to women with no trauma exposure, women with 4–7 PTSD symptoms at baseline were of similar age, were more likely to have ever used oral contraceptives and to have ever smoked, and were less likely to have a healthful BMI (Table 1). Over the 24-year follow-up period, 73 women developed SLE. In time-updated models, smoking, oral contraceptive use, and BMI were each associated with increased risk of developing SLE, while alcohol use and sedentary behavior were not (Table 2). Nearly all women with SLE in our sample had seen an ACR member rheumatologist and were antinuclear antibody positive (Table 3).

Table 1. Baseline age-standardized characteristics of the subjects in the Nurses’ Health Study II (assessed in 1989) by trauma and PTSD status (n = 50,242)a
No trauma Trauma, no PTSD PTSD, 1–3 symptoms PTSD, 4–7 symptoms
(n = 14,885) (n = 19,579) (n = 9,514) (n = 6,264)
Age in 1989, mean ± SD yearsb 34.1 ± 4.8 34.8 ± 4.6 35.2 ± 4.5 35.2 ± 4.4
Nonwhite 5 5 6 6
Census tract median income <$40,000 11 13 13 15
Parents’ education, high school or less 50 49 49 48
Oral contraceptive use
Never 19 16 14 14
Past 67 73 74 76
Current 14 12 11 10
Smoking status
Never 72 66 64 60
Past 19 22 24 26
Current 10 12 12 14
Alcohol consumption ≥5 gm/day 20 20 21 20
BMI, mean ± SD kg/m2 23.6 ± 4.6 23.9 ± 4.8 24.0 ± 4.9 24.2 ± 5.2
Exercise
0–9 METs/week 38 37 38 37
≥10 METs/week 62 62 62 63
Lifetime history of depression (assessed in 2001) 5 8 8 20
  • a Values are standardized to the age distribution of the study population. Values of polytomous variables may not sum to 100% due to rounding. Except where indicated otherwise, values are the percent of subjects. PTSD = posttraumatic stress disorder; BMI = body mass index; METs = metabolic equivalents.
  • b Not age adjusted.
Table 2. Association of health risk factors with SLE incidence among women followed up in the Nurses’ Health Study IIa
Model Person-years SLE cases HR (95% CI)
BMI, kg/m2
18.5 to <25 596,488 34 1.0 (referent)
25 to <30 295,029 17 1.11 (0.61–2.00)
≥30 237,617 19 1.71 (0.95–3.04)
Smoking status
Never 764,548 37 1.0 (referent)
Past 297,275 26 1.93 (1.16–3.21)
Current 93,212 10 2.06 (1.01–4.18)
Oral contraceptive use
Never 150,051 3 1.0 (referent)
Ever 1,004,984 70 3.62 (1.14–11.52)
Exercise, METs/week
0–9 427,431 33 1.0 (referent)
≥10 691,039 39 0.74 (0.46–1.17)
Alcohol consumption
None 283,434 18 1.0 (referent)
>0 to <5 gm/day 599,448 38 1.08 (0.61–1.90)
≥5 gm/day 272,153 17 1.15 (0.59–2.26)
  • a All models are adjusted for race. Each model contains only 1 health risk factor. SLE = systemic lupus erythematosus; HR = hazard ratio; 95% CI = 95% confidence interval; BMI = body mass index; METs = metabolic equivalents.
Table 3. Characteristics of subjects with incident systemic lupus erythematosus in the Nurses’ Health Study II from 1989 to 2011 (n = 73)a
White race 68 (93.2)
ANA positive 72 (98.6)
Anti-dsDNA positive 39 (53.4)
Arthritis present 53 (72.6)
Hematologic involvement 47 (63.4)
Renal involvement 7 (9.6)
Seen by an ACR member rheumatologist 65 (89.0)
  • a Values are the number (%) of subjects. ANA = antinuclear antibody; anti-dsDNA = anti–double-stranded DNA; ACR = American College of Rheumatology.

In models adjusted only for race and age, a high level of PTSD symptoms 4-7 was associated with increased SLE risk. This association was somewhat attenuated in models further adjusted for smoking, oral contraceptive use, and BMI (Figure 1A). From 1 to 3 PTSD symptoms was associated with elevated risk of SLE; however, this did not reach statistical significance. In models adjusted for race and age, continuous PTSD symptoms were associated with increased risk of incident SLE with borderline statistical significance (per symptom, HR 1.11 [95% CI 0.99–1.24]). Any trauma exposure versus no trauma exposure was strongly associated with increased SLE risk (Figure 1B). This association was slightly attenuated after accounting for smoking, BMI, and oral contraceptive use.

Details are in the caption following the image
Hazard ratios (HRs) with 95% confidence intervals (95% CIs) for systemic lupus erythematosus in association with exposure to trauma and symptoms of posttraumatic stress disorder (PTSD). A, In the base model, for trauma and no PTSD, HR 1.96 (95% CI 0.82–4.66), P > 0.05; for 1–3 PTSD symptoms, HR 1.83 (95% CI 0.74–4.56), P = 0.19; for 4–7 PTSD symptoms, HR 2.94 (95% CI 1.19–7.26), P < 0.05. In the adjusted model, for trauma and no PTSD, HR 1.85 (95% CI 0.77–4.40), P > 0.05; for 1–3 PTSD symptoms, HR 1.68 (95% CI 0.68–4.19), P > 0.05; for 4–7 PTSD symptoms, HR 2.62 (95% CI 1.09–6.48), P < 0.05. B, In the base model, for trauma exposed, HR 2.83 (95% CI 1.29–6.21), P < 0.01. In the adjusted model, for trauma exposed, HR 2.61 (95% CI 1.19–5.73), P < 0.05. All HRs were calculated with Cox proportional hazards models with age in months as the time measure. All models are adjusted for race. BMI = body mass index.

In sensitivity analyses excluding the first 2 years of follow-up, results were similar to those in the main analyses (in race- and age-adjusted models, for 4–7 PTSD symptoms, HR 3.26 [95% CI 1.32–8.05]; for trauma exposure, HR 2.73 [95% CI 1.25–6.00]). In models examining risk of incident SLE in association with trauma and PTSD status at baseline in 1989, there was a strong association of trauma and PTSD with SLE incidence (in race- and age-adjusted models, for trauma and no PTSD, HR 2.41 [95% CI 1.21–4.81]; for 1–3 PTSD symptoms, HR 2.13 [95% CI 0.81–5.63]; for 4–7 PTSD symptoms, HR 3.83 [95% CI 1.65–8.91]). In sensitivity analyses, we did not find evidence that SLE increased risk of subsequently developing PTSD (for developing SLE, HR 0.92 [95% CI 0.29–2.93]). In analyses restricted to women without a diagnosis of depression prior to 2001 and with their worst event occurring prior to 2001 (n = 42,677; 22 cases of SLE), the association of trauma and PTSD symptoms with SLE risk was slightly stronger than in the main analyses, although confidence intervals were wide and estimates did not reach statistical significance, perhaps because there were relatively few cases (for trauma and no PTSD, HR 3.30 [95% CI 0.72–15.12]; for 1–3 PTSD symptoms, HR 2.87 [95% CI 0.58–14.3]; for 4–7 PTSD symptoms, HR 4.06 [95% CI 0.74–22.35]).

Discussion

In this large longitudinal study of civilian women, trauma exposure and PTSD were strongly associated with increased risk of incident SLE. We found a nearly 3-fold elevated risk of incident SLE among women with probable PTSD and a >2-fold higher risk of incident SLE among women who had experienced any traumatic event compared with trauma-unexposed women.

These associations do not appear to result from either confounding or reverse causality in the association, whereby SLE might have caused trauma exposure or PTSD. We excluded trauma caused by illness, and findings were consistent when trauma and PTSD exposure were time lagged and when trauma and PTSD were characterized at baseline, substantially prior to most SLE diagnoses. Results were also largely similar when we excluded women who had received a diagnosis of depression. Moreover, we found that SLE diagnosis itself did not predict risk of subsequently developing PTSD. These results strengthen evidence that the experience of trauma and PTSD may increase risk of subsequent SLE.

We examined whether several health risk factors accounted for the association between trauma or PTSD and SLE and found that an elevated risk of SLE in women with trauma or PTSD remained after accounting for these factors. These results indicate that biologic changes subsequent to trauma and PTSD should be further explored mechanisms by which trauma and PTSD increase risk of SLE. To date, much of the research on biologic changes associated with trauma and PTSD has been conducted examining whether higher levels of inflammation are evident 37-45 and considering alterations to the functioning of the hypothalamic–pituitary–adrenal (HPA) axis 46-48. As both HPA axis functioning and dysregulated inflammatory processes have been implicated in SLE, they are promising candidates for underlying mechanisms linking trauma–PTSD with subsequent SLE 1. PTSD has been associated with dysregulation of the HPA axis 46-48. HPA axis function differs in persons with versus those without SLE 49, although it is not known whether these abnormalities precede SLE onset.

Animal models have demonstrated a link between PTSD and increased systemic inflammation. For example, in rats exposed to predator-induced PTSD, inflammatory micro-RNAs were up-regulated in the brain, adrenal glands, and blood 50. In humans, numerous studies have found associations of PTSD and trauma exposure with elevated circulating inflammatory molecules, including tumor necrosis factor, C-reactive protein, and interleukin-6 37-45. Additionally, persons with PTSD have a more hyperactive immune response and higher circulating IgM levels than those without 10, 51. It is also possible that there may be additional relevant health risk factors that we did not measure. For example, sleep disturbance has been associated with PTSD 52 and is prevalent among patients with SLE 53. In a mouse model of SLE, sleep deprivation induced earlier disease onset 54.

Our findings are subject to several limitations. Our sample was predominantly white; therefore, this association should be studied in women of other races. Because of the timing of our PTSD assessment, lifetime exposure to trauma and PTSD symptoms was reported after many SLE cases had occurred (65 of 73). Moreover, our trauma and PTSD assessment was in 2008; thus, women may have experienced trauma and PTSD between 2008 and the end of follow-up in 2013. Misclassification of trauma- and PTSD-exposed women as unexposed is likely to have biased results toward the null hypothesis. Although we conducted multiple analyses to assess if our associations might be a result of SLE leading to trauma and PTSD, and did not find evidence to support this, our study design cannot definitively rule out this possibility. Although our sample was large, the number of incident SLE cases was moderate, limiting statistical power. Moreover, the women who enrolled in the NHSII cohort were nurses and were likely more interested in health-protective behaviors than women in the general population, and this difference may have biased our results. Our study has a number of important strengths. It is the first longitudinal study to examine this question among a healthy civilian cohort with incident SLE validated by medical record review. Participants were not selected on the basis of trauma or PTSD status; thus, our results are more generalizable than those of clinic-based studies.

Our study contributes to growing evidence that psychosocial trauma and associated stress responses lead to autoimmune disease. Identification of the biologic pathways by which psychosocial trauma may increase risk of autoimmune disease is crucial and may provide greater insight into disease etiology, as well as strategies for prevention. In addition, identification of mechanisms by which trauma and PTSD are associated with increased risk of SLE may indicate mechanisms for the association of PTSD and trauma exposure with other chronic diseases. Future studies are needed to determine whether treatment for PTSD affects these pathways and whether lifestyle interventions can reduce the risk of autoimmune disease subsequent to trauma or PTSD.

Acknowledgment

We acknowledge the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, for its management of the Nurses’ Health Study II.

    Author Contributions

    All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Roberts had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Study conception and design

    Roberts, Kubzansky, Feldman, Costenbader.

    Acquisition of data

    Chang, Koenen, Costenbader.

    Analysis and interpretation of data

    Roberts, Malspeis, Kubzansky, Feldman, Costenbader.