Background/Purpose: Although patients with SLE may report that psychosocial stress is linked with disease flares, research results on stress-disease activity associations are mixed. The lack of consistent results may be due to lack of true associations, difficulty in measuring stress, or to lack of precision in capturing the onset of SLE flares. Recently, the presence of complement activation products on circulating blood cells has emerged as a novel biomarker for diagnosis and disease activity in SLE. Complement activation products have been detected on reticulocytes, which are new blood cells that emerge from the bone marrow and are in circulation for just 1-2 days before becoming erythrocytes. Reticulocytes bearing complement activation product C4d (R-C4d) are potential biomarkers of new onset SLE disease activity. The purpose of this study was to evaluate the association between psychosocial stress, self-reported disease activity, and early signs of complement activation as measured by R-C4d in patients with SLE.

Methods: After completing informed consent, 123 SLE patients completed the 10-item Perceived Stress Scale (PSS), the Center for Epidemiologic Studies Depression scale (CESD), and the Positive Affect scale of the PANAS (Positive and Negative Affect Scale), as well as the self-report Systemic  Lupus Activity Questionnaire (SLAQ) at up to 4 clinic visits.  Reticulocytes were evaluated for presence of C4d using median fluorescence intensity (MFI) analysis by flow cytometry.  R-C4d units were dichotomized at 3.35 MFI, a score indicative of abnormally elevated R-C4d level due to complement activation. Mixed regression modeling was used to evaluate concurrent associations between psychosocial variables, SLAQ, and R-C4d.

Results:  The majority of participants were female (94%), non-Hispanic (96%), and non- African American (86%).  The mean (SD) age was 45 (13) years.  Mean (SD) SLAQ score was 11.4 (5.7) at study entry.  R-C4d was concurrently associated with higher perceived stress; those with elevated R-C4d were 2.18 points higher on the PSS (p= 0. 01).  There was a trend for lower Positive Affect scores to be associated with R-C4d (p= 0.06). Depressive symptoms (CESD), which averaged 16.2 (11.6) at study entry, were not associated with R-C4d (p = 0.25). SLAQ total score was not associated with elevated R-C4d (p = 0.58), but was associated with CESD (β=0.19, p<0.001), PANAS (β=-0.21, p<0.001) and PSS (β=0.2, p<0.001).

Conclusion: SLE patients with elevated levels of R-C4d had higher levels of perceived stress or feeling overwhelmed compared to patients without R-C4d elevation.  This, in combination with the trend toward lower levels of positive affect, supports the idea of biological links between early SLE flares and perceptions of stress and malaise. The finding that CESD was not associated with R-C4d may be related to the breadth of depressive symptoms assessed by CESD, which range from social isolation to sleep problems in addition to sad mood.  Whether psychosocial stress precedes or results from disease flares remains unknown given the concurrent measurements used in this study.  Future studies should examine prospective links between stress and SLE disease biomarkers and should include physician ratings of SLE disease activity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/psychosocial-stress-and-complement-activation-product-c4d-on-reticulocytes-in-patients-with-systemic-lupus-erythematosus/