Objective The link between neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) and heightened morbidity, mortality, and organ damage, as well as detrimental impacts on health-related quality of life has been well-documented. However, the direct association between NPSLE and specific SLICC/ACR damage index (SDI) items, especially non-neuropsychiatric items, remains unclear. Herein, we sought to investigate the impact of NPSLE on organ damage accrual in a large lupus cohort.

Methods We conducted an analysis of baseline data derived from five phase III trials (BLISS-52, BLISS-76, BLISS-SC, BLISS-NEA, EMBRACE), encompassing a total of 3645 SLE participants. NPSLE involvement was defined as NP BILAG A/B/C/D or scores on any of the NP SLEDAI-2K domains (n=372); the non-NPSLE group comprised patients with NP BILAG E and no neuropsychiatric involvement based on the NP SLEDAI-2K domains (n=3273). We employed univariable logistic regression analysis in case of < 30 events, or multivariable analysis to adjust for age, disease duration, sex, and ethnic origin in all other cases.

Results The median/mean (IQR; SD) SDI score and SLE disease duration were 0; 0.62 (0–1; 1.09) and 4.51; 6.44 (1.56–9.32; 6.33) years, respectively. Compared with the non-NPSLE group, SLE patients with neuropsychiatric involvement had greater SDI scores (adjusted (a)OR: 2.70; 95% CI: 2.14–3.42; p< 0.001). This held true also after suppression of the NPSLE SDI items from the total SDI score ((a)1.54; 1.22–1.94; p< 0.001). As expected, neuropsychiatric involvement was associated with damage in the neuropsychiatric domain ((a)8.71; 6.64–11.44; p< 0.001). More importantly, neuropsychiatric involvement was associated with damage in the cardiovascular ((a)2.44; 1.61–3.69; p< 0.001), musculoskeletal ((a)1.76; 1.31–2.35; p< 0.001), and skin ((a)1.45; 1.00–2.11; p=0.05) domains. Dissecting the SDI domains into specific items, neuropsychiatric involvement was associated with established damage in terms of coronary artery disease ((a)2.88; 1.34–6.18; p=0.007), myocardial infraction ((a)2.90; 1.41–5.96; p=0.004), valvular disease (4.94; 1.65–14.81; p=0.004), muscle atrophy ((a)3.17; 2.05–4.92; p< 0.001), bowel infarction ((a)1.84; 1.11–3.04; p=0.018), and scarring alopecia ((a)1.69; 1.12–2.56; p=0.013). Lastly, SLE patients with neuropsychiatric involvement were more likely to have developed premature gonadal failure ((a)1.97; 1.06–3.67; p=0.032) compared with SLE patients with no history of neuropsychiatric events.

Conclusions The intricate association between neuropsychiatric involvement in SLE and damage accrual extends beyond the realm of the nervous system, impacting the musculoskeletal, skin, and cardiovascular organ systems. Prospective research, especially survey in non-selected real-world SLE cohorts, would be required to determine the causal relationship between NPSLE and the various components of the SDI. Clarifying this association would contribute to a more comprehensive understanding of the disease and facilitate more targeted management strategies for individuals affected by NPSLE.