Background/Purpose: Identifying populations at risk of SLE is essential to curtail inflammatory damage and identify individuals for prevention trials. Healthy blood relatives (FDRs) of lupus patients have increased risk of SLE. Some FDRs have autoantibodies and SLE clinical features, but do not meet the required ≥ 4 ACR classification criteria (incomplete lupus, ILE), while others remain unaffected. The goal of this study is to determine factors that distinguish previously healthy FDRs who subsequently develop ILE or SLE.

Methods: This study re-enrolled 436 FDRs of SLE patients who previously enrolled in a genetics study (mean time to followup = 6.3 yrs) and did not meet SLE classification criteria (144 with 0 criteria, 251 with 1-2 criteria, and 41 met 3 criteria) to determine evolution of SLE symptoms and classified disease. FDRs provided clinical and demographic information, and completed the SLE-specific portion of the CTD Screening Questionnaire (CSQ) at baseline (BL) and follow-up (FU). Medical records were reviewed for ACR classification criteria. BL and FU plasma samples were assessed for autoantibody production (ANA, anti-dsDNA, aCL, Ro, La, Sm, nRNP, and ribosomal p antibodies) and for 52 soluble inflammatory mediators (BLyS, APRIL, cytokines, chemokines, and shed TNF receptors). Samples were compared among ILE participants, FDRs who transitioned to SLE, and race/gender/age (± 5 years) matched FDRs who remained unaffected (2:1 ratio of unaffected: ILE/SLE).

Results: 56 FDRs transitioned to SLE (≥ 4 ACR criteria) and 34 were considered as ILE (cumulative ACR criteria = 3) at FU. Matched, unaffected FDRs (n=180) had significantly lower CSQ scores (p≤0.0001) at BL and FU than those with ILE or classified SLE. Initial analysis revealed a number of soluble mediators that positively correlated with the number of cumulative ACR criteria, including BL levels of MIP-1β, MCP-1, MCP-3, and Eotaxin, as well as SCF (p≤0.01). TNF superfamily member BLyS positively (p<0.0001) correlated with cumulative ACR criteria, while APRIL (p=0.008) and regulatory mediator TGF-β (p=0.002) negatively correlated with ACR criteria. We then determined factors that differentiated FDRs with ILE or classified SLE at FU.  FDRs who transitioned to SLE had significantly higher rate of arthritis and serositis (p<0.01) at BL and higher levels of SCF and MCP-3 (p<0.02) at BL. For FDRs who met fewer than 3 ACR criteria at BL (n = 49 with ILE or SLE at FU), FDRs with ILE at FU (n = 19) were more likely to be female (p=0.0002) and had significantly higher levels of APRIL (p<0.04). For FDRs with ILE at BL (n = 41), FDRs who remained at ILE (n = 15) were more likely to be European-American (p<0.0001) and had significantly lower levels of MCP-3, SCF, and shed TNFRII (p<0.03) than FDRs who transitioned to SLE. BL age and time between BL and FU were not significant factors in distinguishing FDRs with ILE or transition to SLE. 

Conclusion: FDRs of known SLE patients demonstrate elevated inflammatory mediators that correlate with cumulative ACR criteria, distinguishing unaffected FDRs from those with ILE or who transition to SLE. Soluble mediators, as well as gender and race, distinguished FDRs with ILE or who transitioned to SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gender-race-and-soluble-mediators-distinguish-blood-relatives-who-develop-incomplete-lupus-or-classified-sle-in-the-lupus-autoimmunity-in-relatives-laurel-study/