Background/Purpose: Identifying populations at risk of SLE is essential to curtail inflammatory damage and select individuals for prevention trials. First-degree relatives (FDRs) of lupus patients have an increased risk of developing SLE. Using a unique resource of SLE patient family members with longitudinal samples available, the goal of this study is to determine factors that distinguish FDRs who remain unaffected over time from unrelated, unaffected individuals.

Methods:

We evaluated plasma samples from 154 unaffected FDRs of known SLE patients with samples available from previous genetic studies and who remained unaffected at follow-up evaluation (mean time to follow-up 6.8 years). FDRs were matched 2:1 by gender, race and age (±5 years) to 77 unaffected individuals unrelated to SLE patients (Controls). FDRs and Controls provided clinical and demographic information, and completed the SLE-specific portion of the Connective Tissue Disease Screening Questionnaire (CSQ) at baseline (BL) and follow-up (FU). 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). Logistic regression modeling of CSQ scores, number of autoantibody specificities, and select soluble mediators (via Random Forest) was utilized to evaluate whether certain factors distinguished unaffected FDRs from Controls.

Results:

FDRs had significantly higher BL and FU CSQ scores than Controls (p<0.0001); CSQ scores were higher in female FDRs vs. male FDRs or female Controls (p<0.0001). No significant difference in the number of positive autoantibody specificities were noted between FDRs and Controls. FDRs had significant (p≤0.01) alterations in 38 (of 52) soluble mediators compared to Controls, including innate and adaptive mediators of inflammation, chemokines, and TNF superfamily members. APRIL and BLyS, IFN-associated chemokines IP-10, MIG and MIP-1α, as well as the regulatory mediators IL-10 and TGF-β, were significantly higher in FDRs at BL and FU (p≤0.002). A number of mediators (14 at BL and 18 at FU) found to best separate FDRs from Controls by Random Forest strongly correlated with CSQ scores (p≤0.0002). Of these, levels of MIP-1α (p=0.008), MIG (p=0.019), GROα (p=0.001), ICAM-1 (p=0.007), and VEGF (p=0.004), along with CSQ scores (p=0.010), best distinguished FDRs from Controls in logistic regression models.

Conclusion: Unaffected FDRs of SLE patients demonstrate significantly altered levels of soluble inflammatory, as well as regulatory, mediators compared to matched, unrelated, unaffected Controls. These alterations are present despite lack of progression to classified SLE, suggesting that multiple perturbations in immune-mediated inflammatory processes present in family members of SLE patients may be offset by inhibitory factors, providing unique insights for potential autoimmune disease prevention or SLE disease treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/elevated-levels-of-soluble-inflammatory-mediators-and-lupus-specific-connective-tissue-disease-questionnaire-scores-discern-unaffected-first-degree-relatives-of-lupus-patients-from-unaffected-individu/