Background/Purpose: SLE is a complex autoimmune disease marked by autoantibody production and immune dysregulation. Identification of at-risk populations is essential to minimize morbidity and mortality from early inflammatory reactions and to identify appropriate individuals for prevention trials. A number of patients have autoantibodies and some clinical features of SLE, but do not meet the required ≥ 4 ACR criteria (or incomplete lupus, ILE). Healthy blood relatives of lupus patients are known to have significantly increased risk of SLE development. Using a unique resource of family members with samples available before and after transition to SLE, we initially found that blood relatives (FDRs) who transition to SLE have altered inflammatory mediators compared to those who remain unaffected. This study seeks to determine potentially pathogenic inflammatory mediators in blood relatives classified with ILE, compared to those who have transitioned to SLE, and matched blood relatives who remain unaffected.

Methods: This study has initially re-enrolled 375 FDRs of known SLE patients with samples available from previous genetic studies for follow-up evaluation; 22 previously unaffected FDRs have transitioned to SLE (≥ 4 ACR criteria) and 17 are classified as ILE (cumulative ACR criteria = 3). Individuals provided detailed clinical and demographic information, and completed the Connective Tissue Disease Screening Questionnaire (CSQ) at baseline (BL) and follow-up (FU). Medical records were obtained and reviewed for ACR classification criteria. BL and FU serum samples were tested for autoantibody production, including ANA, anti-dsDNA, aCLs and precipitating levels of Ro, La, Sm, nRNP, and ribosomal P autoantibodies. We assessed 52 soluble inflammatory mediators, using either xMAP multiplex technology or sandwich ELISA (BLyS and APRIL). Samples from ILE participants were compared to FDRs who transitioned to SLE, as well as race/gender/age (+/- 5 years)/ANA status matched FDRs who remain unaffected.

Results: ILE FDRs had BL and FU CSQ scores similar to those who transitioned to SLE classification (n.s.), yet > 2 fold higher than matched, unaffected FDRs (p < 0.001). Both ILE and SLE had similar BL and FU levels of a number of chemokines, including MIG, MIP-1α, MIP-1β, MCP-3, and eotaxin. Of particular interest were shed TNFR family members (TNFRI, TNFRII, TRAIL, and CD40L) that were 50% higher in ILE FDRs and those who transitioned to SLE than matched, unaffected FDRs (p ≤ 0.01). Compared with FDRs who transitioned to SLE or remained unaffected, ILE FDRs had significant (p < 0.05) BL and FU alterations in 22 (of 52) soluble mediators, most notably innate and adaptive cytokines, including a >2-fold increase in Th2-type cytokines IL-4, IL-5, and IL-13 and regulatory cytokines IL-10 and TGF-β. 

Conclusion: FDRs of known SLE patients classified with ILE or transition to SLE demonstrate significantly altered levels of soluble inflammatory mediators. These alterations suggest that multiple perturbations in immune-mediated inflammatory processes occur with accumulation of ACR criteria and potentially allow for identification of individuals at high risk for development of SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/altered-soluble-mediators-in-individuals-with-incomplete-lupus-ile-in-the-lupus-autoimmunity-in-relatives-laurel-study/