Background/Purpose: Blood relatives (Rel) of lupus patients have increased risk of SLE. Some have autoantibodies and SLE clinical features, but do not meet ≥ 4 ACR criteria needed to reach SLE classification (incomplete lupus, ILE). Some individuals with ILE may transition to classified SLE, yet many will remain ILE patients without major organ involvement. Using a unique resource of SLE patient family members, the goal of this study is to determine factors that distinguish ILE patients from unaffected Rel and SLE patients.

Methods: This study examined individuals enrolled in the Lupus Family Registry and Repository (LFRR) who only met 3 ACR classification criteria during medical record review and did not meet Systemic Lupus International Collaborating Clinics (SLICC) SLE classification, designated as ILE. ILE patients (n=77) were matched by race, gender, and age (± 5 years) to unaffected Rel and unrelated, unaffected controls (Ctls). We were able to subsequently match a subset of ILE patients (n=55) to medical record-confirmed SLE patients in the LFRR. Study participants provided clinical and demographic information, and completed the SLE-specific portion of the CTD Screening Questionnaire (CSQ). Plasma samples were assessed for autoantibody production and 52 soluble inflammatory mediators (BLyS, APRIL, cytokines, chemokines, and shed TNF receptors).

Results: ILE patients had significantly higher SLE-specific CSQ scores than unaffected Rel and Ctls (p<0.0001); CSQ scores in unaffected Rel > Ctls (p=0.009). Initial analysis revealed a number of soluble mediators that positively correlated with CSQ scores, including SCF (p=0.0001), BLyS (p=0.0086), MCP-3 (p=0.0017), and TNFRI (p=0.0144). Compared to unaffected Rel and Ctls, ILE patients had the highest levels of SCF (p=0.0001), BLyS (p=0.0018), MCP-3 (p=0.0167), and TNFRI (p=0.0196), as well as highest ANA titer (p<0.01) and number of lupus-associated autoantibodies (p<0.01). We subsequently examined factors that differentiated ILE patients matched to SLE patients in the LFRR (n=55). SLE patients had significantly higher rates of arthritis, serositis, and renal disease (p<0.004), as well as increased number of autoantibody specificities (p<0.004) and levels of BLyS (p=0.0138), IL-2Rα (p=0.0201), IP-10 (p=0.0269), and TNFRII (p=0.0309) compared to ILE patients. CSQ scores and SCF levels, which were elevated in ILE patients compared to Rel and Ctl, were equivalent compared to SLE patients. Yet, ILE patients had higher levels of the regulatory mediator TGF-β compared to SLE patients (p=0.0454).

Conclusion: ILE patients are distinguished from unaffected Rel by elevated number of autoantibodies and inflammatory mediators that correlate with SLE-specific CSQ scores, yet have fewer clinical criteria and increased levels of the regulatory mediator, TGF-β, compared to SLE patients. Identification of factors which discern relatives at increased risk of transitioning to classified SLE from relatives who remain unaffected may be beneficial to curtail inflammatory damage and identify individuals for prevention trials.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/altered-soluble-mediators-autoantibodies-and-lupus-specific-connective-tissue-disease-questionnaire-scores-distinguish-blood-relatives-with-incomplete-lupus-from-unaffected-relatives-and-relatives-w/