Background/Purpose: SLE is a heterogeneous autoimmune disease marked by immune dysregulation and a spectrum of pathogenic autoantibodies. Why some patients have only moderate symptoms and others develop organ-threatening manifestations such as nephritis is unclear. We previously identified several cytokines that correlate with increased disease activity. This study evaluates the temporal expression of autoantibodies and cytokines during transition from preclinical lupus to SLE in patients who do or do not present with nephritis.

Methods: Sera from 83 SLE cases with serial specimens spanning from time points of no ACR criteria to SLE classification (average timespan= 4.7 years) were obtained from the Department of Defense Serum Repository (DODSR). Samples were tested for SLE-associated autoantibodies and 32 soluble inflammatory and regulatory mediators, including cytokines, chemokines, and soluble receptors, as well as serum interferon-α (IFN-α) activity by cell reporter assay (WISH). Demographic, clinical, medication data and ACR classification criteria were extracted from medical records.

Results: Thirty (36%) patients who transitioned to SLE met renal criteria within 5.2 (± 5.5) months of disease classification (range -5.2 to +12 months). Patients presenting with renal criteria were more likely to be male compared to patients without renal criteria (p=0.016). Cases who did not meet renal criteria were more likely to have a history of hydroxychloroquine use prior to SLE classification (p<0.0001). Although renal cases experienced earlier onset of autoantibody positivity compared to non-renal cases (mean -3.8 vs -2.6 years relative to SLE classification, p=0.0442), no differences in number or type of autoantibody specificity were detected, including anti-dsDNA. Of interest, cases meeting renal criteria exhibited elevated levels of a number of soluble mediators prior to developing nephritis and reaching SLE classification, including the adaptive mediators IL-4, IL-5, IL-12, and IFN-γ, the IFN-mediated chemokine, IP-10, as well as shed TNFRII (all p<0.05 compared to matched healthy controls), increasing again at the time of nephritis (all p<0.02 compared to pre-nephritis levels), along with the mediator SCF (p<0.0001). SCF, IL-5, IFN-γ, MCP-3, IP-10, and TNFRII were significantly increased at SLE classification in patients with renal criterion vs. non-renal patients (all p<0.0001). Nephritis occurred independently of BLyS and Type I IFN-α serum activity, as there was no difference in levels between renal and non-renal patients who transitioned to SLE.

Conclusion: The subset of severe onset SLE patients who develop early nephritis cannot be predicted by autoantibodies. However, these patients develop significantly altered levels of certain soluble inflammatory mediators as they move from pre-clinical to classified disease. Singular perturbations in immune mediated inflammatory processes, occurring long before clinical classification, may help identify individuals at high risk of renal involvement for early and continued monitoring and intervention.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/development-of-lupus-nephritis-preclinical-evaluation-of-patients-who-subsequently-develop-systemic-lupus-erythematosus-demonstrate-elevation-of-select-soluble-mediators-prior-to-and-at-disease-class/