Background/Purpose: Skin disease affects >80% of lupus patients and has been linked to lupus nephritis (LN) flares. We recently found that skin inflammation caused by UV light can trigger both local and systemic immune responses, in the blood and the kidney. This inflammation also led to kidney injury, associated with increased expression of renal inflammatory and injury markers and proteinuria. The observed renal injury was mediated by neutrophils, which migrated from the inflamed skin to the kidneys, localizing predominantly to the tubulointerstitial areas. These data prompted the hypothesis that presence of concurrent skin disease in lupus patients leads to worse nephritis mediated by neutrophils.

Methods: Kidney biopsies from 43 LN patients (2005-2020, IRB# 02000844) were retrieved from the Dartmouth Hitchcock Medical Center tissue bank and grouped into: i) LN with concurrent skin rash (malar, subacute, or discoid n =15) and ii) LN without skin rash (EMR review and/or skin biopsy, n=6) at the time of LN diagnosis (class IV). Patients with inconclusive or incomplete skin findings were excluded. The study included only female patients. Clinical and laboratory data (absolute neutrophil (ANC) and lymphocyte (ALC) counts, serum creatinine, estimated glomerular filtration rate (GFR), autoantibody titers, and complement levels) were collected by retrospective chart review. Histologic and immunofluorescence data were extracted from kidney biopsy reports. Student’s t-test was performed to detect statistically significant differences between patient groups.

Results: Presence of skin rash at the time of LN flare was indicative of more active disease, reflected by higher ANA and anti-dsDNA IgG titers, and low complement C3 and C4 levels. Of interest, LN patients with concurrent skin disease had higher absolute neutrophil counts (p < 0.05) and neutrophil-lymphocyte ratio (p< 0.01), but not lymphocyte absolute counts, compared to LN patients without a concurrent skin rash. High neutrophil counts in the presence of skin disease associated with lower glomerular filtration rate (GFR < 60; p< 0.01). This association was not seen in the absence of concurrent skin disease and rash alone did not predict GFR. Analysis of kidney immunofluorescence revealed that concurrent skin disease at the time of LN flare associated with greater IgA deposition. In particular, increased renal IgA levels associated with higher neutrophil but not lymphocyte counts (p < 0.01). This was specific to IgA as no associations with IgG or IgM deposition were detected.

Conclusion: Our study provides several novel findings that suggest neutrophils may be the pathogenic link between skin inflammation and lupus nephritis flares: i) higher neutrophil counts are found in the presence of a skin rash at the time of LN flare, ii) neutrophilia but not lymphocytosis in the presence of a skin rash associates with worse kidney function (low GFR), and iii) high neutrophil levels in the presence of skin rash associate with increased renal IgA deposition. The newly identified relationship between neutrophil levels and kidney IgA provides a novel model of IgA-driven activation of neutrophils leading to kidney injury initiated by skin inflammation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-role-of-neutrophils-in-the-clinical-severity-of-lupus-nephritis-patients-with-concurrent-skin-disease/