Background/Purpose: Interferons (IFNs) play critical roles in systemic autoimmune diseases, particularly systemic lupus erythematosus (SLE), where heightened type I IFN signaling is a hallmark. Elevated IFN activity is also observed in rheumatoid arthritis (RA), systemic sclerosis (SSc), and idiopathic inflammatory myopathy (IIM), making IFNs promising therapeutic targets. However, their pathogenic involvement varies among patients. In the TULIP trial, anifrolumab showed greater efficacy in SLE patients with elevated type I IFN signatures. Although IFN signatures derived from transcriptomic profiles are valuable biomarkers, their clinical utility is limited by cost. At ACR 2024, we reported a strong correlation between the neutrophil-to-lymphocyte ratio (NLR) and IFN signatures in patients with SLE. This study investigated whether the NLR can serve as a practical surrogate for IFN signatures in SLE, RA, SSc, and IIM patients.

Methods: We enrolled 236 patients with autoimmune diseases: 36 with SLE, 31 with RA, 95 with SSc, and 74 with IIM. Whole-blood RNA was subjected to transcriptome analysis. Seventy-three genes were assigned as type I IFN-related, 94 as type II, and 10 as type III. The IFN signature score was calculated as the sum of the Z scores for each group. The log₂-transformed NLR (log₂NLR) was derived from clinical blood data obtained at the time of RNA sampling. Correlations between the Log₂NLR and type I–III IFN scores were evaluated.

Results: Log₂NLR significantly correlated with all three IFN signatures across diseases.In SLE, strong correlations were observed with type I IFN (R² = 0.40, P = 5.99×10⁻¹²), type II IFN (R² = 0.29, P = 2.77×10⁻⁸), and type III IFN (R² = 0.57, P = 1.32×10⁻⁷).In SSc, the correlations were even stronger: type I IFN (R² = 0.57, P = 1.74×10⁻⁷), type II IFN (R² = 0.36, P = 1.74×10⁻⁷), and type III IFN (R² = 0.63, P = 9.79×10⁻²²).In RA, the associations were weaker but significant: type I IFN (R² = 0.19, P = 0.013), type II IFN (R² = 0.13, P = 0.042), and type III IFN (R² = 0.44, P = 5.00×10⁻⁵).In IIM, correlations were also significant: type I IFN (R² = 0.17, P = 0.0002), type II IFN (R² = 0.06, P = 0.032), and type III IFN (R² = 0.37, P = 1.01×10⁻⁸).

Conclusion: The NLR was significantly correlated with type I, II, and III IFN signatures in patients with SLE, SSc, RA, and IIM. The strongest associations were observed in SLE and SSc patients, indicating a more consistent IFN-driven pathogenesis in these diseases. In contrast, RA and IIM showed weaker associations, possibly reflecting greater disease heterogeneity and variable IFN involvement. Among the IFN types, the type III IFN signature showed the most consistent and strongest correlation with the NLR. Given its simplicity and availability, the NLR has emerged as a practical and cost-effective surrogate biomarker for IFN activation, with potential utility in clinical decision-making across autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/neutrophil-to-lymphocyte-ratio-nlr-as-a-clinically-accessible-marker-for-interferon-signatures-in-autoimmune-diseases/