Background/Purpose: Patients with systemic autoinflammatory diseases (SAIDs) present with chronic and acute elevations of proinflammatory serum cytokine and chemokine levels during exacerbations of disease flares. Compared to NOMID, patients (pts) with “autoinflammatory interferonopathies” present with elevated interferon (IFN) scores. We profiled serum cytokines/chemokines and whole blood transcriptional profiles in pts with the autoinflammatory diseases CAPS, CANDLE, SAVI, NEMO-NDAS versus healthy controls (HCs) and compared IFN cytokine and gene expression profiles between diseases.

Methods: All pts were enrolled into an IRB-approved natural history protocol (NCT02974595). RNA was extracted from pts and HC whole blood. Transcript counts for 28 Type I IFN, 9 IFNg, and 9 NF-kB-response genes were measured by NanoString, and standardized scores were calculated. Levels of 64 cytokines were measured in matched serum samples.

Results: In CANDLE, SAVI and NEMO-NDAS pts, the Type I IFN score significantly correlated with the NF-κB (r=0.792, r=0.615, r=0.696) and with the IFNγ score (r=0.615, r=0.859 and r=0.745). This was not observed in CAPS, SAAD and IL-18opathies; in these diseases the NF-κB score correlated significantly with the IFNγ score (r=0.615, r=0.859 and r=0.745). Interestingly, key inflammatory cytokines in NOMID were IL-1β, TNF and IL-12p70, which were most highly correlated with the NF-κB score. In SAVI, serum IL-1β, IL-6 and TNF best correlated with the Type I IFN score, which in CANDLE also included IL-18, IFNγ and IL-12 and in NEMO-NDAS was restricted to IFNγ and IL-12. Similarly, elevated markers of endothelial and neutrophil activation correlated with the NF-κB signature in NOMID and with the Type I IFN signature in CANDLE and NEMO-NDAS. Serum IFNα2 positively correlated with the Type I IFN score in CANDLE pts (r=0.74), while in NEMO-NDAS, serum IFNγ levels correlated best with the Type I IFN score, suggesting a potential role of IFNγ in contributing to Type I IFN score abnormalities. Whole blood cell IFNA2 transcription and serum levels only weakly correlated with serum levels in CANDLE and SAVI but IFNG transcription did not correlate with serum levels, suggesting non-hematopoietic production of IFNγ.

Conclusion: Distinct cytokine patterns distinguish active NOMID, SAVI, CANDLE and NEMO-NDAS pts, with proinflammatory cytokines correlating with the NF-κB score in NOMID and with the Type I IFN score in CANDLE and SAVI pts. Broader cytokine dysregulation in CANDLE and SAVI suggests complex immune dysregulation and likely reflect the contribution of organ inflammation to the serum cytokine measures obtained. Correlation with organ inflammation may allow the development of better biomarkers to monitor disease activity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/type-i-and-type-ii-interferon-and-nf-%ce%bab-response-gene-scores-and-serum-cytokine-levels-in-patients-with-various-systemic-autoinflammatory-diseases/