Background/Purpose: Undifferentiated systemic autoinflammatory diseases (USAID) present diagnostic and therapeutic challenges.  Cytokine dysregulation may identify disease groups that respond to targeted treatments. IFN-signaling blocking treatments in patients with high IFN signature and novel treatments for macrophage activation syndrome (MAS) may benefit  patients without a genetic diagnosis. An integrated screening approach of patients with USAIDs that included assessment of an IFN signature and serum cytokines followed by genomic evaluation led to the identification of novel disease subsets that present with an IFN signature.

Methods: We evaluated 66 patients with USAID. Using a Nanostring assay, a 28-gene IFN score of selected interferon response genes (IRGs) was calculated. RNA-seq of matched samples was used for the correlation between RNA-seq and Nanostring for the validation of a 4-gene NF-kB Nanostring subscore. Serum levels of 48 analytes were determined by a multiplex cytokine assay and high IL-18 levels were reanalyzed by ELISA. Whole exome sequencing (WES) and/or whole genome sequencing (WGS) was performed in 61 of the 66 patients.

Results: Of the 66 patients, 36 (55%) had elevated interferon response gene signatures (IRS). Neutrophilic panniculitis (40% vs 0%) basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs 5%) and myositis (60% vs 10%) were significantly higher in pts with elevated IRS.  Eight pts with pulmonary alveolar proteinosis (PAP) had highly-elevated IL-18 serum levels and recurrent macrophage activation syndrome (MAS). Of 11 patients with low IFN score elevation, CANDLE-like panniculitis and progressive cytopenias 2 were compound heterozygous for novel LRBA mutations, 3 males harbor novel splice variants in IKBKG/NEMO, and 6 patients have de novo frameshift mutations in SAMD9L. Of 13 patients with highly elevated IRS and CANDLE-, SAVI- or Aicardi-Goutières-Syndrome (AGS)-like phenotypes, 5 pts had each a mutation in either SAMHD1, TREX1, PSMB8 or PSMG2.  Two patients had anti-MDA5-positive juvenile dermatomyositis, and 7 could not be further characterized.  Different patterns of interferon-response-gene (IRG) elevation with a higher relative expression of 4 IRGs with NF-kB binding sites assessed referred to as 4- NF-kB/24-STAT1 ratio distinguished patients with LRBA, IKBKG/NEMO and SAMD9L mutations from the autoinflammatory interferonopathies CANDLE, SAVI and AGS and suggested proportionally increased concomitant NF-kB signaling in LRBA deficiency and NEMO-NDAS.

Conclusion: IRS elevation, characteristic cytokine elevations and clinical features identified 3 novel diseases, IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMOD5-associated autoinflammatory syndrome (NDAS), and SAMD9L-associated autoinflammatory disease (SAAD), thus expanding the diagnostic armamentarium in assessing patients with USAIDs, and pointing to novel pathways regulating interferon-response-gene-expression.

Funding for this study was provided in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interferon-signature-and-cytokine-patterns-define-novel-autoinflammatory-diseases/