Background/Purpose: Many pediatric patients (pts.) with early-onset autoinflammatory disease (AID) phenotypes are mutation-negative for genetically known AIDs. Recent data suggest a role for Type-I interferon (IFN) dysregulation in causing AID phenotypes with clinical features that are distinct from those found in pts. with IL-1 mediated AIDs. We screened pts. for the presence of IFN–response gene signatures (IRS) to characterize their clinical phenotypes, IFN-related biomarkers and genetic causes.

Methods: We assessed IRS from 63 consecutively evaluated patients (pts.) who were negative for known AID-causing mutations. Gene expression of 28 selected interferon response genes (IRG) was determined by Nanostring and an IFN-score was calculated. Serum levels of 48 cytokines were measured by a multiplex immunoassay. Pts. underwent clinical assessments and genetic analyses were performed by whole exome/genome sequencing (WES/WGS).

Results: Of 63 pts. tested, 36 had elevated IRS. Pts. with high IRS had higher serum levels (all in pg/ml) of: most pronounced in IP-10 (11169 ± 1849 vs 834 ± 117, p<0.0001), and MIG/CXCL9 (7133 ± 2450 vs 706 ± 61), MIP1α (195 ± 23 vs 153 ± 5.8), GROα (423 ± 95 vs 165 ± 14), all p<0.01and MIP1β (301 ± 42 vs 220 ± 13), SCF (63 ± 15 vs 28 ± 4.8), with p<0.05, than those with negative IFN scores. Pts. with high IRS had significantly higher frequencies of panniculitis (58 vs 0%), basal ganglia calcifications (45 vs 0%), interstitial lung disease (ILD) (48 vs 4.8%), myositis (65 vs 15%1), all with p<0.01 and skin vasculitis (29 vs 7.4%,) and arterial hypertension (32 vs 3.7%), p<0.05, and lower frequency of aseptic osteomyelitis (0 vs 22%, p<0.01) than pts. without an IRS. Furthermore, anemia (33 vs 7.4%), lymphopenia (26 vs 0%) and positive ANA (42 vs 11%), all p<0.05, were more frequent in pts. with an IRS. Based on disease manifestations, patients could be assigned to 8 distinct groups. Pts. with ILD and macrophage activation syndrome (MAS) had very high IL-18 serum levels and a cytokine signature seen in other patients with MAS. Two pts. with lipodystrophy had novel LRBA mutations, 2 pts. with lymphohistiocytic panniculitis have a novel NEMO mutation, 5 patients with neutrophilic panniculitis, ILD, cytopenias and white matter disease have de novo truncating mutations in SAMD9L, and 2 with myositis and ILD had anti-MDA5 autoantibodies. One patient with “atypical CANDLE” had a novel PSMB8 mutation, and one pt. each had mutations in a novel proteasome gene, PSMG2, and a de novo somatic mutation in TREX1. IFI27 was the most upregulated gene in patients with SAVI, CANDLE and Aicardi-Goutières syndrome (AGS), but its expression in patients with LRBA and NEMO mediated disease was significantly lower.

Conclusion: The presence of an IFN signature is associated with distinct clinical and cytokine patterns, including pts. with ILD and high serum IL-18 and a predisposition to MAS. Our data suggest that IFN leads to a set of clinical features that combined with the assessment of an IFN response gene signature can identify patients and autoinflammatory interferonopathies and help define clinically distinct disease subsets. Whether IFN is the pathogenic cause of these diseases needs to be further investigated in treatment studies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/high-interferon-ifn-signatures-and-overlapping-clinical-features-characterize-subgroups-of-patients-with-presumed-ifn-mediated-autoinflammatory-diseases/