Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Many infants and children with early-onset autoinflammatory diseases are mutation-negative for genetically known autoinflammatory diseases. Recent data suggest a role for Type-I interferon dysregulation in causing autoinflammatory disease phenotypes with clinical features that are distinct from those found in patients with IL-1 mediated autoinflammatory diseases. We assessed an IFN–response-gene signature (IRS), characterized the clinical phenotypes, IFN-related biomarkers and genetic causes.
Methods: We assessed IFN-response gene signatures (IRS) from 63 consecutively evaluated patients who were negative for known autoinflammatory disease-causing mutations. Whole blood 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.Patients underwent clinical assessments and genetic analyses were performed by whole exome/genome sequencing (WES/WGS).
Results: Of 63 patients tested, 36 had elevated IFN-signatures. Patients with high IRS had higher frequencies of panniculitis (58 vs 0%, p<0.0001), basal ganglia calcifications (45 vs 0%, p=0.0043), interstitial lung disease (ILD) (48 vs 4.8%, p=0.0013), myositis (65 vs 15%, p=0.0005), skin vasculitis (29 vs 7.4%, p=0.05), arterial hypertension (32 vs 3.7%, p=0.011) and liver disease (73 vs 22%, p=0.0002), than patients without an IRS. Of 8 distinct clinical patterns, one group with pulmonary alveolar proteinosis (PAP) and macrophage activation syndrome (MAS) had high IL-18 serum levels. Other groups included 2 patients with novel LRBA mutations, 3 patients with a novel NEMO splice site mutation, 5 with de novo truncating SAMD9L mutations, 2 with myositis and anti-MDA5 autoantibodies, 7 with CANDLE-like panniculitis of which 1 had a known PSMB8 mutations and 2 had novel proteasome mutations in PSMB8 and in PSMG2, respectively. Patients with PAP and MAS, LRBA, NEMO, SAMD9L mutations had overall lower IFN scores and significantly lower USP18 but higher SOCS1 transcript levels compared to CANDLE and SAVI, both negative regulators of IFN signaling. SOCS1 transcription is regulated through the NF-κB signaling pathway and SOCS1 expression dysregulation may point to a different origin of the IFN response gene signature compared to CANDLE and SAVI patients. Interestingly, many of these patients with high SOCS1 and lower USP18 levels responded to TNF inhibition. Additionally, patients with high IRS had significantly higher serum levels of IP-10, MIG, MIP1α, MIP1β, SCF and GROα than those with negative IFN scores.
Conclusion: The assessment of patients with IFN signatures revealed distinct clinical pathogenically defined disease subsets. In 3 subgroups of patients, novel monogenic disease-causing mutations were detected. The contribution of SOCS1 and USP18 may assist in delineating different intracellular pathways that lead to the activation of the IFN response gene signature.
Acknowledgements: This work was supported by the NIH IRP of NIAID. We would like to thank the autoinflammatory disease network of physicians for patient referral.
To cite this abstract in AMA style:Almeida de Jesus A, Hou Y, Malle L, Canna S, Montealegre Sanchez GA, Kim H, VanTries R, Ozen S, Dill S, Chapelle DC, Marrero B, Huang Y, Biancotto A, Goldbach-Mansky R. Different Patterns of Interferon-Response-Gene Expression May Elucidate Different Pathomechanisms That Drive IFN-Response-Gene Activation in Patients with Presumed IFN-Mediated Autoinflammatory Diseases [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/different-patterns-of-interferon-response-gene-expression-may-elucidate-different-pathomechanisms-that-drive-ifn-response-gene-activation-in-patients-with-presumed-ifn-mediated-autoinflammatory-diseas/. Accessed June 3, 2020.
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