Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

HOU, YANFENG; BIANCOTTO, ANGELIQUE; MARRERO, BERNADETTE; DENG, ZUOMING; ALLENSPACH, ERIC; BENSELER, SUSANNE; BRESCIA, ANNEMARIE C.; CALDIROLA, MARÍA SOLEDAD; CIMAZ, ROLANDO; DEGUZMAN, MARIETTA; FERGUSON, POLLY; GROM, ALEXEI A.; HEDRICH, CHRISTIAN M.; JERATH, RITA; KINGSBURY, DANIEL J.; LEE-KIRSCH, MIN AE; LILLEBY, VIBKE; NASRULLAYEVA, GULNARA; OZEN, SEZA; PIOTTO, DANIELA G.P.; REINHARDT, ADAM; RONIS, TOVA; RUTH, NATASHA MCKERRAN; SCHULERT, GRANT; SHULMAN, ANDREW; STEPANOVSKYY, YURIY; TERRERI, MARIA TERESA; TOSI, LAURA; CANNA, SCOTT W.; DE JESUS, ADRIANA A.; MALLE, LOUISE; CALVO, KATHERINE R.; OLER, ANDREW J.; AHMED, AMINA; BEHRENS, EDWARD; BOUT-TABAKU, SHARON; BURNHAM, JON M.; CHAN, ALICE Y.; DARE, JASON; FERGUSON, IAN; GATTORNO, MARCO; HASHKES, PHILIP J.; HORNEFF, GERD; KIM, HANNA; LEE, PUI Y.; LI, SUZANNE; MOORTHY, LAKSHMI N.; ONEL, KAREN; PILLET, PASCAL; REIFF, ANDREAS; RIVAS-CHACON, RAFAEL; ROTH, JOHANNES; SCHMELING, HEINRIKE; SEMINARIO, GISELA; SON, MARY BETH; TABER, SARA; TORGERSON, TROY; WAMPLER MUSKAR

Journal of Clinical Investigation

Rexford S. Ahima

Año: 2019

Background. Undifferentiated systemic autoinflammatory diseases (USAID) presentdiagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.Methods. Sixty-six consecutively-referred USAID patients underwent standardizedevaluation of Type-I IFN-response-gene-signature (IRG-S); cytokine profiling, and genetic evaluation by next-generation sequencing.Results. Thirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs 0%), basal ganglia calcifications (46% vs 0%), interstitial lung disease (47% vs 5%), and myositis (60% vs 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly-elevated serum IL-18 distinguished eight patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, two patients were compound heterozygous for novel LRBA mutations, four patients harbored novel splice variants in IKBKG/NEMO, and six patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières-Syndrome (AGS)-like phenotypes, five patients carried mutations in either SAMHD1, TREX1, PSMB8 or PSMG2. Two patients had anti-MDA5 autoantibody-positive juveniledermatomyositis, and seven could not be classified. Patients with LRBA, IKBKG/NEMO and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NFkB activation different from the canonical interferonopathies CANDLE, SAVI and AGS.Conclusions. In patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMOD5-associated autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.