TY - JOUR
T1 - Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases
AU - de Jesus, Adriana A.
AU - Hou, Yangfeng
AU - Brooks, Stephen
AU - Malle, Louise
AU - Biancotto, Angelique
AU - Huang, Yan
AU - Calvo, Katherine R.
AU - Marrero, Bernadette
AU - Moir, Susan
AU - Oler, Andrew J.
AU - Deng, Zuoming
AU - Montealegre Sanchez, Gina A.
AU - Ahmed, Amina
AU - Allenspach, Eric
AU - Arabshahi, Bita
AU - Behrens, Edward
AU - Benseler, Susanne
AU - Bezrodnik, Liliana
AU - Bout-Tabaku, Sharon
AU - Brescia, Anne Marie C.
AU - Brown, Diane
AU - Burnham, Jon M.
AU - Caldirola, Maria Soledad
AU - Carrasco, Ruy
AU - Chan, Alice Y.
AU - Cimaz, Rolando
AU - Dancey, Paul
AU - Dare, Jason
AU - DeGuzman, Marietta
AU - Dimitriades, Victoria
AU - Ferguson, Ian
AU - Ferguson, Polly
AU - Finn, Laura
AU - Gattorno, Marco
AU - Grom, Alexei A.
AU - Hanson, Eric P.
AU - Hashkes, Philip J.
AU - Hedrich, Christian M.
AU - Herzog, Ronit
AU - Horneff, Gerd
AU - Jerath, Rita
AU - Kessler, Elizabeth
AU - Kim, Hanna
AU - Kingsbury, Daniel J.
AU - Laxer, Ronald M.
AU - Lee, Pui Y.
AU - Lee-Kirsch, Min Ae
AU - Lewandowski, Laura
AU - Li, Suzanne
AU - van Royen-Kerkhof, Annet
N1 - Funding Information:
FUNDING. The Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - BACKGROUND. Undifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic 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 underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (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 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB 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), NEMO deleted exon 5-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.
AB - BACKGROUND. Undifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic 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 underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (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 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB 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), NEMO deleted exon 5-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.
UR - http://www.scopus.com/inward/record.url?scp=85082865229&partnerID=8YFLogxK
U2 - 10.1172/JCI129301
DO - 10.1172/JCI129301
M3 - Article
C2 - 31874111
AN - SCOPUS:85082865229
SN - 0021-9738
VL - 130
SP - 1669
EP - 1682
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -