de Jesus, A. A., Hou, Y., Brooks, S., Malle, L., Biancotto, A., Huang, Y., Calvo, K. R., Marrero, B., Moir, S., Oler, A. J., Deng, Z., Montealegre Sanchez, G. A., Ahmed, A., Allenspach, E., Arabshahi, B., Behrens, E., Benseler, S., Bezrodnik, L., Bout-Tabaku, S., ... Goldbach-Mansky, R. (2020). Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases. Journal of Clinical Investigation, 130(4), 1669-1682. https://doi.org/10.1172/JCI129301
de Jesus, AA, Hou, Y, Brooks, S, Malle, L, Biancotto, A, Huang, Y, Calvo, KR, Marrero, B, Moir, S, Oler, AJ, Deng, Z, Montealegre Sanchez, GA, Ahmed, A, Allenspach, E, Arabshahi, B, Behrens, E, Benseler, S, Bezrodnik, L, Bout-Tabaku, S, Brescia, AMC, Brown, D, Burnham, JM, Caldirola, MS, Carrasco, R, Chan, AY, Cimaz, R, Dancey, P, Dare, J, DeGuzman, M, Dimitriades, V, Ferguson, I, Ferguson, P, Finn, L, Gattorno, M, Grom, AA, Hanson, EP, Hashkes, PJ, Hedrich, CM, Herzog, R, Horneff, G, Jerath, R, Kessler, E, Kim, H, Kingsbury, DJ, Laxer, RM, Lee, PY, Lee-Kirsch, MA, Lewandowski, L, Li, S, Lilleby, V, Mammadova, V, Moorthy, LN, Nasrullayeva, G, O'Neil, KM, Onel, K, Ozen, S, Pan, N, Pillet, P, Piotto, DGP, Punaro, MG, Reiff, A, Reinhardt, A, Rider, LG, Rivas-Chacon, R, Ronis, T, Rösen-Wolff, A, Roth, J, Ruth, NM, Rygg, M, Schmeling, H, Schulert, G, Scott, C, Seminario, G, Shulman, A, Sivaraman, V, Son, MB, Stepanovskiy, Y, Stringer, E, Taber, S, Terreri, MT, Tifft, C, Torgerson, T, Tosi, L, van Royen-Kerkhof, A, Muskardin, TW, Canna, SW & Goldbach-Mansky, R 2020, 'Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases', Journal of Clinical Investigation, vol. 130, n° 4, pp. 1669-1682. https://doi.org/10.1172/JCI129301
@article{297e8aad129b4b2489079915ac501538,
title = "Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases",
abstract = "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-Gouti{\`e}res 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.",
author = "{de Jesus}, {Adriana A.} and Yangfeng Hou and Stephen Brooks and Louise Malle and Angelique Biancotto and Yan Huang and Calvo, {Katherine R.} and Bernadette Marrero and Susan Moir and Oler, {Andrew J.} and Zuoming Deng and {Montealegre Sanchez}, {Gina A.} and Amina Ahmed and Eric Allenspach and Bita Arabshahi and Edward Behrens and Susanne Benseler and Liliana Bezrodnik and Sharon Bout-Tabaku and Brescia, {Anne Marie C.} and Diane Brown and Burnham, {Jon M.} and Caldirola, {Maria Soledad} and Ruy Carrasco and Chan, {Alice Y.} and Rolando Cimaz and Paul Dancey and Jason Dare and Marietta DeGuzman and Victoria Dimitriades and Ian Ferguson and Polly Ferguson and Laura Finn and Marco Gattorno and Grom, {Alexei A.} and Hanson, {Eric P.} and Hashkes, {Philip J.} and Hedrich, {Christian M.} and Ronit Herzog and Gerd Horneff and Rita Jerath and Elizabeth Kessler and Hanna Kim and Kingsbury, {Daniel J.} and Laxer, {Ronald M.} and Lee, {Pui Y.} and Lee-Kirsch, {Min Ae} and Laura Lewandowski and Suzanne Li and Vibke Lilleby and Vafa Mammadova and Moorthy, {Lakshmi N.} and Gulnara Nasrullayeva and O'Neil, {Kathleen M.} and Karen Onel and Seza Ozen and Nancy Pan and Pascal Pillet and Piotto, {Daniela G.P.} and Punaro, {Marilynn G.} and Andreas Reiff and Adam Reinhardt and Rider, {Lisa G.} and Rafael Rivas-Chacon and Tova Ronis and Angela R{\"o}sen-Wolff and Johannes Roth and Ruth, {Natasha Mckerran} and Marite Rygg and Heinrike Schmeling and Grant Schulert and Christiaan Scott and Gisella Seminario and Andrew Shulman and Vidya Sivaraman and Son, {Mary Beth} and Yuriy Stepanovskiy and Elizabeth Stringer and Sara Taber and Terreri, {Maria Teresa} and Cynthia Tifft and Troy Torgerson and Laura Tosi and {van Royen-Kerkhof}, Annet and Muskardin, {Theresa Wampler} and Canna, {Scott W.} and Raphaela Goldbach-Mansky",
note = "Funding Information: FUNDING. The Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center. Funding Information: We would like to thank Samantha Dill, Dawn Chapelle, and Laura Failla for excellent patient care; and Nicole Plass, Wendy Goodspeed, Michelle O{\textquoteright}Brian, and Susan Pfeiffer for scheduling patients. We would also like to thank Jacob Mitchell and Rachel VanTries for running experiments. We further thank Paul Wakim for his review and advice on the statistical aspects of the correlation analyses. Funding was provided by the Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center. Funding Information: Conflict of interest: RGM received investigator-initiated grants under government collaborative agreements from SOBI, Lilly, Regeneron and Novartis. SWC received grants from Novartis and AB2Bio. JAD received grants from Pfizer, Roche, and Bristol-Myers Squibb. AAG received grants from NovImmune, grants and personal fees from Ab2Bio, and grants from Novartis. RML received consultant fees from SOBI and Novartis. LGR received research support from Hope Pharmaceuticals, Bristol-Myers Squibb, and Elli Lily. GS received personal fees from Novartis. TLWM received grants from Arthritis National Research Foundation, NYU Clinical & Translational Science Institute; personal fees from Novartis; and has a patent Methods and Materials for Treating Autoimmune Conditions issued. Copyright: {\textcopyright} 2020, American Society for Clinical Investigation. Submitted: April 2, 2019; Accepted: December 18, 2019; Published: February 24, 2020. Reference information: J Clin Invest. 2020;130(4):1669–1682. https://doi.org/10.1172/JCI129301. Publisher Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",
year = "2020",
month = apr,
day = "1",
doi = "10.1172/JCI129301",
language = "English",
volume = "130",
pages = "1669--1682",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",
}
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 - Lilleby, Vibke
AU - Mammadova, Vafa
AU - Moorthy, Lakshmi N.
AU - Nasrullayeva, Gulnara
AU - O'Neil, Kathleen M.
AU - Onel, Karen
AU - Ozen, Seza
AU - Pan, Nancy
AU - Pillet, Pascal
AU - Piotto, Daniela G.P.
AU - Punaro, Marilynn G.
AU - Reiff, Andreas
AU - Reinhardt, Adam
AU - Rider, Lisa G.
AU - Rivas-Chacon, Rafael
AU - Ronis, Tova
AU - Rösen-Wolff, Angela
AU - Roth, Johannes
AU - Ruth, Natasha Mckerran
AU - Rygg, Marite
AU - Schmeling, Heinrike
AU - Schulert, Grant
AU - Scott, Christiaan
AU - Seminario, Gisella
AU - Shulman, Andrew
AU - Sivaraman, Vidya
AU - Son, Mary Beth
AU - Stepanovskiy, Yuriy
AU - Stringer, Elizabeth
AU - Taber, Sara
AU - Terreri, Maria Teresa
AU - Tifft, Cynthia
AU - Torgerson, Troy
AU - Tosi, Laura
AU - van Royen-Kerkhof, Annet
AU - Muskardin, Theresa Wampler
AU - Canna, Scott W.
AU - Goldbach-Mansky, Raphaela
N1 - Funding Information:
FUNDING. The Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.
Funding Information:
We would like to thank Samantha Dill, Dawn Chapelle, and Laura Failla for excellent patient care; and Nicole Plass, Wendy Goodspeed, Michelle O’Brian, and Susan Pfeiffer for scheduling patients. We would also like to thank Jacob Mitchell and Rachel VanTries for running experiments. We further thank Paul Wakim for his review and advice on the statistical aspects of the correlation analyses. Funding was provided by the Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.
Funding Information:
Conflict of interest: RGM received investigator-initiated grants under government collaborative agreements from SOBI, Lilly, Regeneron and Novartis. SWC received grants from Novartis and AB2Bio. JAD received grants from Pfizer, Roche, and Bristol-Myers Squibb. AAG received grants from NovImmune, grants and personal fees from Ab2Bio, and grants from Novartis. RML received consultant fees from SOBI and Novartis. LGR received research support from Hope Pharmaceuticals, Bristol-Myers Squibb, and Elli Lily. GS received personal fees from Novartis. TLWM received grants from Arthritis National Research Foundation, NYU Clinical & Translational Science Institute; personal fees from Novartis; and has a patent Methods and Materials for Treating Autoimmune Conditions issued. Copyright: © 2020, American Society for Clinical Investigation. Submitted: April 2, 2019; Accepted: December 18, 2019; Published: February 24, 2020. Reference information: J Clin Invest. 2020;130(4):1669–1682. https://doi.org/10.1172/JCI129301.
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
UR - http://www.scopus.com/inward/citedby.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 -