Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

Adriana A. de Jesus; Yangfeng Hou; Stephen Brooks; Louise Malle; Angelique Biancotto; Yan Huang; Katherine R. Calvo; Bernadette Marrero; Susan Moir; Andrew J. Oler; Zuoming Deng; Gina A. Montealegre Sanchez; Amina Ahmed; Eric Allenspach; Bita Arabshahi; Edward Behrens; Susanne Benseler; Liliana Bezrodnik; Sharon Bout-Tabaku; Anne Marie C. Brescia; Diane Brown; Jon M. Burnham; Maria Soledad Caldirola; Ruy Carrasco; Alice Y. Chan; Rolando Cimaz; Paul Dancey; Jason Dare; Marietta DeGuzman; Victoria Dimitriades; Ian Ferguson; Polly Ferguson; Laura Finn; Marco Gattorno; Alexei A. Grom; Eric P. Hanson; Philip J. Hashkes; Christian M. Hedrich; Ronit Herzog; Gerd Horneff; Rita Jerath; Elizabeth Kessler; Hanna Kim; Daniel J. Kingsbury; Ronald M. Laxer; Pui Y. Lee; Min Ae Lee-Kirsch; Laura Lewandowski; Suzanne Li; Vibke Lilleby; Vafa Mammadova; Lakshmi N. Moorthy; Gulnara Nasrullayeva; Kathleen M. O'Neil; Karen Onel; Seza Ozen; Nancy Pan; Pascal Pillet; Daniela G.P. Piotto; Marilynn G. Punaro; Andreas Reiff; Adam Reinhardt; Lisa G. Rider; Rafael Rivas-Chacon; Tova Ronis; Angela Rösen-Wolff; Johannes Roth; Natasha Mckerran Ruth; Marite Rygg; Heinrike Schmeling; Grant Schulert; Christiaan Scott; Gisella Seminario; Andrew Shulman; Vidya Sivaraman; Mary Beth Son; Yuriy Stepanovskiy; Elizabeth Stringer; Sara Taber; Maria Teresa Terreri; Cynthia Tifft; Troy Torgerson; Laura Tosi; Annet van Royen-Kerkhof; Theresa Wampler Muskardin; Scott W. Canna; Raphaela Goldbach-Mansky

doi:10.1172/JCI129301

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

Adriana A. de Jesus, Yangfeng Hou, Stephen Brooks, Louise Malle, Angelique Biancotto, Yan Huang, Katherine R. Calvo, Bernadette Marrero, Susan Moir, Andrew J. Oler, Zuoming Deng, Gina A. Montealegre Sanchez, Amina Ahmed, Eric Allenspach, Bita Arabshahi, Edward Behrens, Susanne Benseler, Liliana Bezrodnik, Sharon Bout-Tabaku, Anne Marie C. BresciaDiane Brown, Jon M. Burnham, Maria Soledad Caldirola, Ruy Carrasco, Alice Y. Chan, Rolando Cimaz, Paul Dancey, Jason Dare, Marietta DeGuzman, Victoria Dimitriades, Ian Ferguson, Polly Ferguson, Laura Finn, Marco Gattorno, Alexei A. Grom, Eric P. Hanson, Philip J. Hashkes, Christian M. Hedrich, Ronit Herzog, Gerd Horneff, Rita Jerath, Elizabeth Kessler, Hanna Kim, Daniel J. Kingsbury, Ronald M. Laxer, Pui Y. Lee, Min Ae Lee-Kirsch, Laura Lewandowski, Suzanne Li, Vibke Lilleby, Vafa Mammadova, Lakshmi N. Moorthy, Gulnara Nasrullayeva, Kathleen M. O'Neil, Karen Onel, Seza Ozen, Nancy Pan, Pascal Pillet, Daniela G.P. Piotto, Marilynn G. Punaro, Andreas Reiff, Adam Reinhardt, Lisa G. Rider, Rafael Rivas-Chacon, Tova Ronis, Angela Rösen-Wolff, Johannes Roth, Natasha Mckerran Ruth, Marite Rygg, Heinrike Schmeling, Grant Schulert, Christiaan Scott, Gisella Seminario, Andrew Shulman, Vidya Sivaraman, Mary Beth Son, Yuriy Stepanovskiy, Elizabeth Stringer, Sara Taber, Maria Teresa Terreri, Cynthia Tifft, Troy Torgerson, Laura Tosi, Annet van Royen-Kerkhof, Theresa Wampler Muskardin, Scott W. Canna, Raphaela Goldbach-Mansky

Medicine

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170 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	1669-1682
Número de páginas	14
Publicación	Journal of Clinical Investigation
Volumen	130
N.º	4
DOI	https://doi.org/10.1172/JCI129301
Estado	Published - abr. 1 2020

Nota bibliográfica

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.

ASJC Scopus Subject Areas

General Medicine

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10.1172/JCI129301

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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.º 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.

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DO - 10.1172/JCI129301

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Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

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