Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases
Adriana A. de Jesus, … , Scott W. Canna, Raphaela Goldbach-Mansky
Adriana A. de Jesus, … , Scott W. Canna, Raphaela Goldbach-Mansky
Published December 24, 2019
Citation Information: J Clin Invest. 2020;130(4):1669-1682. https://doi.org/10.1172/JCI129301.
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Clinical Research and Public Health Immunology Inflammation Article has an altmetric score of 28

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-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.TRIAL REGISTRATION ClinicalTrials.gov NCT02974595.FUNDING The Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.

Authors

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, AnneMarie 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

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Figure 2

Shared clinical features and different cytokine profiles in patients with and without elevated IFN scores.

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Shared clinical features and different cytokine profiles in patients wit...
(A) An elevated IFN-response gene score (IRG-S) distinguishes 36 patients during active disease from 29 patients who had normal IFN scores during bouts of active disease. Nonparametric (Kruskal-Wallis) test was used for multiple comparisons of IFN or Non-IFN groups with healthy controls (HC) or with CANDLE and SAVI patients combined. Depicted in the graph are the statistical significances (Kruskal-Wallis test) from the comparisons of each group (NOMID, IFN, and Non-IFN groups) with CANDLE and SAVI patients combined. Each individual patient is represented by a different symbol shape. ****P < 0.0001; NS, not significant. Bars and error lines indicate median and interquartile range, respectively; dotted line indicates the 28-gene IFN score cutoff (48.9) previously described (34). Multiple comparisons of each group (NOMID, CANDLE, and SAVI combined; IFN and Non-IFN) with HC (not depicted): NOMID P = 0.5004, CANDLE + SAVI P < 0.0001, IFN P < 0.0001, Non-IFN P = 0.2986. For HC, NOMID, and non-IFN groups, the same symbol is used for different individuals, as only 1 sample per patient is included. For CANDLE, SAVI, and IFN groups, each patient is represented by a different symbol. (B–G) Characteristic clinical features that were present only in patients with elevated IFN scores included panniculitis with lipoatrophy (B), neutrophilic vasculitis (C), erythematous macular rash (D), Gottron’s papules (E), interstitial lung disease (F), and basal ganglia calcifications (G). Four patients (per groups defined in Table 2; Group 1 – patient 3 [G1-P3] and G1-P5, G4-P2 and G4-P5) had negative IRG-S but were later added to the respective groups when a clinical or genetic diagnosis was made (not depicted).