Clinical and Immunologic Description Of Pediatric Conditions With Interferon-Regulated Gene Signatures (Chronic Atypical Neutrophilic Dermatosis Lipodystrophy Elevated Tempature, Aicardi Goutieres Syndrome, Juvenile Dermatomyositis, Juvenile Systemic Lupus Erythematosus)

Hanna Kim¹, Adriana Almeida de Jesus², Yin Liu³, Yan Huang¹, Gina Montealegre⁴, Dawn Chapelle⁵, Nicole Plass¹, Wanxia Tsai⁶, Massimo Gadina⁷, Lisa G. Rider⁸, Adeline Vanderver⁹ and Raphaela Goldbach-Mansky¹, ¹Translational Autoinflammatory Diseases Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, ²Translational Autoinflammatory Disease Section, NIAMS/NIH, Bethesda, MD, ³Translational Autoinflammatory Disease Section, Office of the Clinical Director, NIAMS/NIH, Bethesda, MD, ⁴Office of the Clinical DIrector, NIAMS / NIH, Bethesda, MD, ⁵Office of the Clinical Director, NIAMS / NIH, Bethesda, MD, ⁶Translational Immunology Section, NIAMS / NIH, Bethesda, MD, ⁷Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, ⁸Environmental Autoimmunity Group, NIEHS, NIH, Bethesda, MD, ⁹Pediatric Neurology, Children's National Medical Center, Washington, DC

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: cytokines, Gene Expression, interferons and pediatric rheumatology

Session Information

Title: Pediatric Rheumatology - Pathogenesis and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Increased interferon (IFN) regulated gene (IRG) expression has been reported in juvenile systemic lupus (JSLE)¹ and juvenile dermatomyositis (JDM)².Recently, two monogenic conditions chronic atypical neutrophilic dermatosis lipodystrophy elevated temperature (CANDLE) syndrome³ and Aicardi Goutieres syndrome (AGS)⁴ have demonstrated IRG signatures. The goal of this study is to characterize their phenotypic and immunologic features versus neonatal-onset multiple inflammatory disease (NOMID), IL-1 mediated disease control and healthy controls, and identify potential disease activity biomarkers.

Methods:

History, physical, and laboratory evaluation performed on 9 CANDLE, 7 AGS, 4 JSLE, 5 JDM, and 5 NOMID disease control patients (prior to IL-1 blocking therapy). Cytokine profile done on serum (ratios of means versus 3 pediatric controls) and CSF (CSF:serum ratios compared to non-inflammatory neurologic diseases)⁵ using Luminex (Austin, TX) assay. Gene expression analyzed with RNA-seq. Data analyzed with Partek 6.6 and Ingenuity Pathway Analysis.

Results:

A. Table of Clinical Characteristics

Systemic inflammatory markers were highest in NOMID and CANDLE patients. AGS, JDM and SLE patients were only mildly clinically active at time of sampling.

B. Serum/Plasma Cytokine Profiles

5 most distinguishing serum cytokines (Panel B, radar plots) show IP-10 was highly elevated in CANDLE and JSLE and IL-13 elevated in JDM. IP-10 and MCP-1 CSF/serum ratios were elevated for AGS. Gene expression identified upregulated IRGs for the 4 interferonpathies not present in the healthy controls or NOMID. There was a difference in disease-specific IFN signatures, with subsets uniquely upregulated and downregulated in each condition. IRGs were most upregulated in CANDLE, with greatest similarity to JSLE. AGS and JDM had other pathways higher-ranked than IFN pathways.

Conclusion:

There are specific areas of phenotypic overlap such as basal ganglia calcifications (CANDLE, AGS), lipodystrophy (CANDLE, JDM), and myositis (CANDLE, JDM, less common JSLE). Disease-specific cytokine patterns included increased serum IP-10 (CANDLE, p=0.002), increased serum IL-13 (JDM, p=0.005), and increased CSF IP-10 and MCP-1 (AGS). These differences may indicate distinct and potentially organ-specific inflammatory pathways. Disease-specific differential gene expression patterns within the IFN response signature may reflect different pathogenesis, which may be due to differing triggers of IFN response.

¹Bennett L, 2003; ²Baechler E, 2007; ³Liu Y, 2012; ⁴Rice G, 2012; ⁵Pranzatelli J, 2013.

Disclosure:

H. Kim,
None;

A. Almeida de Jesus,
None;

Y. Liu,
None;

Y. Huang,
None;

G. Montealegre,
None;

D. Chapelle,
None;

N. Plass,
None;

W. Tsai,
None;

M. Gadina,
None;

L. G. Rider,
None;

A. Vanderver,
None;

R. Goldbach-Mansky,
None.

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