Recent discoveries in genomics of sJIA

Mariana Correia Marques, MD Lawrence Shulman Scholar in Translational Research Translational Genetics and Genomics Section National Institute of Arthritis and Musculoskeletal and Skin Diseases

Disclosures

• · None

What insights can we gain from genetics?


Variant Impact

Impact on genetics on the risk of developing disease



Variant Frequency

Variant Impact

Impact on genetics on the risk of developing disease



Variant Frequency

Common variants - Candidate Gene Studies



Marques, Ombrello, Schulert, 2024, Expert Rev

Common variants - GWAS


• · HLA-DRB1*11 and MHC class II locus - strongest association with sJIA - (OR 2.3)
• · Implicated adaptive immune system in sJIA
• · sJIA has different genetic architecture from other forms of JIA
• · SNPs in the IL1RN promoter region associated with lower IL1RN expression also associated with sJIA (OR 1.3)
• ❖ Regulatory haplotype of CXC4 is associated with sJIA and is correlated with neutrophil and monocyte migration

Ombrello et al , 2015, PNAS Ombrello et al , 2017, ARD Arthur et al, 2018, A&R Nakano et at, ACR Convergence 2022


Variant Impact

Impact on genetics on the risk of developing disease



Variant Frequency

Rare / Low frequency variants



Marques et al, 2024, A&R

• · Rare/ultra-rare variants in HLH genes associated with sJIA in general
• · STXBP2 and UNC13D individually associated with sJIA
• · sJIA patients more often carried 2 variants in HLH genes
• · PRF1 A91V not associated with sJIA or MAS
Variant Impact

Impact on genetics on the risk of developing disease



Variant Frequency

Rare variants causing monogenic disease


• · 12 girls 1 boy who met ILAR criteria for sJIA
• · Fever + symmetrical polyarthritis + maculopapular rash
• · 8/13 + ANA, 5/13 + RF
• · Segregated with homozygous LACC1 variant
• · Same variant also reported in IBD with severe arthropathy
• · Other variants in LACC1 associated with non-systemic JIA

Mimickers



What insights can we gain from genetics?



Treatment response



Original Article Full Access

ILIRN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis

Alan M. Rosenberg MD Lucy R. Wedderburn MD, PhD Jordi Anton MD, PhD Johannes-Peter Haas MD Angela Rösen-Wolff MD, PhD Kirsten Minden MD, PhD Ann Marie Szymanski MD See fewer authors



Early Treatment and ILIRN Single-Nucleotide Polymorphisms Affect Response Anakinra in Systemic Juvenile Idiopathic Arthritis to

Marianna Nicoletta Rossi Denise Pires Marafon Emanuela Sacco Anna Tulone Giusi Prencipe Fabrizio De Benedetti



Impact of ILIRN Variants on Response to Interleukin-1 Blocking Therapy in Systemic Juvenile Idiopathic Arthritis



Claas Hinze

Treatment response



Original Article Full Access

ILIRN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis

Alan M. Rosenberg MD Lucy R. Wedderburn MD, PhD Jordi Anton MD, PhD Johannes-Peter Haas MD Angela Rösen-Wolff MD, PhD Kirsten Minden MD, PhD Ann Marie Szymanski MD See fewer authors



Early Treatment and ILIRN Single-Nucleotide Polymorphisms Affect Response Anakinra in Systemic Juvenile Idiopathic Arthritis to

Marianna Nicoletta Rossi Denise Pires Marafon Emanuela Sacco Anna Tulone Giusi Prencipe Fabrizio De Benedetti



Impact of ILIRN Variants on Response to Interleukin-1 Blocking Therapy in Systemic Juvenile Idiopathic Arthritis



Claas Hinze

Treatment response



Original Article Full Access

ILIRN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis

Michael J. Ombrello MD See fewer authors



Early Treatment and ILIRN Single-Nucleotide Polymorphisms Affect Response to Anakinra in Systemic Juvenile Idiopathic Arthritis

Manuela Pardeo Marianna Nicoletta Rossi Denise Pires Marafon Emanuela Sacco Claudia Bracaglia, Chiara Passarelli; Ivan Caiello Giulia Marucci , Antonella Insalaco Chiara Perrone Anna Tulone Giusi Prencipe Fabrizio De Benedetti



IL1RA IL1RA ILIRN Variants

risk of sJIA response to anakinra See fewer authors



Impact of ILIRN Variants on Response to Interleukin-1 Blocking Therapy in Systemic Juvenile Idiopathic Arthritis



Claas Hinze Boris Hügle Johannes-Peter Haas, Gerd Ganser, Elisabeth Weißbarth-Riedel, Annette Jansson Dirk Foell

Treatment response



Original Article Full Access

ILIRN Variation Influences Both Disease Sul Response to Recombinant Human Interleul Antagonist Therapy in Systemic Juvenile Id

MD Michael J. Ombrello MD See fewer authors



Full Length

Full Access

Early Treatment and ILIRN Single-Nucleotide Polymorphisms Affect Response to Anakinra in Systemic Juvenile Idiopathic Arthritis

Manuela Pardeo Marianna Nicoletta Rossi Denise Pires Marafon Emanuela Sacco Claudia Bracaglia, Chiara Passarelli; Ivan Caiello Giulia Marucci , Antonella Insalaco Chiara Perrone Anna Tulone Giusi Prencipe Fabrizio De Benedetti

Population

OR

UK

13

Germany

10

Turkey

Italy

1.6

Brazil

1.5

Argentina

Canada

1,4

Spain

1.7

1.2

1.2



rs55663133 (AAT allele)

IL1RA

IL1RA ukin-1 Receptor Antagonist Is an Effective

risk of sJIA



response to anakinra prg Van Loosdregt Sebastiaan J. Vastert See fewer authors



AMERICANCOLLEGE

0.1

1.0

4.0

heumatology

Brief Report

Open Access

Impact of ILIRN Variants on Response to Interleukin-1 Blocking Therapy in Systemic Juvenile Idiopathic Arthritis



Claas Hinze Boris Hügle Johannes-Peter Haas, Gerd Ganser, Elisabeth Weißbarth-Riedel, Annette Jansson Dirk Foell

What insights can we gain from genetics?



Disease prognosis

Dr. Cron

Dr. Ombrello

HLH variants associated with risk of MAS

HLA-DRB1*15 associated with lung disease and reactions to biologics

The NIAMS Still's Disease Team



Translational Genetics and Genomics Section, NIAMS

Michael Ombrello, MD Dale Kobrin, MD Navid Chowdhury Anthony Cruz Brooke Boyd

Sophia Chou Mallika Datta Elizabeth Schmitz

Alana Platukus



Michael Ombrello, MD Principal Investigator

Biodata Mining Section, NIAMS

Zuoming Deng, PhD Stephen Brooks, PhD

Translational Immunology Section, NIAMS

Massimo Gadina, PhD Shajia Lu

Genome Technology Section, NIAMS

Stefania Dell'Orso, PhD

We appreciate the contributions of our patients and their families to our studies of sJIA and AOSD.



National Institute of Arthritis and Musculoskeletal and Skin Diseases