'Clinical Utility of Genetics in Systemic JIA'

Randy Q. Cron, MD, PhD University of Alabama at Birmingham

NextGen Conference 2024

Washington, D.C.

THE UNIVERSITY OF

Disclosures

Randy Q. Cron, M.D., Ph.D.

SOBI - investigator initiated clinical trial of anakinra to treat MAS

SOBI - advisory board for MAS therapy

SOBI - paid speaker/moderator for MEDSCAPE/WebMD

Novartis - consultant on switching therapy

Pfizer - clinical trial MAS adjudication committee chair

Sironax - consultant on RIP1 inhibitor

AbbVie - clinical trial MAS adjudication committee member

Lilly - paid speaker

CareerPhysician - advisory council

American Board of Pediatrics - Subboard of Pediatric Rheumatology

Springer - royalties on Cytokine Storm Syndrome textbook


juvenile rheumatoid arthritis and macrophage activation syndrome



Alexei A Grom, Joyce Villanueva, Susan Lee, Ellen A Goldmuntz, Murray H Passo, Alexandra Filipovich.

Grom

J Pediatr. 2003 Mar;142(3):292-6.



Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome.

Villanueva J, Lee S, Giannini EH, Graham TB, Passo MH, Filipovich A, Grom AA.

Arthritis Res Ther. 2005;7(1):R30-7.

juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms.



Zhang K, Biroschak J, Glass DN, Thompson SD, Finkel T, Passo

Zhang

MH, Binstadt BA, Filipovich A, Grom AA. Arthritis Rheum. 2008 Sep;58(9):2892-6.

9/16 sJIA/MAS patients (57%) vs. 6/73 sJIA without MAS (8.2%) vs.

27/229 healthy controls (12%)



1047 aa Mutations of the hemophagocytic lymphohistiocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis. Hazen MM, Woodward AL, Hofmann I, Degar BA, Grom A, Filipovich AH, Binstadt BA. Arthritis Rheum . 2008 Feb;58(2):567-70.

Novel UNC13D intronic variant disrupting a NFκB enhancer in a patient with recurrent macrophage activation syndrome and systemic juvenile idiopathic arthritis Grant S Schulert , Mingce Zhang, Ammar Husami, Ndate Fall, Hermine Brunner, Kejian Zhang, Randy Q Cron, Alexei A Grom. Arthritis Rheumatol . 2018 May 2;70(6):963-970


RHEUMATOLOGY

Original article

Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis

Sebastiaan J. Vastert',2 Richard van Vooght , Wilco de Jager',2 Angelo Ravellis , 4 Silvia Magni-Manzonis , Antonella Insalacos Elisabetta Cortis Wouter W_ van Solinge3 Berent J. Prakken',2 Nico M Wulffraat',2 Fabrizio de Benedetti4 and Wietse Kuis',2



PRF1 A91V mutation sJIA/MAS - 20% vs. sJIA no MAS - 10%




Almost 20% of the SoJIA patients harbour heterozygous mutations In PRF1

HLH Genetics of MAS Patients at Children's of Alabama


Whole Exome Sequencing Reveals Overlap Between Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis and Familial Hemophagocytic

Lymphohistiocytosis

Kenneth M. Kaufman1,4 Bolan Ammar Husami2 Fan and Alexei A. Grom1



Heterozygous FHL gene mutations:

5/14 sJIA/MAS - 36% vs.

4/29 sJIA no MAS - 14%

Role of DOCK8 in Cytokine Storm Syndromes.

Zhang M, Cron RR, Chu N, Nguyen J, Gordon SM, Eloseily EM, Atkinson TP, Weiser P, Walter MR, Kreiger PA, Canna SW, Behrens EM, Cron RQ.

J Allergy Clin Immunol . 2024. Online ahead of print.



A

Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis Arthritis & Rheumatology

Mariana Correia Marques, Mallika Datta, Elizabeth Schmitz, 1 3 4 ID Gustavo Gutierrez Cruz, Andrew Patt, Elizabeth Bennett, Alexei Grom, Dirk Foell, Marco Gattorno; 6 Sampath Prahalad; ' iD Elizabeth Mellins 8 Jordi Anton,? Claudio A. Len,10 Zuoming Deng Michael J. Ombrello; 1 INCHARGE Consortium Yeung


MAS Genetics in Systemic JIA



The genetics of macrophage activation syndrome The genetics of macrophage activation syndrome

Grant 5 Schulrt' Grant 5 Schulert'

Randy Q Cron'

The Multifaceted Immunology of Cytokine Storm Syndrome

and Randy Q Cron

The Journal of Immunology 2023, 210: 1015-1024


Value of genetic knowledge in sJIA/MAS

• · IRF5 , IL1RN , HLA-DRB1*15 - Ombrello
• · HLH gene associations (e.g. PRF1 , UNC13D )
• · Potential explanation for diminished NK cell cytolyic function
• · Risk of recurrence
• · Genetic counseling
• · One nucleotide change, even missense, does not necessarily …
• · Rarity of mutation
• · Prediction of disruption (e.g. PolyPhen-2)
• · Prior publication of MAS/HLH association
• · Test individual mutations in lab (e.g. in vitro )