NextGen 2024: Genetics in SJIA Session Part 1

NextGen 2024: Genetics in SJIA Session Part 1

@SJIA_Foundation
@SJIA_Foundation
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3 months ago 258
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Key Insights
  • Genetics play a significant role in systemic juvenile idiopathic arthritis (sJIA) and macrophage activation syndrome (MAS).
  • Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome
  • Mutations in genes like PRF1 can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis.
  • Certain genes like UNC13D, STXBP2, and PRF1 are implicated in HLH genetics of MAS patients
  • Genetic knowledge is valuable in sJIA/MAS for understanding disease mechanisms, assessing recurrence risk, and genetic counseling.
#sjiafoundation #sjia #curesjia #genetics

NextGen 2024: Genetics in SJIA Session Part 1

@SJIA_Foundation3 months ago

'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%)

        Binstadt

        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%

            Vastert

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

              HLH Genetics of MAS Patients at Children's of Alabama

                Kaufman

                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

                    Ombrello

                      MAS Genetics in Systemic JIA

                      Schulert

                      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 )
“Clinical Utility of Genetics 
in Systemic JIA” 
Randy Q. Cron, MD, PhD
University of Alabama at…
1/12
Disclosures 
Randy Q. Cron, M.D., Ph.D.
SOBI – investigator initiated clinical trial of anakinra …
2/12
Natural killer cell dysfunction in patients with systemic-onset 
juvenile rheumatoid arthritis and…
3/12
Macrophage activation syndrome in patients with systemic 
juvenile idiopathic arthritis is associa…
4/12
Novel UNC13D intronic variant disrupting a NFκB enhancer in a patient with recurrent 
macrophage a…
5/12
Vastert
PRF1 A91V mutation
sJIA/MAS – 20%
vs.
sJIA no MAS – 10%
6/12
Pt Age Sex Diagnosis Trigger Gene Mutation Amino Acid 
Change
Prior 
Association
Outcome
1 15 …
7/12
Heterozygous FHL
gene mutations:
5/14 sJIA/MAS – 36%
vs.
4/29 sJIA no MAS – 
14%
Kaufman
8/12
Role of DOCK8 in Cytokine Storm Syndromes.
Zhang M, Cron RR, Chu N, Nguyen J, Gordon SM, Eloseily …
9/12
Ombrello
10/12
MAS Genetics in Systemic JIA
Schulert
Lee
11/12
Value of genetic knowledge in 
sJIA/MAS
•IRF5, IL1RN, HLA-DRB1*15 - Ombrello
•HLH gene associati…
12/12


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