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Research Updates in SJIA & MAS - Grant Schulert

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This talk was given by Dr. Grant Schulert Cincinnati Children's Hospital to a group of patient families, at Systemic Juvenile Idiopathic Arthritis (or SJIA) Family Day on July 22nd, 2017.

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Research Updates in SJIA & MAS - Grant Schulert

  1. 1. Research update on SJIA and MAS SJIA Family Education Day July 22, 2017 Grant Schulert, MD PhD Assistant Professor of Pediatrics Cincinnati Children’s Hospital Medical Center
  2. 2. Key Questions • What is the cause of systemic JIA? • What happens during MAS, and why do only some patients get MAS?
  3. 3. Autoimmune Disease (1900s) Adaptive immunity High-titer autoantibodies and/or autoreactive, antigen-specific T cells Destructive immune response to self antigens Lupus, rheumatoid arthritis Autoinflammatory Disease (late 1990s) Innate immunity NO high-titer autoantibodies or autoreactive, antigen- specific T cells Episodes of seemingly unprovoked inflammation that sometimes results in tissue destruction Periodic fever syndromes (FMF, TRAPs, etc); Systemic JIA?
  4. 4. Complex diseases: (many) genes and the environment Source: CDC
  5. 5. Genetics and systemic JIA • Systemic JIA is rarely familial* although twins/siblings with disease have been described • Higher incidence in some ethnic groups (Asia, Northern vs Southern Europe) suggests shared genetic risk
  6. 6. DNA Sequence Variation in the Human Genome • In general, each human’s genome is >99.5% identical to any other humans • But, that means up to 10-20 million bases of differences – Mostly single nucleotide changes • Nomenclature: – Single nucleotide polymorphism (SNP) – change present in at least 1% of population – Rare variant – present in less than 1% of population
  7. 7. SNPs and genome-wide association studies (GWAS) • GWAS are large-scale studies to identify associations between SNPs and phenotypes (diseases) • Compare SNP prevalence between thousands of patients and controls • SNPs that are associated with disease are considered to mark genomic regions that may influence risk of disease • Results: Manhattan plots, where height of peak reflects strength of association
  8. 8. GWAS in (non-systemic) JIA • Examined 2816 patients with JIA oligoarticular or RF- negative polyarticular JIA (poligos) compared to 13000 controls • Used Immunochip – 123,000 SNPs with minor allele frequency >1% Nature Genetics 45, 664–669 (2013)
  9. 9. GWAS in (non-systemic) JIA Nature Genetics 45, 664–669 (2013)
  10. 10. GWAS in (non-systemic) JIA • Highest single SNP in HLA-DQB1 region, 2% in controls vs. 12% in patients (OR=6.01, p=3.14x10-174) • Other identified genes with known functions in immunity and roles in other autoimmune diseases
  11. 11. GWAS in systemic JIA • Large, multinational collaborative led by Dr. Michael Ombrello at NIH • Examined 982 children with systemic JIA compared to ~9000 controls – 770 SJIA patients stratified into 9 geographically defined, ancestrally matched case-control collections • 27-35K SNPs in the MHC region, overall 4-6million genotypes or imputed SNPs Proc Natl Acad Sci USA (2015) 112: 15970
  12. 12. GWAS in systemic JIA Proc Natl Acad Sci USA (2015) 112: 15970 Ann Rheum Dis (2016)
  13. 13. GWAS in systemic JIA • Clearly identified the MHC locus as a significant (if weaker) bona fide susceptibility region for systemic JIA in multiple populations • Top SNP: HLA- DRB1*11, OR 2.6 (p=2.8x10-17) Proc Natl Acad Sci USA (2015) 112: 15970
  14. 14. GWAS in systemic JIA • In addition, 24 genetic regions with suggestive association with systemic JIA • None previously associated with any rheumatic diseases • No evidence for shared genetic architecture between systemic JIA and other JIA subtypes Ann Rheum Dis (2016)
  15. 15. Key Questions • What is the cause of systemic JIA? • What happens during MAS, and why do only some patients get MAS?
  16. 16. MΦ Proposed Pathogenic Mechanism of Macrophage Activation Syndrome CD8+ IFN-γ GM-CSF MΦ MΦ MΦ MΦ MΦMΦ MΦ Mo TNF-α IL-6 IL-1 IL-18 M-CSF Hemostatic Tissue Factor sCD163 sCD8 sIL-2Rα CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ MΦ Cytokine storm
  17. 17. IFNgamma and MAS/HLH • IFNg believed to be key driver of inflammation in familial HLH – High levels in patients – IFNg blockade protective in mice – Promising early results in clinical trial of anti-IFNg monoclonal antibody • Does IFNg have similar central role in MAS? Hemophagocytic macrophages in MAS
  18. 18. 1 Number (percentile); 2 Median (IQR); 3 At least one time during disease course 4 Complete remission of MAS/HLH episode after treatment according to the judgment of the investigator 5 Clinical inactive disease according to Wallace Criteria PATIENTS NUMBER OF SAMPLES ACTIVE DISEASE INACTIVE DISEASE sec-HLH n=14 11 114 Gender, Female1 5 (36) Age at disease onset (years)2 8.6 (4.1 – 12.9) sJIA n=54 48 355 Gender, Female1 26 (48) Age at disease onset (years)2 7.9 (4.6 – 13.6) sJIA with MAS3 n=27 20 204 Gender, Female1 13 (48) Age at disease onset (years)2 9.4 (4.8 – 13.8) sJIA without MAS n=27 28 155 Gender, Female1 13 (48) Age at disease onset (years)2 7.3 (4.1 – 12.1) Patients’ samples collected at OPBG in Roma, IGG in Genova, and CCHMC in Cincinnati Bracaglia et al (in revision
  19. 19. Active sHLH (n=11) Active MAS (n=20) Active sJIA No MAS (n=28) Inactive sJIA (n=35) IL-6 11.4 (3.2-49.3) 22.9 (5.5-45.6) 20.3 (5.9-54.9) 3.2 (3.2-7.9) TNFa 27.6 (10.8-49.2) 14.7 (7.1-33.1) 10 (5.3-15.0) 9.4 (6.1-18.5) IFNg 34.7 (23.9-170.1) 15.4 (5.1-52.6) 4.9 (3.2-8.6) 4.2 (3.2-9.3) CXCL9 33598 (3083-127687) 13392 (2163-35452) 837 (471-2505) 901 (466-1213) CXCL10 4420 (799-8226) 1612 (425-4309) 307 (199-694) 235 (172-407) CXCL11 1327 (189-2000) 565 (198-1007) 122 (62-197) 111 (63-187) *p<0.01 MAS vs Active sJIA Bracaglia, et al. Ann Rheum Dis 2016
  20. 20. Serum IFNγ and IFN-induced chemokines in MAS versus active SJIA Bracaglia, et al. Ann Rheum Dis 2016
  21. 21. IFNg and IFN-induced chemokines and laboratory features of MAS Bracaglia, et al. Ann Rheum Dis 2016
  22. 22. IFNg, IL-18 and MAS • IL-18 is a key proinflammatory cytokine – Inflammasome-mediated production in myeloid cells – Key driver of IFNg production by CD8 cells and NK cells • IL-18 hypersecretion  recurrent MAS – NLRC4 gain-of-function mutations (Canna et al) Nature Immunology (2012) 13:115–117
  23. 23. High IL-18 subset of SJIA patients develop MAS • Cytokine levels during active disease can define two subsets of SJIA patients: – High IL-18/IL-6 – high risk of MAS (green) – Low IL-18/IL-6 – older, more arthritis, no MAS (n=33) Clinical Immunology 160 (2015) 277–281
  24. 24. Cytolytic Defects in FHLH Cytolytic cells cause destruction of target cells by delivering granules that contain proteins such as perforin and granzymes1 Recognition of target Polarization of the cytoskeleton Movement of cytolytic granules along MTs to the site of contact Degranulation and release of contents Delivery of content of granules to target cell aided by Perforin 24 Apoptosis Target Cell Effector Cell (NK Cell) Granzyme B Fusion Priming Docking Munc13-4 Munc18-2 Syntaxin 11 Rab27a Nucleus Cytolytic Granule Perforin MTOC Cytolytic Pathway1,2 Granzymes
  25. 25. HLH mutations associated with MAS • Several reports have identified rare mutations in cytolytic pathway genes in patients with MAS – PRF1: Vastert et al (2010), Unal et al (2013), Schulert et al (2015) – UNC13D: Hazen et al (2008), Zhang et al (2008) • Could there be a genetic predisposition to MAS in some patients with systemic JIA?
  26. 26. Genetics of MAS in systemic JIA • Trio-based whole exome sequencing performed for 14 patients with SJIA and MAS and unaffected parents – Comparison: 29 patients with SJIA and no history of MAS • Primary analysis – variants in HLH-associated genes – PRF1, MUNC13-4, Syntaxin 11, STXBP2, LYST, Rab27A • Secondary analysis – Identification of other candidate genes / rare variants Kaufman et al (2014) Arthritis Rheum
  27. 27. Kaufman et al (2014) Arthritis Rheum Top IPA category of all identified genes: “Cellular assembly and organization” (p<3.1 x 10-5) 5/14 36%
  28. 28. Current model for MAS in systemic JIA
  29. 29. Some answers, many new questions … • How do genetic and environmental factors interact to cause systemic JIA? • Can cytokine-targeted therapy treat (anti- IFNg, anti-IL-18) MAS? • Can genetic or cytokine testing predict risk for MAS?

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