clinical science session : gout - newer understanding in the pathogenesis of gout - dr vikas...
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Newer understanding in the pathogenesis of gout
Prof. Vikas AgarwalClinical Immunology,SGPGIMS, Lucknow
Layout• Genetics• Environmental factors• Host factors Urate clearance Dysregulated innate immunity Role of neutrophils Resolution of acute attack
Layout• Genetics• Environmental factors• Host factors Urate clearance Dysregulated innate immunity Role of neutrophils Resolution of acute attack• Therapeutic insights
Uric acid metabolism
Firestein and Kelley’s Textbook of Rheumatology 10 th Edition 2017
OVERPRODUCERS•HGPRT1 deficiency•PRPP synthetase hyperactivity
Uric acid transport proteins
Arthritis Research & Therapy (2015) 17:98
GWAS studies
Rheum Dis Clin N Am 40 (2014) 279–290
Common in most studies•SLC2A9•ABCG2•SLC22A12
Layout• Genetics• Environmental factors• Host factors Urate clearance Dysregulated innate immunity Role of neutrophils Resolution of acute attack• Therapeutic insights
Dietary factors
Rheum Dis Clin North Am. 2014 November ; 40(4): 581–604.
Fructose (soft drinks)
Firestein and Kelley’s Textbook of Rheumatology 10th Edition 2017
Layout• Genetics• Environmental factors• Host factors Urate clearance Dysregulated innate immunity Role of neutrophils Resolution of acute attack• Therapeutic insights
Gene environment interaction - SLC2A9 genotype and sugar exposure
Arthritis Research & Therapy (2015) 17:98
Patients with gout handle urate load differently
Joint Bone Spine (2016) (online first)
Layout• Genetics• Environmental factors• Host factors Urate clearance Dysregulated innate immunity Role of neutrophils Resolution of acute attack• Therapeutic insights
Initiation of acute gout attack
Semin Immunopathol (2013) 35:501–512
J Mol Med 2015; 93(7):727-34.
Acute gout
RMD Open 2015;1:e000046.
Layout• Genetics• Environmental factors• Host factors Urate clearance Dysregulated innate immunity Role of neutrophils Resolution of acute attack• Therapeutic insights
Neutrophils• Most abundant leukocytes in blood: 50-70%• Antimicrobial defense
– Chemotaxis– Intracellular killing
• Oxidative: ROS• Non Oxidative- Proteases
•Neutrophil Extracellular Traps (NETs)
Neutrophils and NETS
Semin Immunopathol (2013) 35:501–512
Ex-vivo activation of neutrophils when exposed to gout synovial fluid
Semin Immunopathol (2013) 35:501–512
J Mol Med 2015; 93(7):727-34.
Summary – acute gout
RMD Open 2015;1:e000046.
Layout• Genetics• Environmental factors• Host factors Urate clearance Dysregulated innate immunity Role of neutrophils Resolution of acute attack• Therapeutic insights
Resolution of acute attacks• NETs• IL-37• Anti-inflammatory cytokines - IL-10, TGF-β• ACTH, MSH
Aggregated NETs limit inflammation by degrading cytokines and chemokines
Nat Med. 2014 May;20(5):511-7
Aggregated NETs limit inflammation by degrading cytokines and chemokines
Nature Reviews Rheumatology 10, 319 (2014)
Nat Med. 2014 May;20(5):511-7
Expression of IL-37 in patients with gouty arthritis
SYNOVIUM
TOPHI
RMD Open 2015;1:e000046.
Neutrophil extracellular traps mediate
A. Inflammation in acute attack of goutB. Helps in resolution of acute attack of goutC. BothD. None
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