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