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Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment
  1. Rebeccah J Mathews1,
  2. James I Robinson1,2,
  3. Michele Battellino1,3,
  4. Chi Wong1,2,
  5. John C Taylor2,4,
  6. Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS)5,
  7. Steve Eyre6,
  8. Sarah M Churchman1,2,
  9. Anthony G Wilson7,
  10. John D Isaacs8,9,
  11. Kimme Hyrich6,
  12. Anne Barton6,10,
  13. Darren Plant10,
  14. Sinisa Savic2,11,
  15. Graham P Cook2,4,
  16. Piercarlo Sarzi-Puttini3,
  17. Paul Emery1,2,
  18. Jennifer H Barrett2,4,
  19. Ann W Morgan1,2,
  20. Michael F McDermott1,2
  1. 1Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, Chapel Allerton Hospital, UK
  2. 2NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  3. 3Rheumatology Unit, L. Sacco University Hospital, Milan, Italy
  4. 4Institute of Cancer Studies and Pathology, The University of Leeds, Leeds, UK
  5. 5Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate, ARC-EU, Stopford Building, Manchester, UK
  6. 6Arthritis Research UK-Epidemiology Unit, The University of Manchester, Manchester, UK
  7. 7Department of Infection and Immunity, The University of Sheffield, Sheffield, UK
  8. 8Musculoskeletal Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, UK
  9. 9National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle upon Tyne, UK
  10. 10NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
  11. 11Department of Clinical Immunology and Allergy, The University of Leeds, Leeds, UK
  1. Correspondence to Professor Michael McDermott, Leeds Institute of Rheumatic and Musculoskeletal Medicine, Wellcome Trust Brenner Building, St. James's University Hospital, Leeds LS9 7TF, UK; m.mcdermott{at}leeds.ac.uk

Abstract

Background The NLRP3-inflammasome, implicated in the pathogenesis of several inflammatory disorders, has been analysed in rheumatoid arthritis (RA).

Methods Relative gene expression of NLRP3-inflammasome components was characterised in PBMCs of 29 patients receiving infliximab. A total of 1278 Caucasian patients with RA from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort receiving tumour necrosis factor (TNF) antagonists (infliximab, adalimumab and etanercept) were genotyped for 34 single nucleotide polymorphisms (SNPs), spanning the genes NLRP3, MEFV and CARD8. Regression analyses were performed to test for association between genotype and susceptibility and treatment response (disease activity score across 28 joints (DAS28) and EULAR improvement criteria) at 6 months, with secondary expression quantitative trait loci (eQTL) analyses.

Results At baseline, gene expression of ASC, MEFV, NLRP3-FL, NLRP3-SL and CASP1 were significantly higher compared with controls whereas CARD8 was lower in the patients. Caspase-1 and interleukin-18 levels were significantly raised in patients with RA. SNPs in NLRP3 showed association with RA susceptibility and EULAR response to anti-TNF in the BRAGGSS cohort, and in monocytes but not B cells, in eQTL analysis of 283 healthy controls. CARD8 SNPs were associated with RA susceptibility and DAS28 improvement in response to anti-TNF and eQTL effects in monocytes and B cells.

Conclusions This study found evidence of modulation of the NLRP3-inflammasome in patients with RA prior to receiving infliximab and some evidence of association for SNPs at NLRP3 and CARD8 loci with RA susceptibility and response to anti-TNF. The SNPs associated with susceptibility/response are not the main eQTL variants for either locus, and the associations with treatment response require replication in an independent cohort.

  • Anti-TNF
  • Inflammation
  • Rheumatoid Arthritis
  • Treatment

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