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Systemic inflammatory cytokine profiles in patients with gout during flare, intercritical and treat-to-target phases: TNFSF14 as new biomarker
  1. Hang-Korng Ea1,
  2. Brenda Kischkel2,
  3. Twinu Wilson Chirayath3,
  4. Viola Klück2,
  5. Caroline Aparicio4,
  6. Hoang-Uyen Loeung4,
  7. Philippe Manivet5,
  8. Tim Jansen6,
  9. Mylène Zarka3,
  10. Frédéric Lioté1,
  11. Augustin Latourte1,
  12. Thomas Bardin1,
  13. Alan Gauffenic1,
  14. Eric Vicaut7,
  15. Tania Octavia Crișan8,
  16. Mihai G Netea2,
  17. Pascal Richette1,
  18. Leo AB Joosten2,8
  1. 1 Bioscar, INSERM UMR-1132, hôpital Lariboisière, centre Viggo Petersen, DMU Locomoteur, AP-HP, Universite Paris Cite, Paris, France
  2. 2 Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
  3. 3 Bioscar, INSERM UMR-1132, Universite Paris Cite, Paris, France
  4. 4 Policlinique, hôpital Lariboisière, AP-HP, Paris, France
  5. 5 Assistance Publique-Hôpitaux de Paris, Centre de Ressources Biologiques, Paris, France
  6. 6 Rheumatology, VieCuri, Venlo, The Netherlands
  7. 7 Unité de recherche clinique, Groupe hospitalier Lariboisiere Fernand-Widal, Paris, France
  8. 8 Department of Medical Genetics, Universitatea de Medicina si Farmacie Iuliu Hatieganu, Cluj-Napoca, Romania
  1. Correspondence to Dr Hang-Korng Ea, Bioscar, INSERM UMR-1132, hôpital Lariboisière, centre Viggo Petersen, DMU Locomoteur, AP-HP, Universite Paris Cite, Paris, Île-de-France, France; korngea{at}


Introduction Untreated gout is characterised by monosodium urate (MSU) crystal accumulation responsible for recurrent flares that are commonly separated by asymptomatic phases. Both phases are inflammatory conditions of variable intensity. Gout flares are self-limited inflammatory reactions involving multiple mediators. This study aimed to characterise the inflammatory profiles of gout at different phases.

Methods Using the Olink targeted proteomics, levels of 92 inflammation-related proteins were measured in plasma samples of a prospective gout population (GOUTROS), collected at gout flare (T1), the intercritical phase (T2) and after reaching the target serum urate level under urate-lowering therapy (T3). Results were validated in an independent cohort (OLT1177-05) with plasmas collected at T1 and T2. Ex vivo and in vitro experiments were performed to assess the inflammatory properties of new biomarkers.

Results In total, 21 inflammatory new biomarkers were differentially expressed during the three time-points of gout disease. The levels of four of these proteins (interleukin 6 (IL-6), colony-stimulating factor 1, vascular endothelial growth factor A and tumour necrosis factor superfamily 14 (TNFSF14)) were increased during gout flare in an independent cohort. IL-6 and TNFSF14 had the highest fold change in expression during T1 versus T2 or T3. TNFSF14 was produced at the inflamed joint and enhanced the inflammatory response induced by lipopolysaccharide and MSU crystal stimulation. Conversely, TNFSF14 blockade reduced the inflammatory response. Additionally, single nucleotide polymorphisms of TNFSF14 affected the ability of myeloid cells to produce inflammatory cytokines.

Conclusion Gout flare involves multiple inflammatory mediators that may be used as potential therapeutic targets.

  • gout
  • crystal arthropathies
  • cytokines
  • inflammation

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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  • Handling editor Josef S Smolen

  • X @A_Latourte

  • H-KE and BK contributed equally.

  • PR and LAJ contributed equally.

  • Correction notice This article has been corrected since it published Online First. The last author's name has been updated.

  • Contributors Collection of the prospective GOUTROS samples and SF (H-KE, CA, H-UL, AL, AG, FL, TB, PR, PM), OLT1177-05 cohort (TJ), 200FG cohort (TOC, LJ); measurement of human synovial fluid parameters (TWC); collection of mouse air-pouch membranes (TWC, MZ, H-KE); proteomics OLINK assessment (BK, VK, TOC, LJ); PBMC isolation and experiments (BK, VK, TOC); measurement of TNFSF14 concentration (BK, TWC); genetics SNP analysis (BK, VK, TOC, LJ, MGN); data analysis and interpretation (H-KE, BK, PR, LJ, TOC, MGN); drafting manuscript (H-KE, BK, MGN, TJ, PR, LJ); editing manuscript (H-KE, BK, PR, LJ). H-KE, PR, LJ, MGN, TOC secured funding. All authors participated to final approval of the manuscript. H-KE and LJ are responsible for overall content as guarantors.

  • Funding This work was supported by grants from ArtViggo and the Prevention et Traitement des Décalcifications association, DMU Locomotion research funding.

  • Competing interests LJ is member of the scientific advisory board of Olatec Therapeutics. All other authors declare no competing financial interests in relation to the work described.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.