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Phagocyte-specific S100 proteins and high-sensitivity C reactive protein as biomarkers for a risk-adapted treatment to maintain remission in juvenile idiopathic arthritis: a comparative study
  1. Joachim Gerss1,2,
  2. Johannes Roth3,
  3. Dirk Holzinger2,3,4,
  4. Nicolino Ruperto5,
  5. Helmut Wittkowski4,
  6. Michael Frosch4,
  7. Nico Wulffraat6,
  8. Lucy Wedderburn7,
  9. Valda Stanevicha8,
  10. Dimitrina Mihaylova9,
  11. Miroslav Harjacek10,
  12. Claudio Len11,
  13. Claudia Toppino12,
  14. Massimo Masi13,
  15. Kirsten Minden14,
  16. Traudel Saurenmann15,
  17. Yosef Uziel16,
  18. Richard Vesely17,
  19. Maria Teresa Apaz18,
  20. Rolf-Michael Kuester19,
  21. Maria Jesus Rua Elorduy20,
  22. Ruben Burgos-Vargas21,
  23. Maka Ioseliani22,
  24. Silvia Magni-Manzoni23,
  25. Erbil Unsal24,
  26. Jordi Anton25,
  27. Zsolt Balogh26,
  28. Stefan Hagelberg27,
  29. Henryka Mazur-Zielinska28,
  30. Tsivia Tauber29,
  31. Alberto Martini5,30,
  32. Dirk Foell2,3,
  33. for the Paediatric Rheumatology International Trials Organization (PRINTO)
  1. 1Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany
  2. 2Interdisciplinary Centre of Clinical Research, University of Muenster, Muenster, Germany
  3. 3Institute of Immunology, University of Muenster, Muenster, Germany
  4. 4Department of General Pediatrics, University Children's Hospital of Muenster, Muenster, Germany
  5. 5IRCCS G Gaslini, Pediatria II, Reumatologia, PRINTO, Genova, Italy
  6. 6Department of Paediatric Immunology and Rheumatology, Wilhelmina Children's Hospital, Utrecht, The Netherlands
  7. 7Rheumatology Unit, Institute of Child Health UCL, London, UK
  8. 8Riga Stradins University, Pediatric, Riga, Latvia
  9. 9University Children Hospital, Department of Paediatric Rheumatology, Sofia, Bulgaria
  10. 10Children's Hospital Zagreb, Department of Pediatrics, Immmunology/Rheumatology, Zagreb, Croatia
  11. 11Universitade Federal de Sao Paolo, Dep. De Pediatria, Sao Paulo, Brazil
  12. 12Clinica Pediatrica Università di Torino, Dipartimento di Scienze Pediatriche e dell'Adolescenza, Torino, Italy
  13. 13Clinica Pediatrica, Università di Bologna, Policlinico S.Orsola Malpighi, Bologna, Italy
  14. 14Charite University Hospital Berlin, Kinderklinik, Rheumatologie, Berlin, Germany
  15. 15University Children's Hospital, Pediatric Rheumatology, Zurich, Switzerland
  16. 16Meir Medical Centre, Dept of Pediatrics, Kfar Saba, Israel
  17. 17Detska Fakultna Nemocnica, 1st Pediatric Dept, Kosice, Slovakia
  18. 18Universidad Catolica, Clinica Reina Fabiola – GESER (Rheumatology), Cordoba, Argentina
  19. 19Rheumaklinik Bad Bramstedt, Norddeutsches Zentrum für Kinder- und Jugendrheumatologie, Bad Bramstedt, Germany
  20. 20Hospital de Cruces, Unidad de Reumatología Pediátrica, Bilbao Vizcaya, Spain
  21. 21Hospital General de Mexico, Servicio de Reumatologia, Mexico City, Mexico
  22. 22M. Iashvili Children's Central Clinic, Division of Rheumatology, Tbilisi, Georgia
  23. 23Fondazione IRCCS Policlinico S. Matteo, S.C. Pediatria Ospedaliera, Pavia, Italy
  24. 24Dokuz Eylul University Medical Faculty, Division of Pediatric Rheumatology-Immunology, Balcova, Izmir, Turkey
  25. 25Hospital Sant Joan de Deu, Unidad de Reumatología Pediatrica, Esplugues (Barcelona), Spain
  26. 26National Institute of Rheumatology and Physiotherapy (ORFI), III General and Pediatric Rheumatology Department, Budapest, Hungary
  27. 27Karolinska University Hospital, Pediatric Rheumatology Unit, Stockholm, Sweden
  28. 28Medical University of Silesia, Department of Pediatrics, Zabrze, Poland
  29. 29Asaf Harofe Medical Center, Pediatric Rheumatology Clinic, Zrifin, Israel
  30. 30Università degli studi di Genova, Dipartimento di Pediatria, Genova, Italy
  1. Correspondence to Professor Dirk Foell, Institute of Immunology, University of Muenster, Roentgenstr. 21, D-48149 Muenster, Germany; dfoell{at}


Objectives Juvenile idiopathic arthritis (JIA) is a chronic inflammatory joint disease affecting children. Even if remission is successfully induced, about half of the patients experience a relapse after stopping anti-inflammatory therapy. The present study investigated whether patients with JIA at risk of relapse can be identified by biomarkers even if clinical signs of disease activity are absent.

Methods Patients fulfilling the criteria of inactive disease on medication were included at the time when all medication was withdrawn. The phagocyte activation markers S100A12 and myeloid-related proteins 8/14 (MRP8/14) were compared as well as the acute phase reactant high-sensitivity C reactive protein (hsCRP) as predictive biomarkers for the risk of a flare within a time frame of 6 months.

Results 35 of 188 enrolled patients experienced a flare within 6 months. Clinical or standard laboratory parameters could not differentiate between patients at risk of relapse and those not at risk. S100A12 and MRP8/14 levels were significantly higher in patients who subsequently developed flares than in patients with stable remission. The best single biomarker for the prediction of flare was S100A12 (HR 2.81). The predictive performance may be improved if a combination with hsCRP is used.

Conclusions Subclinical disease activity may result in unstable remission (ie, a status of clinical but not immunological remission). Biomarkers such as S100A12 and MRP8/14 inform about the activation status of innate immunity at the molecular level and thereby identify patients with unstable remission and an increased risk of relapse.

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  • Funding This work was supported by a grant from the Interdisciplinary Centre of Clinical Research at the University of Muenster (IZKF CRA04) and FP7-Network PHARMACHILD. The clinical trial was supported by grants from the non-for-profit organisation PRINTO.

  • Competing interests None.

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