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The Toll-like receptor 4 agonist MRP8/14 protein complex is a sensitive indicator for disease activity and predicts relapses in systemic-onset juvenile idiopathic arthritis
  1. Dirk Holzinger1,2,
  2. Michael Frosch3,
  3. Astrid Kastrup1,
  4. Femke H M Prince4,
  5. Marieke H Otten4,
  6. Lisette W A Van Suijlekom-Smit4,
  7. Rebecca ten Cate5,
  8. Esther P A H Hoppenreijs6,
  9. Sandra Hansmann7,
  10. Halima Moncrieffe8,
  11. Simona Ursu8,
  12. Lucy R Wedderburn8,
  13. Johannes Roth1,2,
  14. Dirk Foell1,2,
  15. Helmut Wittkowski3
  1. 1Institute of Immunology, University Hospital Muenster, Muenster, Germany
  2. 2Interdisciplinary Centre for Clinical Research IZKF, University Hospital Muenster, Muenster, Germany
  3. 3Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
  4. 4Department of Paediatrics/Paediatric Rheumatology, Erasmus MC Sophia Children's Hospital Rotterdam, Rotterdam, The Netherlands
  5. 5Department of Paediatrics/Paediatric Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands
  6. 6Department of Paediatrics/Paediatric Rheumatology, St Maartenskliniek and Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  7. 7Pediatric Rheumatology Clinics, Department of Pediatrics, University Hospital Tuebingen, Tuebingen, Germany
  8. 8Rheumatology Unit, Institute of Child Health, University College London, London, UK
  1. Correspondence to Dirk Holzinger, Institute of Immunology, University Hospital Muenster, Roentgenstr. 21, 48149 Muenster, Germany; dirk.holzinger{at}


Background Analysis of myeloid-related protein 8 and 14 complex (MRP8/14) serum concentrations is a potential new tool to support the diagnosis of systemic-onset juvenile idiopathic arthritis (SJIA) in the presence of fever of unknown origin.

Objective To test the ability of MRP8/14 serum concentrations to monitor disease activity in patients with SJIA and stratify patients at risk of relapse.

Methods Serum concentrations of MRP8/14 in 52 patients with SJIA were determined by a sandwich ELISA. The monitoring of therapeutic regimens targeting interleukin 1 and tumour necrosis factor α, and methotrexate treatment was analysed and diagnostic power to predict flares was tested.

Results MRP8/14 levels were clearly raised in active disease and decreased significantly in response to successful treatments. Serum concentrations of MRP8/14 increased significantly (p<0.001) (mean±95% CI 12.030±3.090 ng/ml) during disease flares compared with patients with inactive disease (864±86 ng/ml). During clinical remission MRP8/14 serum levels of >740 ng/ml predicted disease flares accurately (sensitivity 92%, specificity 88%). MRP8/14 levels correlated well with clinical disease activity, as assessed by physician's global assessment of disease activity (r=0.62), Childhood Health Assessment Questionnaire (r=0.56), active joint count (r=0.46) and with C-reactive protein (r=0.71) and erythrocyte sedimentation rate (r=0.72) (for all p<0.001).

Conclusion MRP8/14 serum concentrations correlate closely with response to drug treatment and disease activity and therefore might be an additional measurement for monitoring anti-inflammatory treatment of individual patients with SJIA. MRP8/14 serum concentrations are the first predictive biomarker indicating subclinical disease activity and stratifying patients at risk of relapse during times of clinically inactive disease.

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  • Funding Supported by grants from the Interdisciplinary Centre for Clinical Research at the University of Muenster (project Foe2/005/06 and Ro2/004/10), the Deutsche Forschungsgemeinschaft (DFG project FO 354/2-2), the Innovative Medizinische Forschung (IMF project WI 120733), the Bundesministerium für Bildung und Forschung (AID-NET, project 01GM08100), FP7 programme (Pharmachild; GA-No 260353), SPARKS-UK (08ICH09) and the Big Lottery Fund UK (RG/1/010135231). The development and maintenance of the ABC Register has been unconditionally supported by the Dutch Board of Health Insurances (from 2003 to 2006), Pfizer (formerly Wyeth International, since 2007), and Abbott (since 2010).

  • Competing interests None.

  • Ethics approval Ethics committee, University of Muenster, Germany and Institute of Child Health / Great Ormond Street Hospital , London, UK..

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

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