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MRP8 and MRP14, phagocyte-specific danger signals, are sensitive biomarkers of disease activity in cryopyrin-associated periodic syndromes
  1. Helmut Wittkowski1,
  2. Jasmin B Kuemmerle-Deschner2,
  3. Judith Austermann3,
  4. Dirk Holzinger3,4,
  5. Raphaela Goldbach-Mansky5,
  6. Katharina Gramlich2,
  7. Peter Lohse6,
  8. Thomas Jung7,
  9. Johannes Roth3,
  10. Susanne M Benseler8,
  11. Dirk Foell3
  1. 1Department of General Paediatrics, University Children's Hospital Muenster, Muenster, Germany
  2. 2Division of Pediatric Rheumatology, Department of Pediatrics, University Hospital Tuebingen, Tuebingen, Germany
  3. 3Institute of Immunology, University of Muenster, Muenster, Germany
  4. 4Interdisciplinary Centre for Clinical Research IZKF, University of Muenster, Muenster, Germany
  5. 5National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA
  6. 6Department of Clinical Chemistry - Großhadern, University of Munich, Munich, Germany
  7. 7Novartis Pharma, Basel, Switzerland
  8. 8Division of Rheumatology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada
  1. Correspondence toHelmut Wittkowski, Department of General Pediatrics, University Children's Hospital Muenster, Albert-Schweitzer-Str 33, 48149 Muenster, Germany; h_wittkowski{at}


Objectives To assess the sensitivity of the phagocyte-specific molecules myeloid-related protein (MRP) 8 and MRP14 (calprotectin) for monitoring disease activity during anti-interleukin (IL)-1 therapies in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and chronic infantile neurological, cutaneous and articular (CINCA) syndrome.

Methods A total of 39 patients with CAPS, including 5 FCAS, 16 MWS and 18 CINCA syndrome, received anti-IL-1 therapy. All patients with CINCA and 12 with MWS were treated with IL-1Ra (anakinra), 14 patients with MWS with a monoclonal anti-IL-1β antibody (canakinumab) and patients with FCAS received IL-1 Trap (rilonacept). During serial clinical visits serum amyloid A, C-reactive protein, erythrocyte sedimentation rate and MRP8/14 serum levels were analysed.

Results Untreated patients with CAPS had significantly elevated MRP8/14 values. In response to treatment there was a significant reduction of MRP8/14 levels in CINCA (2,830 (range 690 – 8,480) ng/ml to 670 ng/ml, p < 0.001) and MWS patients (anakinra-treated: 4,390 (1790 – 9780) ng/ml to 1,315 ng/ml (p = 0.003); canakinumab-treated: 3,000 (500 – 13060) ng/ml to 630 ng/ml (p=0.001)). However, in many patients with CAPS, MRP8/14 levels were still elevated compared with healthy individuals, reflecting residual disease activity. However, canakinumab-treated patients with CAPS showed normalised MRP8/14 levels, suggesting control of phagocyte activation.

Conclusions Monitoring of cellular systems involved in inflammatory cascades of the innate immunity was successfully applied to the IL-1-driven CAPS diseases. This is the first study illustrating different states of subclinical disease activity in all types of CAPS depending on the type of anti-IL-1 therapy. MRP8/14 is a sensitive biomarker for monitoring disease activity, status of inflammation and response to IL-1 blockade in patients with CAPS.

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  • HW and JBK-D have contributed equally to the manuscript

  • Funding Supported by grants from the Interdisciplinary Centre for Clinical Research at the University of Muenster (project Foe2/005/06), the Deutsche Forschungsgemeinschaft (DFG project FO 354/2-2), and the Bundesministerium für Bildung und Forschung (AID-NET, project 01GM08100).

  • Ethics approval This study was conducted with the approval of the institutional review boards of the NIH, the University Hospital Tuebingen and the University Hospital Muenster.

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