title: MRP8 and MRP14, phagocyte-specific danger signals, are sensitive biomarkers of disease activity in cryopyrin-associated periodic syndromes.
abstract: OBJECTIVE
  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.
authors: Department of General Paediatrics, University Children's Hospital Muenster, Muenster, Germany.
authors: Helmut
authors: H
authors: Wittkowski
authors: Division of Pediatric Rheumatology, Department of Pediatrics, University Hospital Tuebingen, Tuebingen, Germany.
authors: Jasmin B
authors: JB
authors: Kuemmerle-Deschner
authors: Institute of Immunology, University of Muenster, Muenster, Germany.
authors: Judith
authors: J
authors: Austermann
authors: Institute of Immunology, University of Muenster, Muenster, Germany.|Interdisciplinary Centre for Clinical Research IZKF, University of Muenster, Muenster, Germany.
authors: Dirk
authors: D
authors: Holzinger
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA.
authors: Raphaela
authors: R
authors: Goldbach-Mansky
authors: Division of Pediatric Rheumatology, Department of Pediatrics, University Hospital Tuebingen, Tuebingen, Germany.
authors: Katharina
authors: K
authors: Gramlich
authors: Department of Clinical Chemistry - Großhadern, University of Munich, Munich, Germany.
authors: Peter
authors: P
authors: Lohse
authors: Novartis Pharma, Basel, Switzerland.
authors: Thomas
authors: T
authors: Jung
authors: Institute of Immunology, University of Muenster, Muenster, Germany.
authors: Johannes
authors: J
authors: Roth
authors: Division of Rheumatology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada.
authors: Susanne M
authors: SM
authors: Benseler
authors: Institute of Immunology, University of Muenster, Muenster, Germany.
authors: Dirk
authors: D
authors: Foell
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000097:blood*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D040502:Calgranulin B / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D056587:Cryopyrin-Associated Periodic Syndromes / Q000097:blood* / Q000188:drug therapy / Q000276:immunology; D016903:Drug Monitoring / Q000379:methods; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors; D008875:Middle Aged; D011446:Prospective Studies; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C435500:ABCC11 protein, human; D018528:ATP-Binding Cassette Transporters; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015415:Biomarkers; D040502:Calgranulin B; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053583:Interleukin-1beta; D011993:Recombinant Fusion Proteins; C541220:canakinumab; C531377:rilonacept; D002097:C-Reactive Protein