MRP8 and MRP14, phagocyte-specific danger signals, are sensitive biomarkers of disease activity in cryopyrin-associated periodic syndromes

• Published in: Annals of the rheumatic diseases Vol. 70; no. 12; pp. 2075 - 2081
• Main Authors: Wittkowski, Helmut, Kuemmerle-Deschner, Jasmin B, Austermann, Judith, Holzinger, Dirk, Goldbach-Mansky, Raphaela, Gramlich, Katharina, Lohse, Peter, Jung, Thomas, Roth, Johannes, Benseler, Susanne M, Foell, Dirk
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and European League Against Rheumatism 01.12.2011; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Adolescent; Adult; Aged; Allergic diseases; Antibodies, Monoclonal - therapeutic use; Antirheumatic Agents - therapeutic use; Arthritis; ATP-Binding Cassette Transporters - blood; Biological and medical sciences; Biomarkers; Biomarkers - blood; C-Reactive Protein - metabolism; Calgranulin B - blood; Child; Child, Preschool; Cryopyrin-Associated Periodic Syndromes - blood; Cryopyrin-Associated Periodic Syndromes - drug therapy; Cryopyrin-Associated Periodic Syndromes - immunology; Cytokines; Dermatology; Disease; Diseases of the osteoarticular system; Drug Monitoring - methods; Hereditary diseases of the skin. Congenital diseases of the skin. Haemangioma of the skin, of mucosae and of soft tissue; Humans; Immunopathology; Inflammation; Inflammation Mediators - blood; Interleukin 1 Receptor Antagonist Protein - therapeutic use; Interleukin-1 - antagonists & inhibitors; Interleukin-1beta - antagonists & inhibitors; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Middle Aged; Prospective Studies; Proteins; Recombinant Fusion Proteins - therapeutic use; Skin allergic diseases. Stinging insect allergies; Studies; Treatment Outcome; Young Adult; Familial cold urticaria; Allergy; Immunopathology; Skin disease; Activity index; Diseases of the osteoarticular system; Rheumatology; Hereditary periodic fever; Biological marker; Genetic disease; Phagocyte
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/ard.2011.152496

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.