title: β-Defensin 2 is a responsive biomarker of IL-17A-driven skin pathology in patients with psoriasis.
abstract: BACKGROUND
  IL-17A is a key driver of human autoimmune diseases, particularly psoriasis.
  
  
  OBJECTIVE
  We sought to determine the role of IL-17A in psoriasis pathogenesis and to identify a robust and measurable biomarker of IL-17A-driven pathology.
  
  
  METHODS
  We studied 8 healthy subjects and 8 patients with psoriasis before and after administration of secukinumab, a fully human anti-IL-17A mAb, and used a combination of classical techniques and a novel skin microperfusion assay to evaluate the expression of 170 proteins in blood, nonlesional skin, and lesional skin. For validation, we also tested stored sera from 601 patients with a variety of autoimmune diseases.
  
  
  RESULTS
  IL-17A was specifically expressed in lesional compared with nonlesional psoriatic skin (9.8 vs 0.8 pg/mL, P < .001). Proteomic and gene transcription analyses revealed dysregulated antimicrobial peptides, proinflammatory cytokines, and neutrophil chemoattractants, levels of which returned to normal after treatment with secukinumab. β-Defensin 2 (BD-2) was identified as a biomarker of IL-17A-driven pathology by comparing protein expression in patients with psoriasis versus that in healthy subjects (5746 vs 82 pg/mL in serum, P < .0001; 2747 vs <218 pg/mL in dermis, P < .001), responsiveness to secukinumab therapy, and synergistic induction by IL-17A and TNF-α in epidermal keratinocytes. In a validation set of sera from 601 patients with autoimmune diseases thought to be IL-17A driven, we found that BD-2 levels are most highly increased in patients with psoriatic skin lesions, and in patients with psoriasis, BD-2 levels correlated well with IL-17A levels (r = 0.70, n = 199, P < .001) and Psoriasis Area and Severity Index scores (r = 0.53, n = 281, P < .001).
  
  
  CONCLUSIONS
  IL-17A is a primary driver of skin pathology in patients with psoriasis, and serum BD-2 is an easily measurable biomarker of IL-17A-driven skin pathology.
authors: Novartis Institutes for BioMedical Research Shanghai, China.
authors: Frank
authors: F
authors: Kolbinger
authors: Novartis Institutes for BioMedical Research Shanghai, China.
authors: Christian
authors: C
authors: Loesche
authors: Novartis Institutes for BioMedical Research Shanghai, China.
authors: Marie-Anne
authors: MA
authors: Valentin
authors: Novartis Institutes for BioMedical Research Shanghai, China.
authors: Xiaoyu
authors: X
authors: Jiang
authors: Novartis Pharma, Basel, Switzerland, and Shanghai, China.
authors: Yi
authors: Y
authors: Cheng
authors: Novartis Pharma, Basel, Switzerland, and Shanghai, China.
authors: Philip
authors: P
authors: Jarvis
authors: Novartis Institutes for BioMedical Research Shanghai, China.
authors: Thomas
authors: T
authors: Peters
authors: Novartis Institutes for BioMedical Research Shanghai, China.
authors: Claudio
authors: C
authors: Calonder
authors: Novartis Institutes for BioMedical Research Shanghai, China.
authors: Gerard
authors: G
authors: Bruin
authors: Novartis Institutes for BioMedical Research Shanghai, China.
authors: Florine
authors: F
authors: Polus
authors: HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H., and the Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University Graz, Graz, Austria.
authors: Birgit
authors: B
authors: Aigner
authors: Novartis Institutes for BioMedical Research Shanghai, China.
authors: David M
authors: DM
authors: Lee
authors: HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H., and the Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University Graz, Graz, Austria.
authors: Manfred
authors: M
authors: Bodenlenz
authors: HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H., and the Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University Graz, Graz, Austria.
authors: Frank
authors: F
authors: Sinner
authors: HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H., and the Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University Graz, Graz, Austria.
authors: Thomas Rudolf
authors: TR
authors: Pieber
authors: Novartis Institutes for BioMedical Research Shanghai, China. Electronic address: dhavalkumar.patel@novartis.com.
authors: Dhavalkumar D
authors: DD
authors: Patel
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D001327:Autoimmune Diseases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000097:blood*; D008297:Male; D011565:Psoriasis / Q000097:blood* / Q000188:drug therapy / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000473:pathology; D023083:beta-Defensins / Q000097:blood*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; C106641:DEFB4A protein, human; C508717:IL17A protein, human; C440021:IL17F protein, human; D020381:Interleukin-17; D023083:beta-Defensins; C555450:secukinumab
keywords: IL-17; ankylosing spondylitis; autoimmunity; biomarker; dermal interstitial fluid; microperfusion; multiple sclerosis; psoriasis; psoriatic arthritis; rheumatoid arthritis; secukinumab; β-defensin 2