title: Evidence that a neutrophil-keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis.
abstract: The response of psoriasis to antibodies targeting the interleukin (IL)-23/IL-17A pathway suggests a prominent role of T-helper type-17 (Th17) cells in this disease. We examined the clinical and immunological response patterns of 100 subjects with moderate-to-severe psoriasis receiving 3 different intravenous dosing regimens of the anti-IL-17A antibody secukinumab (1 × 3 mg/kg or 1 × 10 mg/kg on Day 1, or 3 × 10 mg/kg on Days 1, 15 and 29) or placebo in a phase 2 trial. Baseline biopsies revealed typical features of active psoriasis, including epidermal accumulation of neutrophils and formation of microabscesses in >60% of cases. Neutrophils were the numerically largest fraction of infiltrating cells containing IL-17 and may store the cytokine preformed, as IL-17A mRNA was not detectable in neutrophils isolated from active plaques. Significant clinical responses to secukinumab were observed 2 weeks after a single infusion, associated with extensive clearance of cutaneous neutrophils parallel to the normalization of keratinocyte abnormalities and reduction of IL-17-inducible neutrophil chemoattractants (e.g. CXCL1, CXCL8); effects on numbers of T cells and CD11c-positive dendritic cells were more delayed. Histological and immunological improvements were generally dose dependent and not observed in the placebo group. In the lowest-dose group, a recurrence of neutrophils was seen in some subjects at Week 12; these subjects relapsed faster than those without microabscesses. Our findings are indicative of a neutrophil-keratinocyte axis in psoriasis that may involve neutrophil-derived IL-17 and is an early target of IL-17A-directed therapies such as secukinumab.
authors.affiliation: Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany.
authors.forename: Kristian
authors.initials: K
authors.lastname: Reich
authors.affiliation: Probity Medical Research Inc, Waterloo, ON, Canada.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Papp
authors.affiliation: Oregon Medical Research Center PC, Portland, OR, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Matheson
authors.affiliation: Skin Search of Rochester, Rochester, NY, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Tu
authors.affiliation: Innovaderm Research Inc, Montreal, QC, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Bissonnette
authors.affiliation: Dermatology Clinic, Moncton, NB, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Bourcier
authors.affiliation: International Dermatology Research, Montreal, QC, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Gratton
authors.affiliation: Ultranova Skincare, Barrie, ON, Canada.
authors.forename: Rodion A
authors.initials: RA
authors.lastname: Kunynetz
authors.affiliation: Centre de Recherche Dermatologique du Québec Métropolitain, Quebec City, QC, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: Poulin
authors.affiliation: North Bay Dermatology Centre, North Bay, ON, Canada.
authors.forename: Les A
authors.initials: LA
authors.lastname: Rosoph
authors.affiliation: Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Stingl
authors.affiliation: Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Bauer
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Janeen M
authors.initials: JM
authors.lastname: Salter
authors.affiliation: Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Falk
authors.affiliation: Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany.
authors.forename: Norbert A
authors.initials: NA
authors.lastname: Blödorn-Schlicht
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hueber
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Sommer
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Schumacher
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Peters
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Ernst
authors.initials: E
authors.lastname: Kriehuber
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: David M
authors.initials: DM
authors.lastname: Lee
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Grazyna A
authors.initials: GA
authors.lastname: Wieczorek
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Kolbinger
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Conrad C
authors.initials: CC
authors.lastname: Bleul
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D002450:Cell Communication / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors*; D015603:Keratinocytes / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D011565:Psoriasis / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D013997:Time Factors; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C508717:IL17A protein, human; D020381:Interleukin-17; C555450:secukinumab
keywords: IL-17A; neutrophils; psoriasis; secukinumab
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