Evidence that a neutrophil–keratinocyte crosstalk is an early target of IL‐17A inhibition in psoriasis |
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| Authors: | Kristian Reich Kim A. Papp Robert T. Matheson John H. Tu Robert Bissonnette Marc Bourcier David Gratton Rodion A. Kunynetz Yves Poulin Les A. Rosoph Georg Stingl Wolfgang M. Bauer Janeen M. Salter Thomas M. Falk Norbert A. Blödorn‐Schlicht Wolfgang Hueber Ulrike Sommer Thomas Peters Ernst Kriehuber David M. Lee Grazyna A. Wieczorek Frank Kolbinger Conrad C. Bleul |
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| Affiliation: | 1. Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany;2. Probity Medical Research Inc, Waterloo, ON, Canada;3. Oregon Medical Research Center PC, Portland, OR, USA;4. Skin Search of Rochester, Rochester, NY, USA;5. Innovaderm Research Inc, Montreal, QC, Canada;6. Dermatology Clinic, Moncton, NB, Canada;7. International Dermatology Research, Montreal, QC, Canada;8. Ultranova Skincare, Barrie, ON, Canada;9. Centre de Recherche Dermatologique du Québec Métropolitain, Quebec City, QC, Canada;10. North Bay Dermatology Centre, North Bay, ON, Canada;11. Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria;12. Novartis Institutes for BioMedical Research, Basel, Switzerland |
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| 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. |
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| Keywords: | IL‐17A neutrophils psoriasis secukinumab |
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