Exp Dermatol. 2015 Jul;24(7):529-35. doi: 10.1111/exd.12710.
Evidence that a neutrophil-keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis.
- 1Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany.
- 2Probity Medical Research Inc, Waterloo, ON, Canada.
- 3Oregon Medical Research Center PC, Portland, OR, USA.
- 4Skin Search of Rochester, Rochester, NY, USA.
- 5Innovaderm Research Inc, Montreal, QC, Canada.
- 6Dermatology Clinic, Moncton, NB, Canada.
- 7International Dermatology Research, Montreal, QC, Canada.
- 8Ultranova Skincare, Barrie, ON, Canada.
- 9Centre de Recherche Dermatologique du Québec Métropolitain, Quebec City, QC, Canada.
- 10North Bay Dermatology Centre, North Bay, ON, Canada.
- 11Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
- 12Novartis Institutes for BioMedical Research, Basel, Switzerland.
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.
KEYWORDS: IL-17A; neutrophils; psoriasis; secukinumab