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.

An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

“…Our results support and extend previous findings on a suppression of Th cytokine expression in patients responding to treatment with MTX. 25 While the observed changes are unlikely to represent a unique pattern induced by successful MTX therapy, 13,25 they add to the emerging concept of a spectrum of cutaneous immunologic effects mediated by the drug that warrant further investigation including the analysis of early skin responses before the onset of a marked clinical improvement.…”

“…Quantitative real-time PCRs were carried out in duplicate using a Bio-Rad iQ5 Cycler (Bio-177 Rad Laboratories, Hercules, CA, USA) as described. 13 Results for IL17A, IFNG and TNFA were 178 evaluated using the iQ5 Optical System Software, Version 2.0 (Bio-Rad Laboratories 18,19 Limitations of the study primarily relate to the relatively small number of 337 patients enrolled and the lack of an active comparator arm with oral MTX. Additionally, the study 338 population was mainly white so further study in non-white participants might be necessary to fully 339 understand the efficacy and safety in a more genetically diverse population.…”

Safety of secukinumab in the treatment of psoriasis

“…In a pooled safety analysis of 10 studies (4 Phase II and 6 Phase III; Table 1) [8][9][10][11][12]14,[21][22][23], secukinumab demonstrated a favorable safety profile in patients with moderate-to-severe plaque psoriasis over a total follow-up period of 52 weeks [15]. Exclusion criteria were similar across all 10 studies.…”

Mechanism of action of the biologics used in the treatment of plaque psoriasis

“…The inhibition of IL-17 by SEC (human IgG1κ monoclonal antibody that binds to soluble interleukin IL-17A) reduces the production of various chemokines by keratinocytes including the ones responsible for the arrival of neutrophils in the skin [6,12]. SEC causes rapid disappearance of neutrophils (potent sources of IL-17A) in psoriasis lesions [12].…”

“…SEC causes rapid disappearance of neutrophils (potent sources of IL-17A) in psoriasis lesions [12]. The disappearance of neutrophils correlates with the decrease in proliferation of keratinocytes, demonstrating a strong interaction between these cells in the immune response [12].…”