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Psoriasis improvements and inflammatory biomarker normalization with secukinumab: the randomized ObePso-S study

Open AccessPublished:January 09, 2023DOI:https://doi.org/10.1016/j.jdermsci.2023.01.003

      Highlights

      • Secukinumab reduced the severity of psoriasis and promoted histologic reversal of psoriasiform hyperplasia at Week 12.
      • These responses were maintained through Week 52 in most patients.
      • Patients who attained Week 52 PASI90 responses had improvement in psoriasis-associated gene expression as early as Week 12.
      • Patients who had suboptimal cellular and molecular responses at Week 12 failed to achieve PASI90 at Week 52.
      • Increasing levels of disease control at Week 52 were associated with increased improvements in inflammatory gene expression.

      Abstract

      Background

      The IL-17A inhibitor secukinumab has demonstrated consistent efficacy and safety in patients with moderate-to-severe plaque psoriasis, with normalization of molecular and histopathologic psoriasis markers.

      Objective

      To investigate treatment effects of secukinumab on clinical signs and psoriatic inflammation markers over 52 weeks in patients with psoriasis.

      Methods

      In the ObePso-S study (NCT03055494), patients with psoriasis were randomized 2:1 to receive secukinumab 300 mg (n = 54) or placebo (n = 28), stratified by body weight (<90 or ≥90 kg), for 52 weeks. At Week 12, patients receiving placebo were switched to secukinumab. Psoriasis Area and Severity Index improvement of 90% (PASI90) and Investigator’s Global Assessment modified 2011 0/1 responses were assessed at Weeks 12 and 52. Immunohistochemistry for keratin 16 (K16) and gene expression profiles were evaluated in lesional and non-lesional skin biopsies collected at baseline, Week 12, and Week 52.

      Results

      Of patients receiving secukinumab, 55.8% and 59.6% achieved PASI90 at Weeks 12 and 52, respectively. K16 was absent in 93.1% of Week 12 PASI90 responders and 93.6% of Week 52 PASI90 responders, which mirrored the down-regulated expression of psoriatic inflammation. Week 52 PASI90 non-responders experienced regression of clinical and inflammatory marker responses toward baseline levels. Lower control of inflammatory gene expression at Week 12 was associated with suboptimal clinical responses at Week 52.

      Conclusion

      Sustained clinical responses with secukinumab were associated with rapid and sustained normalization of K16 and inflammatory gene expression in most patients. Molecular anti-inflammatory effects of secukinumab at Week 12 were associated with clinical responses at Week 52.

      Abbreviations:

      CI (confidence interval), GSVA (gene set variation analysis), IGA (Investigator’s Global Assessment modified 2011), IL (interleukin), K16 (keratin 16), PASI (Psoriasis Area and Severity Index), PSTR (psoriasis transcriptome), TNF-α (tumor necrosis factor alpha), VNN2 (vanin 2), IFNγ (Interferon-gamma)

      Keywords

      1. Introduction

      The interleukin (IL)‐23/IL‐17 immunologic axis is regarded as a central contributor to the pathogenesis of psoriasis [
      • Menter A.
      • Krueger G.G.
      • Paek S.Y.
      • Kivelevitch D.
      • Adamopoulos I.E.
      • Langley R.G.
      Interleukin-17 and interleukin-23: a narrative review of mechanisms of action in psoriasis and associated comorbidities.
      ]. There are 6 members of the IL-17 family of cytokines, designated as IL-17A–F, with IL-17A acting as the key effector cytokine in psoriatic disease [
      • Krueger J.G.
      • Wharton K.A.
      • Schlitt T.
      • Suprun M.
      • Torene R.I.
      • Jiang X.
      • et al.
      IL-17A inhibition by secukinumab induces early clinical, histopathologic, and molecular resolution of psoriasis.
      ,
      • Blauvelt A.
      • Chiricozzi A.
      The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis.
      ,
      • Brembilla N.C.
      • Senra L.
      • Boehncke W.H.
      The IL-17 family of cytokines in psoriasis: IL-17A and beyond.
      ]. Although IL-17A is involved in normal regulation of skin and mucosal immunity, its overexpression in psoriatic plaques suggests that it plays a pivotal role in psoriasis pathogenesis [
      • Menter A.
      • Krueger G.G.
      • Paek S.Y.
      • Kivelevitch D.
      • Adamopoulos I.E.
      • Langley R.G.
      Interleukin-17 and interleukin-23: a narrative review of mechanisms of action in psoriasis and associated comorbidities.
      ,
      • Blauvelt A.
      • Chiricozzi A.
      The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis.
      ,
      • Brembilla N.C.
      • Senra L.
      • Boehncke W.H.
      The IL-17 family of cytokines in psoriasis: IL-17A and beyond.
      ,
      • Chiricozzi A.
      • Nograles K.E.
      • Johnson-Huang L.M.
      • Fuentes-Duculan J.
      • Cardinale I.
      • Bonifacio K.M.
      • et al.
      IL-17 induces an expanded range of downstream genes in reconstituted human epidermis model.
      ,
      • Iwakura Y.
      • Ishigame H.
      The IL-23/IL-17 axis in inflammation.
      ].
      Secukinumab is a fully human monoclonal antibody that selectively neutralizes IL-17A, ultimately inhibiting the release of downstream keratinocyte-derived pro-inflammatory molecules [
      • Kolbinger F.
      • Di Padova F.
      • Deodhar A.
      • Hawkes J.E.
      • Huppertz C.
      • Kuiper T.
      • et al.
      Secukinumab for the treatment of psoriasis, psoriatic arthritis, and axial spondyloarthritis: physical and pharmacological properties underlie the observed clinical efficacy and safety.
      ]. Secukinumab has demonstrated sustained efficacy in the treatment of moderate-to-severe psoriasis as well as other immune-mediated diseases and has a favorable safety profile [
      • Langley R.G.
      • Elewski B.E.
      • Lebwohl M.
      • Reich K.
      • Griffiths C.E.
      • Papp K.
      • et al.
      Secukinumab in plaque psoriasis--results of two phase 3 trials.
      ,
      • Blauvelt A.
      • Prinz J.C.
      • Gottlieb A.B.
      • Kingo K.
      • Sofen H.
      • Ruer-Mulard M.
      • et al.
      Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE).
      ,
      • Paul C.
      • Lacour J.P.
      • Tedremets L.
      • Kreutzer K.
      • Jazayeri S.
      • Adams S.
      • et al.
      Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial (JUNCTURE).
      ,
      • Thaci D.
      • Blauvelt A.
      • Reich K.
      • Tsai T.F.
      • Vanaclocha F.
      • Kingo K.
      • et al.
      Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial.
      ,
      • Blauvelt A.
      • Reich K.
      • Tsai T.F.
      • Tyring S.
      • Vanaclocha F.
      • Kingo K.
      • et al.
      Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: results from the CLEAR study.
      ,
      • Bagel J.
      • Nia J.
      • Hashim P.W.
      • Patekar M.
      • de Vera A.
      • Hugot S.
      • et al.
      Secukinumab is superior to ustekinumab in clearing skin in patients with moderate to severe plaque psoriasis (16-Week CLARITY results).
      ,
      • Bagel J.
      • Blauvelt A.
      • Nia J.
      • Hashim P.
      • Patekar M.
      • de Vera A.
      • et al.
      Secukinumab maintains superiority over ustekinumab in clearing skin and improving quality of life in patients with moderate to severe plaque psoriasis: 52-week results from a double-blind phase 3b trial (CLARITY).
      ,

      R. Langley, B. Sigugeirsson, J. Szepietowski, T.F. Tsai, A. de Vera, P. Charef, et al., Secukinumab maintains improvements in psoriasis through five years of treatment: a randomized extension of the phase III ERASURE and FIXTURE trials, AAD Annual Meeting, March 1–5, 2019; Washington, DC. Abstract 10052.

      ,
      • Bissonnette R.
      • Luger T.
      • Thaci D.
      • Toth D.
      • Lacombe A.
      • Xia S.
      • et al.
      Secukinumab demonstrates high sustained efficacy and a favourable safety profile in patients with moderate-to-severe psoriasis through 5 years of treatment (SCULPTURE Extension Study).
      ,
      • Blair H.A.
      Secukinumab: a review in psoriatic arthritis.
      ,
      • Blair H.A.
      Secukinumab: a review in ankylosing spondylitis.
      ]. Although secukinumab and other biologics targeting IL-17A are commonly selected as first-line therapies for psoriasis treatment, not all patients respond equally well to treatment, and more information is needed to discern the relationships between clinical response to secukinumab and resolution of cellular and molecular markers of inflammation [
      • Krueger J.G.
      • Wharton K.A.
      • Schlitt T.
      • Suprun M.
      • Torene R.I.
      • Jiang X.
      • et al.
      IL-17A inhibition by secukinumab induces early clinical, histopathologic, and molecular resolution of psoriasis.
      ]. In the ObePso-S study, we explored the anti-inflammatory effects of secukinumab vs placebo by examining the treatment effects of secukinumab on clinical signs and gene expression changes in patients with psoriasis over 52 weeks.

      2. Materials and methods

      2.1 Patient population and study design

      ObePso-S (NCT03055494) was a randomized, double-blind, placebo-controlled, phase 4 trial investigating the efficacy and safety of secukinumab and the modulation of skin inflammation in patients with moderate-to-severe plaque psoriasis. The study was conducted from April 2017 to February 2019, was approved by a central institutional review board and by the institutional review board or independent ethics committee at each participating institution, and was conducted in accordance with the Declaration of Helsinki. Patients provided written informed consent before starting any study-related procedures.
      Eligible patients had moderate-to-severe plaque psoriasis and were candidates for systemic therapy, with the following disease characteristics: ≥10% body surface area involvement, a Psoriasis Area and Severity Index (PASI) of ≥12, and an Investigator’s Global Assessment modified 2011 (IGA) score of ≥3 (scale, 0–4). Candidates for systemic therapy were defined as those having psoriasis that was inadequately controlled by topical treatment (including topical corticosteroids), phototherapy, and/or previous systemic therapy. Key exclusion criteria were previous exposure to any biologic directly targeting IL-17A or IL-17A receptors and active, ongoing skin diseases (other than psoriasis), or skin infections.
      Patients were randomized 2:1 via Interactive Response Technology to receive secukinumab (n = 54) or placebo (n = 28) for 12 weeks. Secukinumab dosing was consistent with the label (300 mg subcutaneously at Weeks 0, 1, 2, 3, and 4, and every 4 weeks thereafter); patients randomized to placebo received matching subcutaneous placebo injections. After the placebo-controlled phase, all patients were re-inducted in a blinded fashion and assigned to treatment with secukinumab every 4 weeks. Randomization was stratified by weight (<90 or ≥90 kg).

      2.2 Assessments and outcomes

      The 2 primary binary efficacy variables were PASI90 (≥90% reduction in PASI from baseline) and achievement of no keratin 16 (K16) expression, a marker of keratinocyte hyperproliferation [
      • Leigh I.M.
      • Navsaria H.
      • Purkis P.E.
      • McKay I.A.
      • Bowden P.E.
      • Riddle P.N.
      Keratins (K16 and K17) as markers of keratinocyte hyperproliferation in psoriasis in vivo and in vitro.
      ]. The primary analysis time point was Week 12; the secondary analysis time point was Week 52. Missing data were imputed using non-responder imputation. Biopsies were taken at baseline and at Weeks 12 and 52 from the center of typical psoriatic plaques that were representative of the overall PASI and from a non-lesional control area. Biopsies from patients without psoriasis and not receiving treatment (n = 17) served as controls. All consecutive biopsies (lesional and non-lesional) were obtained in the same manner from the same areas. Half of the skin biopsies were placed in formalin, and immunohistochemistry was performed for K16 as previously described [
      • Tomalin L.E.
      • Russell C.B.
      • Garcet S.
      • Ewald D.A.
      • Klekotka P.
      • Nirula A.
      • et al.
      Short-term transcriptional response to IL-17 receptor-A antagonism in the treatment of psoriasis.
      ]. Additional secondary assessments included absent K16 expression and PASI90 at Week 52 and PASI100 and IGA 0/1 responses (score of 0 or 1 and ≥2-point IGA improvement from baseline) through Week 52.

      2.3 Gene expression exploratory analyses

      Half of the lesional and non-lesional psoriatic skin biopsies were placed in RNALater, and gene expression arrays were performed as described elsewhere [
      • Tomalin L.E.
      • Russell C.B.
      • Garcet S.
      • Ewald D.A.
      • Klekotka P.
      • Nirula A.
      • et al.
      Short-term transcriptional response to IL-17 receptor-A antagonism in the treatment of psoriasis.
      ]. Inflammatory gene expression in both lesional and non-lesional psoriatic skin was normalized to gene expression profiles generated from healthy skin isolated from patients without psoriasis. The psoriasis transcriptome is defined here as the 50 genes with the largest expression changes from healthy controls. Expression of the psoriasis transcriptome was correlated with clinical responses at Weeks 12 and 52. Inflammatory gene expression was assessed at Week 12 and compared between patients who achieved PASI90 at Week 52 (PASI90 responders) and those who did not (PASI90 non-responders) (GEO ID: GSE201827).

      2.4 Statistical analyses

      Approximately 75 patients (50 secukinumab, 25 placebo) were to be randomized to estimate between-group differences in response rates at Week 12 for each of the primary efficacy variables. With a sample size of 75 patients, the difference between the 2 treatment groups at Week 12 had a half-width of the 2-sided 95% confidence interval (CI) of no more than 27% [
      • Kianifard F.
      • Islam M.Z.
      A guide to the design and analysis of small clinical studies.
      ].
      For the 2 primary efficacy variables, 95% CIs for the between-group difference were calculated using the normal approximation to the binomial distribution. No statistical hypothesis tests for the primary analysis of the 2 primary efficacy variables were planned for in the protocol, and none were performed.
      Descriptive subgroup analyses were performed by body weight (<90 kg, ≥90 kg) and sex (female, male). Mean age was compared between PASI90 responders and non-responders. Statistical analyses for exploratory assessments, including gene expression data, were performed by estimating a mixed-effect model [
      • Detry M.A.
      • Ma Y.
      Analyzing repeated measurements using mixed models.
      ]. Treatment (secukinumab, placebo), time point (baseline, Week 12, Week 52), and tissue (lesional, non-lesional) were considered as fixed factors, and random effect for patients was included. Because the mixed-effect model is capable of handling missing values, all 82 patients were included in the analysis.

      3. Results

      A total of 82 patients were randomized to receive secukinumab (n = 54) or placebo (n = 28). After 12 weeks, all patients receiving placebo were switched to active treatment with secukinumab at the psoriasis-approved dose. Baseline demographics and disease characteristics are shown in Table S1. At Week 12, 29 patients (55.8%) receiving secukinumab achieved PASI90 compared with 0 patients (0.0%) receiving placebo (difference 55.8%; 95% CI 42.3%, 69.3%) (Fig. S1). At Week 52, 31 patients (59.6%) from the initial secukinumab group and 20 patients (71.4%) from the initial placebo group achieved PASI90. Biopsy evaluation at Week 12 showed that 79.6% of patients receiving secukinumab had no detectable K16 expression compared with 3.6% of patients receiving placebo (difference 76.1%; 95% CI 63.3%, 88.8%) (Fig. S1). Normalization of K16 was evident in most patients in both groups at Week 52. K16 staining was absent for 93.1% and 93.6% of Week 12 and Week 52 PASI90 responders, respectively. Secukinumab treatment also resulted in rapid achievement of PASI100 in a subset of patients, with 26.9% and 32.7% of patients in the secukinumab group achieving PASI100 at Weeks 12 and 52, respectively (Fig. S2). Among patients receiving secukinumab, the proportions of patients achieving IGA 0/1 were 75.6% and 72.7% at Weeks 12 and 52, respectively (Fig. S2). Responses to secukinumab differed by patient body weight (Figs. S1, S3). PASI90 response rates at Week 12 in the secukinumab<90-kg and ≥90-kg subgroups were 60.0% and 51.9%, respectively. In the continuous secukinumab treatment group, the Week 52 PASI90 response rate was 68.0% in patients weighing<90 kg vs 51.9% in those weighing ≥90 kg. The placebo/secukinumab group had a higher mean baseline weight than the secukinumab group (Table S1), and PASI90 responses at Week 52 were 92.3% in patients weighing<90 kg and 53.3% in patients weighing ≥90 kg.
      There were evolving and mostly increasing clinical responses to secukinumab over 52 weeks at the individual patient level (Table S2). A total of 6 PASI75 to<PASI90 responders at Week 12 (55%) achieved at least PASI90 at Week 52, and 6 PASI90 to<PASI100 responders at Week 12 (35%) achieved PASI100 at Week 52, while some patients experienced decreased PASI responses between Week 12 and Week 52. PASI responses over 52 weeks of treatment differed by weight. Among patients weighing< 90 kg (mean, 73.6 kg), 18 (69%) experienced continuing improvements or maintained PASI responses after Week 12; however, only 15 patients (54%) weighing ≥90 kg (mean, 107.5 kg) further improved or maintained PASI responses after Week 12. By contrast, PASI90 responses at Weeks 12 or 52 did not differ by sex, and mean age was not significantly different between responders and non-responders (Table S3). No new safety signals were observed in this study, and the overall safety profile was consistent with previously published reports (Table S4).

      3.1 Gene expression analyses

      The psoriasis transcriptome in this study consisted of 6751 transcripts (3212 up- and 3539 down-regulated) comparing baseline lesional skin to non-lesional skin using criteria of ≥ 1.5 foldchange and a false discovery rate of ≤0.05 (Table S5). Secukinumab treatment over 12 weeks modulated 5664 transcripts by the same statistical criteria, while no transcripts were significantly modulated by placebo. After 52 weeks of continuous secukinumab treatment, 4895 transcripts were modulated from baseline lesional skin. Overall improvement of the psoriasis transcriptome is shown in Fig. 1 for Weeks 12 and 52. During the placebo-controlled period, up-regulated inflammatory transcripts were improved by 2% in the placebo group vs 89% in the secukinumab treatment group (P <.001). At Week 52, the transcriptome was approximately 65% to 71% improved in both the secukinumab group and the placebo/secukinumab group. Fig. 2A shows a heatmap of the top 50 up-regulated transcriptome genes modulated over 52 weeks in both the secukinumab and placebo/secukinumab groups; Fig. 2B includes additional gene transcripts of interest not determined to be among the top 50 up-regulated genes. At Week 12, the placebo group showed no significant change from baseline, while the secukinumab group demonstrated marked improvement. Important transcripts that were down-regulated by secukinumab treatment include IL-36A, IL-36G, IL-19, CCL20, CXCL1, S100A12, LCN2, and IL-23p40. Each of these genes participate in the IL-17–associated keratinocyte amplification response [
      • Brodmerkel C.
      • Li K.
      • Garcet S.
      • Hayden K.
      • Chiricozzi A.
      • Novitskaya I.
      • et al.
      Modulation of inflammatory gene transcripts in psoriasis vulgaris: differences between ustekinumab and etanercept.
      ,
      • Hawkes J.E.
      • Yan B.Y.
      • Chan T.C.
      • Krueger J.G.
      Discovery of the IL-23/IL-17 signaling pathway and the treatment of psoriasis.
      ]. The overall improvement in psoriasis- and IL-17–related inflammatory pathways was reflected by 80%−90% improvement in consensus transcriptomes for psoriasis, such as the MAD3/5 gene sets and cellular responses to specific inflammatory cytokines (Fig. S4A; P < .001). Gene set variation analysis (GSVA) also showed strong modulation of psoriasis- and IL-17–related gene sets with secukinumab treatment, but not with placebo, at Week 12 (Fig. S4B; P < .001). Stable improvements in GSVA scores were seen in the secukinumab group at Week 52, and improvements were observed in the placebo/secukinumab group at Week 52 after patients were switched to secukinumab at Week 12.
      Fig. 1
      Fig. 1Improvements in down- and up-regulated psoriasis-associated gene expression at Weeks 12 and 52 in patients randomized to receive secukinumab or placebo.a
      PSTR, psoriasis transcriptome; W12, Week 12; W52, Week 52.
      a Percentages refer to the mean improvement from baseline for each group. Values above the plots are differences between mean group improvements. Multiple t tests were performed for comparison across groups, and the Benjamini-Hochberg procedure was considered to adjust P values for multiple comparisons.
      *** P < .001 vs placebo.
      Fig. 2
      Fig. 2Expression of (A) the top 50 up-regulated psoriasis-associated genes and (B) selected psoriasis-associated genes not among the top 50 up-regulated genes at baseline, Week 12, and Week 52 in patients randomized to receive secukinumab or placebo.
      a Values are expressed as fold change in expression from baseline non-lesional samples (for baseline lesional values) or baseline lesional skin (for Week 12 and 52 values).
      BL, baseline; LS, lesional; NL, non-lesional; PBO, placebo; SEC, secukinumab; W12, Week 12; W52, Week 52.
      a Multiple t tests were performed for comparison across groups.
      *** P < .001, differences between means.

      3.2 Differences in transcript modulation in clinical responders

      The high rate of PASI90 responses and relatively large group size for the secukinumab group (n = 54) allowed for comparison of responders vs non-responders along with analysis of response trajectories through 52 weeks of treatment. This analysis was focused on molecular factors associated with response status after 52 weeks of treatment, defining responders as those patients achieving PASI90 at Week 52 (attained in 31 of 52 patients [59.6%]). In the secukinumab group at Week 12, responders had 95% improvement in genes initially up-regulated in the baseline transcriptome and 87% improvement in down-regulated genes (Fig. 3). After 52 weeks of treatment, both up- and down-regulated transcripts were improved by ≈ 85%− 87% for responders. Non-responders had lower molecular improvements in Week 12 biopsies (75%−84% improvement), and this response declined to 40%−43% in Week 52 biopsies. In an analysis of response by more specific pathways, non-responders showed a significant loss of improvement between Weeks 12 and 52 in consensus psoriasis gene sets, such as MAD3, and in pathways modulated by IL-17 in different cell types (Fig. S5B). By contrast, responders showed stable improvement in IL-17–related cellular responses, often with> 100% improvement in these pathways. However, some small reductions in improvement in psoriasis consensus gene sets were observed for responders at Week 52 (Fig. S5A). An analysis of responders vs non-responders showed stable improvement in consensus psoriasis transcriptomes in responders, but a loss of improvement between Weeks 12 and 52 in non-responders (Fig. S6). Among individual genes differentially expressed in non-responders, increasing expression of key Th17/IL-17-regulated genes, such as IL12B, IL26, IL19, CCL20, LCN2, IL36A, and IL36G, was observed from Week 12 to Week 52 (Fig. S7). Approximately 20% of genes modulated among Week 12 PASI75 responders were unique to secukinumab compared with previous analyses of etanercept and ustekinumab (Fig. S8) [
      • Brodmerkel C.
      • Li K.
      • Garcet S.
      • Hayden K.
      • Chiricozzi A.
      • Novitskaya I.
      • et al.
      Modulation of inflammatory gene transcripts in psoriasis vulgaris: differences between ustekinumab and etanercept.
      ].
      Fig. 3
      Fig. 3Improvements in down- and up-regulated psoriasis-associated genes at Weeks 12 and 52 in patients receiving secukinumab who achieved a PASI90 response at Week 52 (responders) and those who did not achieve PASI90 (non-responders).a
      NR, non-responder; PASI90, ≥ 90% improvement in Psoriasis Area and Severity Index; PSTR, psoriasis transcriptome; R, responder; W12, Week 12; W52, Week 52.
      a Percentages refer to the mean improvement from baseline for each group. Multiple t tests were performed for comparison across groups, and the Benjamini-Hochberg procedure was considered to adjust P values for multiple comparisons.
      *** P < .001 vs non-responders.

      3.3 Histologic findings

      In 4 patients with decreased PASI responses between Weeks 12 and 52, fully suppressed psoriasis with absent K16 staining at Week 12 was observed, but Week 52 biopsies showed full re-emergence of psoriasis-associated features, including increased acanthosis, return of K16 staining, and increased skin infiltration by T cells and dendritic cells (Fig. 4A). By contrast, most responders had suppressed psoriasis-associated features (thin epidermis, absence of K16, and reduced T-cell and dendritic cell infiltrates) at both Weeks 12 and 52 (Fig. 4B, Fig. S9). This histologic pattern of fully suppressed disease at Week 52 was observed in all patients achieving PASI100 (Table S6).
      Fig. 4
      Fig. 4Immunohistochemistry images of skin biopsy samples from patients receiving secukinumab.
      (A) Histologic responder at Week 12 who lost response by Week 52 (non-responder). (B) Histologic responder at Week 12 who maintained response through Week 52 (responder). LS, lesional; NL, non-lesional.

      3.4 Differences in transcript modulation by body weight

      We separately evaluated molecular improvement in the continuous secukinumab group as a function of body weight (<90 vs ≥90 kg). Week 12 responses were dramatically different between groups (Fig. S10), with> 100% mean improvement in up-regulated genes in the< 90-kg group vs 77% mean improvement in the ≥ 90-kg group (P < .001). Greater improvement in the transcriptome was observed in Week 52 biopsies for the< 90-kg group than the ≥90-kg group (Fig. S10; P < .001). In the analysis of disease pathways, significant differences (P < .001) were observed between subgroups with respect to IL-17 effects on multiple cell types and consensus psoriasis transcriptomes (Fig. S11). These data establish that body weight is a major determinant of the extent of molecular improvement in the psoriasis disease transcriptome over 52 weeks of secukinumab treatment.

      3.5 Potential predictors of Week 52 PASI90 response

      For the secukinumab treatment group, Week 12 transcriptome improvements were generally greater in Week 52 clinical responders than in Week 52 non-responders. Changes in expression of some genes in Week 12 biopsies were highly correlated with PASI outcomes at Week 52 (Fig. 5). For example, PASI improvements at Week 52 were highly correlated with mean changes in vanin 2 (VNN2; r = −0.71; 95% CI −0.86, −0.44; P < .001) and IL-6 (r = −0.72; 95% CI −0.87, −0.45; P < .001) expression at Week 12. Changes in IL-6 and VNN2 expression at Week 12 were used to construct a model to predict PASI response at Week 52, which correlated well with observed PASI responses at Week 52 (r = 0.80; 95% CI 0.59, 0.91; P < .001). All patients with observed PASI90 responses at Week 52 had ≥ 88% predicted improvement in this model. This prediction model was largely independent of weight categorization of patients.
      Fig. 5
      Fig. 5Pearson correlation of change in expression of VNN2 (A) and IL-6 (B) in lesional skin at Week 12 and PASI improvement (change from baseline in PASI) at Week 52. (C) Pearson correlation of observed PASI improvement and predicted PASI improvement at Week 52.a
      BL, baseline; IL, interleukin; Impr, improvement; MA, microarray; PASI, Psoriasis Area and Severity Index; VNN2, vanin 2; W12, Week 12; W52, Week 52.
      a Coefficients were estimated with PASI improvement at Week 52 as the dependent variable and VNN2 and IL-6 changes at Week 12 as predictors. The correlations (and 95% CIs) between predicted and observed PASI improvements at Week 52 are shown.

      3.6 Extent of molecular improvement is related to differing degrees of PASI improvement

      We sought to determine whether higher PASI responses at Week 52 were related to greater modulation of psoriasis transcriptome genes. We considered 4 mutually exclusive subgroups of PASI responses at Week 52: PASI75 non-responders (PASI<75), PASI75 responders who did not achieve PASI90 (PASI75 to< 90), PASI90 responders who did not achieve PASI100 (PASI90 to< 100), and PASI100 responders. Transcriptome improvements for both up-regulated and down-regulated genes increased in each PASI category, with PASI100 responders having 95% improvement in up-regulated genes compared with 76% improvement in PASI90 to< 100 responders (Fig. S12; P < .001). Similar differences were also observed at Week 52 in the placebo/secukinumab group after switching to secukinumab at Week 12 (Fig. S12). We then used pathway improvement percentages to compare the extent of responses in each subgroup (Fig. 6). Most pathways related to psoriasis transcriptomes defined in previously published studies and those related to effects of IL-17 or other cytokines in cultured cell systems [
      • Brodmerkel C.
      • Li K.
      • Garcet S.
      • Hayden K.
      • Chiricozzi A.
      • Novitskaya I.
      • et al.
      Modulation of inflammatory gene transcripts in psoriasis vulgaris: differences between ustekinumab and etanercept.
      ,
      • Hawkes J.E.
      • Yan B.Y.
      • Chan T.C.
      • Krueger J.G.
      Discovery of the IL-23/IL-17 signaling pathway and the treatment of psoriasis.
      ] showed progressive improvements from patients with PASI75 non-response to those with PASI100 response, with strong statistical significance between PASI subgroups. Gene sets that were significantly different in each of the 4 response subgroups included those modulated by tumor necrosis factor alpha (TNF-α) in keratinocytes; by IFNγ in keratinocytes, fibroblasts, and normal human skin (in vivo injection); by IL-17 in monocytes; and by genes associated with T cells, monocytes, and inflammatory myeloid dendritic cells in psoriasis (P < .05). Several microRNA pathways implicated in psoriasis disease progression, such as miR150, miR155, and miR17 [
      • Wang H.
      • Zhang Y.
      • Luomei J.
      • Huang P.
      • Zhou R.
      • Peng Y.
      The miR-155/GATA3/IL37 axis modulates the production of proinflammatory cytokines upon TNF-α stimulation to affect psoriasis development.
      ,
      • Li Y.
      • Su J.
      • Li F.
      • Chen X.
      • Zhang G.
      MiR-150 regulates human keratinocyte proliferation in hypoxic conditions through targeting HIF-1α and VEGFA: implications for psoriasis treatment.
      ,
      • Hawkes J.E.
      • Nguyen G.H.
      • Fujita M.
      • Florell S.R.
      • Callis Duffin K.
      • Krueger G.G.
      • et al.
      MicroRNAs in psoriasis.
      ,
      • Beer L.
      • Kalinina P.
      • Köcher M.
      • Laggner M.
      • Jeitler M.
      • Abbas Zadeh S.
      • et al.
      MiR-155 contributes to normal keratinocyte differentiation and is upregulated in the epidermis of psoriatic skin lesions.
      ], were also differentially modulated across response subgroups (Fig. 6). Differences between PASI100 responders and those who did not achieve PASI100 were also highly significant for several pathways stimulated by IL-17 in keratinocytes or other cultured cells. At the level of individual gene products, the top 100 transcriptome genes (up-regulated at baseline) were analyzed for differential modulation in PASI100 vs PASI90 to< 100 responders (Table S7). Expression of 92% of these mRNAs was reduced from baseline to Week 52 to a greater extent in the PASI100 group than in the PASI90 to< 100 group, while 8% had a greater reduction in the PASI90 to< 100 group (P < .00001). Specific genes with greater down-regulation in PASI100 responders vs PASI90 to< 100 responders included S100A7A, IL19, IL20, S100A9, CXCL17, LCN2, IL36A, VNN1, and CCL20, all genes that reflect the IL-17–induced feed-forward inflammation pathway in psoriasis.
      Fig. 6
      Fig. 6Improvement in gene expression in psoriasis-associated pathways in subgroups defined by Week 52 PASI responses.a
      BL, baseline; LS, lesional; NL, non-lesional; PASI, Psoriasis Area and Severity Index.
      a Multiple t tests were performed for comparison across groups, and the Benjamini-Hochberg procedure was considered to adjust P values for multiple comparisons.
      * P < .05 vs PASI100.
      ** P < .01 vs PASI100.
      *** P < .001 vs PASI100.

      4. Discussion

      The primary objective of this study was to explore the clinical and molecular responses to secukinumab treatment in patients with moderate-to-severe plaque psoriasis after 12 weeks of treatment and to investigate the clinical, histologic, and molecular changes over 52 weeks of treatment. At Week 12, secukinumab treatment resulted in higher PASI90 response rates (55.8% vs 0%) and reversed histologic psoriasiform hyperplasia to a much greater extent (79.6% vs 3.6%) than placebo, consistent with previous studies [
      • Blauvelt A.
      • Prinz J.C.
      • Gottlieb A.B.
      • Kingo K.
      • Sofen H.
      • Ruer-Mulard M.
      • et al.
      Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE).
      ,
      • Paul C.
      • Lacour J.P.
      • Tedremets L.
      • Kreutzer K.
      • Jazayeri S.
      • Adams S.
      • et al.
      Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial (JUNCTURE).
      ,
      • Leigh I.M.
      • Navsaria H.
      • Purkis P.E.
      • McKay I.A.
      • Bowden P.E.
      • Riddle P.N.
      Keratins (K16 and K17) as markers of keratinocyte hyperproliferation in psoriasis in vivo and in vitro.
      ,
      • Bhawan J.
      • Bansal C.
      • Whren K.
      • Schwertschlag U.
      IL-11 Psoriasis Study Group
      K16 expression in uninvolved psoriatic skin: a possible marker of pre-clinical psoriasis.
      ]. Over 90% of PASI90 responders at Week 12 had no detectable K16 expression, and complete suppression of K16 was seen in all patients achieving PASI100 at Week 12. For patients who maintained PASI90 responses through Week 52, absence of K16 expression and normalization of abnormal baseline gene expression persisted, whereas patients who lost PASI90 responses from Week 12 to Week 52 displayed re-emergent K16 expression and regression of pro-inflammatory gene expression toward baseline levels.
      For patients receiving secukinumab, changes in expression of specific genes at Week 12 correlated with PASI improvement at Week 52. Using VNN2 and IL-6 expression, a predictive regression model of PASI90 outcome at Week 52 was developed that showed 81% accuracy, 89% sensitivity, and 66% specificity. Vanins are IL-17–regulated proteins expressed in differentiated keratinocytes in psoriasis lesions [
      • Jansen P.A.
      • Kamsteeg M.
      • Rodijk-Olthuis D.
      • van Vlijmen-Willems I.M.
      • de Jongh G.J.
      • Bergers M.
      • et al.
      Expression of the vanin gene family in normal and inflamed human skin: induction by proinflammatory cytokines.
      ], while IL-6 is a pro-inflammatory cytokine induced in response to TNF-α, IL-1, or IL-17A [
      • Saggini A.
      • Chimenti S.
      • Chiricozzi A.
      IL-6 as a druggable target in psoriasis: focus on pustular variants.
      ]. Stable control of psoriasis likely involves modulation of innate cytokines as well as adaptive T-cell–derived immune cytokines like IL-17A [
      • Chiricozzi A.
      • Guttman-Yassky E.
      • Suárez-Fariñas M.
      • Nograles K.E.
      • Tian S.
      • Cardinale I.
      • et al.
      Integrative responses to IL-17 and TNF-α in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis.
      ].
      Our data suggest that markers of inflammation can be effectively utilized to objectively monitor clinical responses after initiating a systemic therapy [
      Biomarkers Definition Working Group
      Biomarkers and surrogate endpoints: preferred definitions and conceptual framework.
      ] and to help identify patients who may lose clinical responses over time [
      • Ryan C.
      • Kelleher J.
      • Fagan M.F.
      • Rogers S.
      • Collins P.
      • Barker J.N.
      • et al.
      Genetic markers of treatment response to tumour necrosis factor-α inhibitors in the treatment of psoriasis.
      ]. Non-responders can also be identified through gene expression analyses, as shown here by differences in psoriasis pathways between Week 52 PASI90 responders and non-responders. These data emphasize that specific molecular changes need to occur early in treatment for patients to exhibit sustained clinical responses over time. One possible clinical scenario is that secukinumab-treated patients with “biomarker non-response” at Week 12 could be treated with higher doses or more frequent administration of drug to maintain efficacy.
      Over 50% of patients treated with secukinumab achieved PASI90 by Week 52, with higher clinical responses in patients weighing< 90 kg. For patients initially receiving placebo who were switched to secukinumab at Week 12, 92% of those weighing< 90 kg achieved PASI90 vs 53% of patients weighing ≥90 kg. Biologics used to treat psoriasis tend to be administered as fixed-dosed treatments that do not account for differences in weight [
      • Puig L.
      Obesity and psoriasis: body weight and body mass index influence the response to biological treatment.
      ], which can limit the achievement of optimal responses for patients who are overweight or gain weight during treatment [
      • Puig L.
      Obesity and psoriasis: body weight and body mass index influence the response to biological treatment.
      ,
      • Bardazzi F.
      • Balestri R.
      • Baldi E.
      • Antonucci A.
      • De Tommaso S.
      • Patrizi A.
      Correlation between BMI and PASI in patients affected by moderate to severe psoriasis undergoing biological therapy.
      ]. A recent study of patients with moderate-to-severe psoriasis found that heavier patients (≥90 kg) responded better to shorter dosing intervals of secukinumab (every 2 vs every 4 weeks) [
      • Augustin M.
      • Reich K.
      • Yamauchi P.
      • Pinter A.
      • Bagel J.
      • Dahale S.
      • et al.
      Secukinumab dosing every two weeks demonstrated superior efficacy compared with dosing every four weeks in patients with psoriasis weighing 90 kg or more: results of a randomised controlled trial.
      ]. Considered together, the available clinical and molecular data suggest that patients weighing ≥ 90 kg may require higher exposure to and higher doses of secukinumab to attain better disease control.
      It is currently unknown if higher levels of clinical responses are associated with differing degrees of improvement in molecular features of psoriasis. Due to the robust set of differentially expressed genes at baseline (>5600 transcripts), a relatively large study group of 82 patients, and the distribution of Week 52 outcomes, we were able to study molecular features of psoriasis associated with more stringent PASI outcomes. Increasing levels of disease control were associated with increasing improvements in consensus psoriasis transcriptomes, including effects of IFNγ, TNF-α, and IL-17 on different cell types (fibroblasts, monocytes, dendritic cells, and T cells). These data suggest that high levels of improvement, such as PASI90 and PASI100, may depend on reducing cytokine-regulated inflammatory pathways in skin cells beyond epidermal keratinocytes. Longer-term studies in diverse patient populations will be necessary to confirm these findings.
      The ObePso-S study demonstrated that early reversal of histologic and transcriptional changes associated with treatment of psoriasis with secukinumab was associated with long-term successful disease control and confirmed the known clinical response and safety of secukinumab in patients with moderate-to-severe psoriasis.

      Funding

      This study was sponsored by Novartis Pharmaceuticals Corporation, East Hanover, NJ.

      CRediT authorship contribution statement

      A. Blauvelt: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. D.M. Pariser: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. S. Tyring: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. J. Bagel: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. A.F. Alexis: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. J. Soung: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. A.W. Armstrong: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. E. Muscianisi: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. F. Kianifard: Conceptualization, Investigation, Formal analysis, Data curation, Writing – original draft, Writing – review & editing. R. Prasad Sarkar: Conceptualization, Investigation, Formal analysis, Data Curation, Writing – original draft, Writing – review & editing. J. Steadman: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. S. Garcet: Conceptualization, Investigation, Formal analysis, Data curation, Writing – original draft, Writing – review & editing. J.G. Krueger: Conceptualization, Investigation, Writing – original draft, Writing – review & editing, Supervision.

      Conflicts of interest

      A. Blauvelt has served as a speaker/received honoraria from AbbVie and UCB; has served as a scientific advisor/received honoraria from AbbVie, Abcentra, Affibody, Aligos, Almirall, Alumis, Amgen, AnaptysBio, Arcutis, Arena, ASLAN, Athenex, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Dermavant, EcoR1, Eli Lilly, Evelo, Evommune, Forte, Galderma, HighlightII Pharma, Incyte, Janssen, Landos, LEO Pharma, Merck, Novartis, Pfizer, Rapt, Regeneron, Sanofi Genzyme, Spherix Global Insights, Sun Pharma, TLL Pharmaceutical, TrialSpark, UCB, Vibliome, and Xencor; and has acted as a clinical study investigator/his institution has received clinical study funds from AbbVie, Acelyrin, Amgen, Arcutis, Athenex, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Eli Lilly, Evelo, Galderma, Incyte, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Regeneron, Sun Pharma, and UCB. D.M. Pariser has served as a consultant for and received honoraria from Abbott, Amgen, Astellas, Bausch Health, Bickel Biotechnology, Celgene, Dermira, DUSA, LEO Pharma, MELA Sciences, Novartis, and Procter & Gamble; has participated in advisory boards and received honoraria from Galderma, Genentech, Janssen Ortho, Medicis, Ortho Dermatologics, Pfizer, and Stiefel; and has served as an investigator for and received research grants from Abbott, Amgen, Astellas, Asubio, Basliea, Bausch Health, Celgene, Dow Pharmaceutical Sciences, Eli Lilly, Galderma, Graceway, Intendis, Johnson & Johnson, LEO Pharma, Novartis, Novo Nordisk, Ortho Dermatologics, Peplin, Pfizer, Photocure ASA, and Stiefel. S. Tyring has served as an investigator for Novartis. J. Bagel has served as an investigator, consultant, and/or speaker for AbbVie, Amgen, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, LEO Pharma, Novartis, and Sun Pharma. A.F. Alexis has received grants or research support from AbbVie, Almirall, Amgen, Arcutis, ASLAN, Bristol Myers Squibb, Cara Therapeutics, Castle, Dermavant, Galderma, LEO Pharma, Novartis, Valeant (Bausch Health), and Vyne; has served as a consultant or on advisory boards for AbbVie, Allergan, Almirall, Amgen, Arcutis, Bausch Health, Beiersdorf, Bristol Myers Squibb, Cara Therapeutics, Cutera, Dermavant, Eli Lilly, EPI, Galderma, Janssen, LEO Pharma, L′Oréal, Novartis, Pfizer, Sanofi-Regeneron, Sol-Gel, Swiss American, UCB, Valeant (Bausch Health), VisualDx, and Vyne; and has served as a speaker for Bristol Myers Squibb, Pfizer, Regeneron, and Sanofi-Genzyme. J. Soung has received speaker honoraria from AbbVie, Actelion, Amgen, Celgene, Dermira, Eli Lilly, National Psoriasis Foundation, Novartis, Ortho Dermatologics, and Regeneron; has received consulting/advisory board honoraria from Eli Lilly, LEO Pharma, and Novartis; and has received grant/research grant funding from AbbVie, Actavis, Actelion, Allergan, Boehringer Ingelheim, Cassiopea, Dr Reddy’s, Galderma, GSK, Janssen, Kadmon, Kyowa Kirin, LEO Pharma, Menlo, Novan, Novartis, Ortho Dermatologics, Pfizer, and UCB. A.W. Armstrong has served as research investigator and/or scientific advisor to AbbVie, ASLAN, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Dermira, Eli Lilly, EPI, Incyte, Janssen, LEO Pharma, Modmed, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB. E. Muscianisi, F. Kianifard, R. Prasad Sarkar, and J. Steadman are employees and stockholders of Novartis. S. Garcet has nothing to disclose. J.G. Krueger has received grants paid to The Rockefeller University from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Dermira, Eli Lilly, Innovaderm, Janssen, Kadmon, Kineta, Kyowa, LEO Pharma, Novartis, Paraxel, Pfizer, Provectus, Regeneron, and Vitae; and has received personal fees from AbbVie, Baxter, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Delenex, Dermira, Eli Lilly, Janssen, Kadmon, Kineta, Merck, Novartis, Pfizer, Sanofi, EMD Serono, and XenoPort.

      Acknowledgements

      Medical writing support was provided by Prasanthi Mandalay, PhD, of ArticulateScience LLC, and Ken Gresham, PhD, of Health Interactions, Inc, and was funded by Novartis Pharmaceuticals Corporation. This manuscript was developed in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Authors had full control of the content and made the final decision on all aspects of this publication.

      Appendix A. Supplementary material

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