Secukinumab efficacy and safety in Japanese patients with moderate‐to‐severe plaque psoriasis: Subanalysis from ERASURE,a randomized,placebo‐controlled,phase 3 study

Secukinumab, a fully human anti‐IL‐17A monoclonal antibody, neutralizes IL‐17A, a key cytokine in the pathogenesis of psoriasis. Efficacy and safety of secukinumab was evaluated in Japanese patients with moderate‐to‐severe plaque psoriasis as part of a large Phase 3 global study (ERASURE). In this 52‐week, double‐blind study (ClinicalTrials.gov Identifier: NCT01365455, JapicCTI‐111529), 87 patients from Japan (11.8% of 738 patients randomized in the overall study population) were equally randomized to receive secukinumab 300 mg or 150 mg, or placebo once weekly at baseline and at Weeks 1, 2, 3 and 4, then every 4 weeks. Co‐primary endpoints (Week 12) were ≥75% improvement in psoriasis area‐and‐severity index (PASI 75) from baseline and a score of 0 (clear) or 1 (almost clear) on a 5‐point Investigator's Global Assessment scale (IGA mod 2011 0/1) versus placebo. PASI 75 and IGA mod 2011 0/1 responses at Week 12 were superior with secukinumab 300 mg (82.8% and 55.2%, respectively) or 150 mg (86.2% and 55.2%, respectively) versus placebo (6.9% and 3.4%, respectively; P < 0.0001 for all). Greater than 90% improvement in PASI (PASI 90) was also superior with secukinumab 300 mg (62.1%) or 150 mg (55.2%) versus placebo (0.0%) at Week 12 (P < 0.0001 for both). Clinical responses were sustained up to Week 52 in the majority of patients. During a 12‐week induction period, adverse event incidences were 48.3% with secukinumab 300 mg, 55.2% with 150 mg, and 41.4% with placebo. Secukinumab showed robust and sustainable efficacy in symptom reduction for moderate‐to‐severe plaque psoriasis in the Japanese patients.     

Granzyme A potentiates chemokine production in IL‐17‐stimulated keratinocytes

Plaque psoriasis presents with focal skin inflammation, partially maintained by IL‐17‐mediated interactions between infiltrating epidermal T cells and activated keratinocytes. Here we show that the majority of lesional epidermal CD8 T cells express granzyme A, alone or in combination with IL‐17. To assess proinflammatory properties of granzyme A in psoriasis, primary human keratinocytes were stimulated with granzyme A in the presence or absence of IL‐17. Out of 33 analysed keratinocyte‐derived inflammatory mediators, granzyme A potentiated IL‐17‐induced secretion of CXCL 1, CXCL 12 and CCL 4. Intriguingly, all three chemokines are implicated in psoriasis pathogenesis and are involved in recruitment of T cells, neutrophils and pDCs into inflamed tissues. Our results indicate that granzyme A produced by lesional CD8 T cells specifically increase the chemokine production from inflamed keratinocytes, thereby amplifying a chemotactic inflammatory loop that sustains psoriasis lesions.     

Efficacy and safety of secukinumab in the treatment of moderate‐to‐severe plaque psoriasis: a randomized,double‐blind,placebo‐controlled phase II dose‐ranging study

Background Conventional systemic therapies for plaque psoriasis have not fully met the needs of patients, and although current biologic treatments are generally well tolerated, concerns exist with respect to long‐term safety. Interleukin (IL)‐17A is believed to be an important effector cytokine in the pathogenesis of psoriasis and is produced by Th17 cells, a class of helper T cells that act outside the established Th1/Th2 paradigm for regulation of innate and adaptive immunity. Objectives To assess the efficacy and safety of different doses of secukinumab, a fully human anti‐IL‐17A IgG1κ monoclonal antibody, in patients with moderate‐to‐severe plaque psoriasis. Methods Patients (n = 125) were randomized 1 : 1 : 1 : 1 : 1 to receive subcutaneous doses of placebo (n = 22) or secukinumab [1 × 25 mg (n = 29), 3 × 25 mg (n = 26), 3 × 75 mg (n = 21) or 3 × 150 mg (n = 27)] at weeks 0, 4 and 8. After the 12‐week treatment period, patients entered a follow‐up period of 24 weeks. The primary efficacy outcome was at least 75% improvement from baseline in the Psoriasis Area and Severity Index score (PASI 75); secondary outcomes included the Investigator’s Global Assessment (IGA) and PASI 90 and 50 response rates. Results After 12 weeks of treatment, secukinumab 3 × 150 mg and 3 × 75 mg resulted in significantly higher PASI 75 response rates vs. placebo (82% and 57% vs. 9%; P < 0·001 and P = 0·002, respectively). Higher PASI 75 response rates compared with placebo were maintained throughout the follow‐up period with these dosages [week 36, 26% (n = 7) and 19% (n = 4) vs. 4% (n = 1), respectively], with a gradual decline of PASI 75 response over time after the dosing period. IGA response rates were significantly higher in the 3 × 150 mg group vs. placebo at week 12 (48% vs. 9%; P = 0·005) and were consistently higher for the 3 × 150 mg and 3 × 75 mg groups vs. placebo at all time points from week 4 onward. The PASI 90 response rate was significantly higher in the 3 × 150 mg group vs. placebo (52% vs. 5%) at week 12 and remained higher during the follow‐up period. Secukinumab was well tolerated. Two cases of neutropenia (≤ grade 2) were reported in the 3 × 150 mg cohort. Conclusions Treatment with subcutaneous secukinumab 3 × 75 mg and 3 × 150 mg met the primary outcome of PASI 75 response achievement after 12 weeks, demonstrating efficacy in moderate‐to‐severe psoriasis.     

Secukinumab demonstrates superior efficacy and a faster response in clearing skin in Asian subjects with moderate to severe plaque psoriasis compared with ustekinumab: Subgroup analysis from the CLEAR study

The 52‐week results from the CLEAR (NCT02074982) study showed high and superior efficacy of secukinumab versus ustekinumab in clearing skin and improving patient‐reported outcomes, with comparable safety profile in subjects with moderate to severe psoriasis. Here, we analyzed the efficacy and safety of secukinumab in Asian subjects from the CLEAR study. In this double‐blind, phase IIIb study, eligible subjects with moderate to severe plaque psoriasis were randomized (1:1) to receive s.c. injection of secukinumab 300 mg or ustekinumab as per label. Of 62 subjects included in Asian subanalyses, 23 were randomized to secukinumab and 39 to ustekinumab. A significantly higher proportion of subjects achieved 90% or more improvement in Psoriasis Area and Severity Index (PASI 90) with secukinumab versus ustekinumab at week 16 (78.3% vs 35.9%, P = 0.0010) and at week 52 (60.9% vs 33.3%, P = 0.0196). Similarly, a higher proportion of subjects achieved PASI 100 with secukinumab versus ustekinumab at week 16 (43.5% vs 10.3%, P = 0.0029) and at week 52 (30.4% vs 12.8%, P = 0.0704). The median time to achieve 50% improvement in baseline PASI was 2.8 weeks in the secukinumab group versus 6.3 weeks in the ustekinumab group. The safety profile of secukinumab was in line with the known profile and no deaths occurred. Overall, 95.7% and 84.6% of subjects remained on secukinumab and ustekinumab, respectively. Similar to the core study, secukinumab showed sustained and superior efficacy with faster response versus ustekinumab, and no new or unexpected safety concerns were identified, in Asian subjects with moderate to severe plaque psoriasis.     

Secukinumab‐induced paradoxical hidradenitis suppurativa

Paradoxical reactions during treatment with biological agents may be defined as an appearance or exacerbation of a pathological condition that usually responds to this class of drug. Typical examples of paradoxical adverse effect are, among others, palmoplantar pustular and psoriasiform reactions or HS, in patients during a treatment of rheumatoid arthitis or IBD mainly. A few reports have been described an exacerbation of psoriasis1, palmoplantar pustular, or pustular psoriasis eruption with secukinumab. Marasca et al. highlights the immunological complexity that surrounds autoinflammatory diseases showing the potential double pathogenetic face of secukinumab in HS, describing a case of secukinumab‐induced HS and a case of HS caused by adalimumab treatment and controlled by secukinumab therapy. Real world evidence and results from clinical trials with secukinumab for HS, will possibly show the real role that anti‐IL‐17 drugs play in this complex disease.     

Effects of tumor necrosis factor‐α, interleukin‐23 and interleukin‐17A inhibitors on bodyweight and body mass index in patients with psoriasis

Treatment with tumor necrosis factor‐α inhibitors has been reported to cause weight gain in patients with psoriasis; however, limited information is available in terms of the effects of interleukin (IL)‐23 and IL‐17A inhibitors on bodyweight (BW) in patients with psoriasis. This study aimed to investigate the effects of infliximab, ustekinumab and secukinumab on BW and body mass index (BMI) in patients with psoriasis. We retrospectively examined changes in BW and BMI among patients treated with these biologics at our hospital. At baseline, no significant differences in BW and BMI were observed among the patients treated with infliximab (n = 18), ustekinumab (n = 30) or secukinumab (n = 20). After 7 months of the therapy, significant increases in mean BW (from 71.4 to 74.3 kg) and mean BMI (from 24.7 to 25.7) were observed in the patients treated with infliximab, whereas no significant changes were observed in those treated with ustekinumab (BW, from 70.3 to 70.1 kg; BMI, from 25.4 to 25.3) or secukinumab (BW, from 69.0 to 68.9 kg; BMI, from 25.2 to 25.2). There were no differences in the proportion of the patients who showed 75% or more improvement in the Psoriasis Area and Severity Index among the three groups. These results suggest that infliximab increases BW in the patients with psoriasis, whereas ustekinumab and secukinumab do not affect the BW in these patients.     

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)

Background

Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL‐17A, has been shown to have significant efficacy and a favourable safety profile in the treatment of moderate‐to‐severe psoriasis and psoriatic arthritis.

Objective

To assess the efficacy and safety of secukinumab through 5 years of treatment in moderate‐to‐severe psoriasis.

Methods

In the core SCULPTURE study, Psoriasis Area and Severity Index (PASI) 75 responders at Week 12 continued receiving subcutaneous secukinumab until Year 1. Thereafter, patients entered the extension phase and continued treatment as per the core trial. Treatment was double‐blinded until the end of Year 3 and open‐label from Year 4. Here, we focus on the 300 mg fixed‐interval (every 4 weeks) treatment, the recommended per label dose. Efficacy data are primarily reported as observed, but multiple imputation (MI) and last observation carried forward (LOCF) techniques were also undertaken as supportive analyses.

Results

At Year 1, 168 patients entered the extension study and at the end of Year 5, 126 patients completed 300 mg (every 4 weeks) treatment. PASI 75/90/100 responses at Year 1 (88.9%, 68.5% and 43.8%, respectively) were sustained to Year 5 (88.5%, 66.4% and 41%). PASI responses were consistent regardless of the analysis undertaken (as observed, MI, or LOCF). The average improvement in mean PASI was approximately 90% through 5 years compared with core study baseline. DLQI (dermatology life quality index) 0/1 response also sustained through 5 years (72.7% at Year 1 and 65.5% at Year 5). The safety profile of secukinumab remained favourable, with no cumulative or unexpected safety concerns identified.

Conclusion

Secukinumab 300 mg treatment delivered high and sustained levels of skin clearance and improved quality of life through 5 years in patients with moderate‐to‐severe psoriasis. Favourable safety established in the secukinumab phase 2/3 programme was maintained through 5 years.     

Long‐term efficacy and safety of secukinumab in Japanese patients with moderate to severe plaque psoriasis: 3‐year results of a double‐blind extension study

Secukinumab, a fully human monoclonal antibody neutralizing interleukin‐17A, has been shown to have significant efficacy in the treatment of moderate to severe psoriasis. Long‐term (3‐year) efficacy and safety of secukinumab in Japanese patients with moderate to severe psoriasis were evaluated in an extension study of a large phase 3 global study (SCULPTURE). In the core study, 52 Japanese patients with 75% improvement of Psoriasis Area and Severity Index (PASI‐75) response at week 12 were re‐randomized to a fixed interval (FI; every 4 weeks) schedule and retreatment as needed (RAN), in which patients received placebo until start of relapse, at which time secukinumab was reinitiated. Fifty Japanese patients completed the 52‐week core study, and 47 patients entered the extension study with the same double‐blind regimens up to week 152. All patients in the secukinumab 300 mg FI and seven patients in 150 mg FI groups completed 3 years of treatment. PASI‐90 and ‐100 at the end of year 3 were achieved in 69.2% and 53.8%, respectively, in 300 mg FI and 42.9% and 42.9%, respectively, in 150 mg FI, indicating high sustained response in 300 mg FI. Mean absolute PASI was continually low in 300 mg FI and numerically higher in 150 mg FI. Dermatology Life Quality Index of 0/1 was maintained by approximately two‐thirds of 300 mg FI patients, and all EuroQoL 5‐Dimension Health Questionnaire domain measures were also improved. FI dosing was consistently more efficacious than RAN. The safety profile of secukinumab remained favorable, with no new safety concerns identified.     

IL‐33 is secreted by psoriatic keratinocytes and induces pro‐inflammatory cytokines via keratinocyte and mast cell activation

IL‐33 is a novel pro‐inflammatory cytokine and ligand for the orphan receptor ST2. Although originally defined as an inducer of Th2‐mediated responses, IL‐33 was recently found to be involved in arthritis, a Th1/Th17‐mediated disease. Here, we assessed the ability of IL‐33 to promote inflammation via mast cells (MCs) and keratinocytes (KCs) activation in psoriasis. IL‐33 resulted elevated in the skin but not in the serum of psoriasis patients. IL‐33 was secreted by psoriasis KCs and HaCaT cells after TNF‐α stimulation. In HMC‐1, TNF‐α, but not IL‐17, could induce a robust increase in IL‐33 expression. In HaCaT cells, TNF‐α was able to induce IL‐6, MCP‐1 and VEGF, and the addition of IL‐33 reinforced these increases. TNF‐α + IL‐33 combination showed similar results in primary KCs and ex vivo skin organ culture. In conclusion, our study suggests that IL‐33 may be involved in psoriasis biology via MCs and KCs.     

Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin‐17 inhibitors and their practical management

The recognition of the central role of interleukin (IL)‐17A in the pathogenesis of psoriasis has led to the development of several monoclonal antibodies targeting this cytokine or its receptors for therapeutic purposes. IL‐17A also plays an important role in immunological protection against infections, especially those due to Candida spp., as evidenced by findings in patients with genetic defects in IL‐17‐related immune responses. To assess the potential of anti‐IL‐17 treatment to promote Candida infections, here we have systematically reviewed published clinical trials of patients with psoriasis or psoriatic arthritis. Candida infections were reported in 4·0% of patients treated with brodalumab, 1·7% with secukinumab and 3·3% with ixekizumab vs. 0·3%, 2·3% and 0·8% of those assigned to placebo, ustekinumab or etanercept, respectively. Although the incidence of Candida infection was found to be increased by only a small degree during anti‐IL‐17 therapy, patients undergoing such treatment should be monitored for fungal infection and treated as necessary. We propose adoption of the recently updated recommendations for the practical management of Candida infection in patients administered IL‐17 inhibitors.     

Development of psoriasis by continuous neutrophil infiltration into the epidermis

Remarkable effects of anti‐IL‐17A and anti‐IL‐23 antibodies on psoriasis indicate deep involvement of IL‐23/Th17 axis in the pathogenesis of psoriasis. According to the current immune theory, activation of dendritic cells initiates the generation of this axis. However, this theory is not enough to explain the mechanism, because the process of this activation is obscure and the antigen that is recognized by antigen‐presenting cells and pathogenic T cells has long been unidentified. Therefore, I thought of another theory as follows. Neutrophils are attracted by LTB4 at subcorneal portion and infiltrate into the epidermis. At the time of neutrophil migration through the basement membrane, basal keratinocytes in G0/G1 phase enter the cell cycle and begin to proliferate, according to the principle, “detachment‐mediated cell proliferation.” This passing is continuously repeated and leads to elongation of rete ridges. The IL‐23/Th17 axis is generated by interactions between infiltrated neutrophils and keratinocytes. Briefly, neutrophils infiltrated into the epidermis secrete IL‐17A, which acts on keratinocytes to express CCL20, a ligand for the chemokine receptor CCR6. Keratinocytes perturbed by neutrophil infiltration produce HSP70, followed by production of IL‐23 via TLR4 using HSP70 as an endogenous ligand for TLR4. Natural Th17 cells expressing CCR6 are recruited to psoriatic epidermis and expand there in the presence of IL‐23 and IL‐1β. In this manner, the framework of the IL‐23/Th17 axis is created, which acts to maintain or exacerbate psoriasis. Noteworthy is the fact that this axis causes positive feedback loop, starting from IL‐17A production by neutrophils and ending in IL‐17A production by nTh17 cells. Therapeutic mechanisms of anti‐IL‐17A and anti‐IL‐23 antibodies, targeting neutrophils, were also described.     

The plot thickens while the scope broadens: a holistic view on IL‐17 in psoriasis and other inflammatory disorders

Psoriasis is an instructive example highlighting our growing knowledge about pathophysiological functions of interleukin (IL)‐17. IL‐17A is the predominant isoform implicated in key pathogenic features in this and other chronic inflammatory disorders. Several monoclonal antibodies targeting IL‐17A (secukinumab, ixekizumab) or its IL‐17RC/RA receptor (brodalumab) are currently in late stages of clinical development, where they have shown impressive efficacy. While the eponymous IL‐17 has been thought to originate primarily from T helper (Th)17 cells, more recent investigations by several groups suggest that other cell types in psoriatic lesions, such as neutrophils and mast cells, are rich sources of IL‐17, thus presumably contributing to the disease process to an as yet underestimated extent. This recent paradigm shift provides a plausible explanation for the rapid and strong efficacy of the novel compounds targeting IL‐17 functions in psoriasis and other inflammatory disorders, and provide a more comprehensive view on the complex cytokine network in these conditions.     

Secukinumab improves psoriasis symptoms in patients with inadequate response to cyclosporine A: A prospective study to evaluate direct switch

There are limited data on the safety and efficacy of switching to secukinumab from cyclosporine A (CyA) in patients with psoriasis. The purpose of the present study was to assess the efficacy and safety of secukinumab for 16 weeks after direct switching from CyA in patients with moderate‐to‐severe psoriasis. In this multicenter, open‐label, phase IV study, 34 patients with moderate‐to‐severe psoriasis and inadequate response to CyA received secukinumab 300 mg s.c. at baseline and weeks 1, 2, 3, 4, 8 and 12. The primary end‐point was ≥75% improvement from baseline in Psoriasis Area and Severity Index score (PASI 75) at week 16. The efficacy of secukinumab treatment was evaluated up to week 16, and adverse events (AE) were monitored during the study. The primary end‐point of the PASI 75 response at week 16 was achieved by 82.4% (n = 28) of patients receiving secukinumab. Early improvements were observed with secukinumab, with PASI 50 response of 41.2% at week 2 and PASI 75 response of 44.1% at week 4. AE were observed in 70.6% (n = 24) of patients, and there were no serious AE or deaths reported in the entire study period. Secukinumab showed a favorable safety profile consistent with previous data with no new or unexpected safety signals. The results of the present study show that secukinumab is effective in patients with psoriasis enabling a smooth and safe direct switch from CyA to biological therapy.     

Effectiveness and safety of secukinumab in 69 patients with moderate to severe plaque psoriasis: A retrospective multicenter study

Secukinumab (anti‐IL17A) is effective as treatment for moderate to severe plaque psoriasis, but real‐life data on effectiveness and safety lack. We aimed to present real‐life data of all Danish patients treated with secukinumab (n = 69). At baseline, before initiation of treatment with secukinumab 300 mg (47.8%) or off‐label treatment with secukinumab 150 mg (52.2%), the median PASI score was 7.1. A total of 66.7% (34/51) and 52.9% (27/51) of patients still on secukinumab at week 12 achieved a PASI (Psoriasis Area and Severity Index)‐50 and PASI‐75 of 66.7% and 52.9%, respectively. A total of 83.0% (44/53) and 60.4% (32/53) of the patients had a PASI‐score < 5 and PASI‐score < 2, respectively, after 12 weeks on treatment with secukinumab. A third of the patients had secukinumab discontinued due to limited clinical improvement or adverse events (n = 23) within a median of 92 days (interquartile range 51–212 days). Notably, the majority of the patients may represent a particularly difficult‐to‐treat group of patients, as 92.8% had been refractory to other biologic treatment. A total of 26.1% (n = 18) experienced adverse events. Secukinumab appears to be an effective treatment option with a favorable side effect profile in patients with plaque psoriasis who are refractory to or have side effects of traditional biologic drugs.     

Acitretin exerted a greater influence on T‐helper (Th)1 and Th17 than on Th2 cells in treatment of psoriasis vulgaris

T‐helper (Th) cells, including Th1, Th2 and Th17 cells, may play an important role in the pathogenesis of psoriasis vulgaris (PV). Acitretin is an effective treatment for PV; however, its influence on Th cells during the treatment of PV is unclear. This study aimed to investigate the influence of acitretin on Th1, Th2 and Th17 cells in PV patients. PV patients (n = 30) received acitretin p.o. (20 mg/day) for 8 weeks. Sera and skin biopsies were obtained before and after treatment. Double‐labeled immunofluorescence was used to analyze T, Th1, Th2 and Th17 cells in skin lesions. Enzyme‐linked immunosorbent assay and western blot were used to analyze the expressions of interferon (IFN)‐γ, interleukin (IL)‐4 and IL‐17 in sera and skin lesions. The expressions of IFN‐γ mRNA, IL‐4 mRNA and IL‐17 mRNA in skin lesions were detected by in situ hybridization. Acitretin decreased the quantity of T, Th1 and Th17 cells in PV lesions, but had no significant influence on Th2 cells. Acitretin also decreased the expression of IFN‐γ and IL‐17 in serum and lesions. The expressions of IFN‐γ mRNA and IL‐17 mRNA decreased significantly after 8 weeks of therapy. However, acitretin had no significant influence on the expression of IL‐4 protein and mRNA. Acitretin can reverse Th1 and Th17 preponderance in PV patients to some degree. This may be due to the mechanism of acitretin on PV; however, Th2 cells were not affected by acitretin treatment.     

Successful treatment with interleukin‐17A antagonists of generalized pustular psoriasis in patients without IL36RN mutations

Generalized pustular psoriasis (GPP) is a potentially life‐threatening disease that can be attributed to mutations in IL36RN in a subgroup of patients. In small trials, interleukin (IL)‐17A and IL‐17RA antagonists have been shown to be effective in patients with generalized pustular psoriasis in Japan. We identified seven patients who received the IL‐17A antagonists secukinumab (six cases) or ixekizumab (one case) in two dermatological centers. All patients showed a good or excellent clinical response. Anti‐IL‐17A therapy was well tolerated and ongoing in all patients after an average therapy duration of 12.9 months. Analysis of IL36RN mutation status was performed in six patients, one patient carried a heterozygous mutation, while the other five patients did not show a mutation in IL36RN. This is the first report of a successful treatment of GPP patients without IL36RN mutations responding to anti‐IL‐17A therapy.     

Mild electrical stimulation with heat shock reduces inflammatory symptoms in the imiquimod‐induced psoriasis mouse model

Psoriasis is a chronic skin disease caused by immune disorder. The chronic skin inflammation involves inflammatory molecules that are released from T lymphocytes and keratinocytes. Therefore, developing an anti‐inflammatory therapy that is suitable for long‐term treatment is needed. Electrical stimulation induces biological responses by modulating intracellular signaling pathways. Our previous studies showed that the optimized combination treatment of mild electrical stimulation (MES, 0.1‐millisecond; ms, 55‐pulses per second; pps) and heat shock (HS, 42°C) modulates inflammatory symptoms of metabolic disorders and chronic kidney disease in mice models and clinical trials. Here, we investigated the effect of MES+HS treatment on imiquimod‐induced psoriasis mouse model. Topical application of imiquimod cream (15 mg) to mice ear induced keratinocyte hyperproliferation and psoriasis‐like inflammation. In MES+HS‐treated mice, imiquimod‐induced skin hyperplasia was significantly decreased. MES+HS treatment reduced the protein expression of IL‐17A and the infiltration of CD3‐positive cells in lesioned skin. In addition, MES+HS‐treated mice had decreased mRNA expression level of antimicrobial molecules (S100A8 and Reg3γ) which aggravate psoriasis. In IL‐17A‐stimulated HaCaT cells, MES+HS treatment significantly lowered the mRNA expression of aggravation markers (S100A8, S100A9 and β‐defensin2). Taken together, our study suggested that MES+HS treatment improves the pathology of psoriasis via decreasing the expression of inflammatory molecules.     

IL‐17A synergistically enhances TLR3‐mediated IL‐36γ production by keratinocytes: A potential role in injury‐amplified psoriatic inflammation

Skin injury can trigger formation of new lesions in psoriasis (Koebner phenomenon). The mechanisms through which injury exacerbates psoriasis are unclear. During wound repair, epidermal keratinocytes are activated and produce abundant IL‐36γ, further promoting the skin inflammation. IL‐17A is the cornerstone cytokine in the pathogenesis of psoriasis. We sought to investigate the effects of IL‐17A on injury‐induced keratinocyte activation and IL‐36γ production. Here, we demonstrated that dsRNA released from necrotic keratinocytes induced the expression of IL‐36γ. Silencing of TLR3 by siRNA decreased the IL‐36γ induction by necrotic keratinocyte supernatant. Co‐stimulation with dsRNA and IL‐17A synergistically increased the expression of IL‐36γ and other proinflammatory mediators (CCL20, CXCL8, DEFB4 and LCN2) in keratinocytes. The synergistic effects were not dependent on TLR3 upregulation, TNF receptor signalling and mRNA stabilization. Co‐stimulation with dsRNA and IL‐17A resulted in an accumulation of IκBζ. The synergistic upregulation of IL‐36γ and proinflammatory mediators were inhibited by IκBζ siRNA. Co‐stimulation with IL‐17A and poly(I:C) markedly activated the p38 MAPK and NF‐κB pathway, compared with poly(I:C). Blockade of p38 MAPK and NF‐κB suppressed dsRNA/IL‐17A–mediated IκBζ and IL‐36γ induction. These findings demonstrated that IL‐17A synergistically enhanced the dsRNA‐mediated IL‐36γ production through a p38 MAPK‐, NF‐κB–, and IκBζ‐dependent mechanism.     

Efficacy and safety of guselkumab in psoriasis patients who failed ustekinumab and/or anti‐interleukin‐17 treatment: A real‐life 52‐week retrospective study

Recent major research advancements have significantly expanded our understanding of psoriasis pathophysiology, resulting in the development of highly effective, targeted therapies. Guselkumab is the first interleukin (IL)‐23 inhibitor approved for the treatment of moderate‐to‐severe‐psoriasis, providing a new therapeutical option for psoriasis. The aim of our study was to evaluate the efficacy of guselkumab in psoriatic patients who previously failed anti‐IL‐12/23 and/or anti‐IL‐17 treatment. A 52‐week single‐center retrospective study was performed enrolling moderate‐to‐severe patients attending our Psoriasis Care Center from October 2018 to May 2020. Study population included 13 patients; 46.1% have been previously treated with ustekinumab, while 69.2% have previously failed an anti‐IL‐17 treatment (38.5% secukinumab, 30.8% ixekizumab, and 38.5% both). At baseline, mean Psoriasis Area and Severity Index was 13.2 ± 6.8, reducing up to 0.5 ± 0.7 at week 52 (P < .001). Body surface area reduced from 22.3 ± 10.5 (baseline) to 0.8 ± 1.1 at week 52 (P < .001). No statistically significant differences have been found between patients previously treated with anti‐IL‐12/23 compared to anti‐IL‐17 or both. Only one patient discontinued guselkumab at week 36 due to secondary inefficacy. This is a single institution study with a relatively small sample size. Our real‐life data confirm trial results, showing guselkumab as a safe and effective option in patients with moderate‐to‐severe psoriasis even in those who previously failed ustekinumab and/or anti‐IL‐17 treatment.     

Secukinumab induction and maintenance therapy in moderate‐to‐severe plaque psoriasis: a randomized,double‐blind,placebo‐controlled,phase II regimen‐finding study

Background Interleukin (IL)‐17A has major proinflammatory activity in psoriatic lesional skin. Objectives To assess the efficacy and safety of secukinumab, a fully human IgG1κ monoclonal anti‐IL‐17A antibody, in moderate‐to‐severe plaque psoriasis in a phase II regimen‐finding study. Methods A total of 404 patients were randomized to subcutaneous placebo (n = 67) or one of three secukinumab 150 mg induction regimens: single (week 0; n = 66), early (weeks 0, 1, 2, 4; n = 133) and monthly (weeks 0, 4, 8; n = 138 patients). The primary outcome was ≥ 75% improvement from baseline Psoriasis Area and Severity Index score (PASI 75) at week 12. PASI 75 responders from active treatment arms at week 12 were rerandomized to either a fixed‐interval (secukinumab 150 mg at weeks 12 and 24; n = 65) or a treatment‐at‐start‐of‐relapse maintenance regimen (secukinumab 150 mg at visits at which a start of relapse was observed; n = 67). Results At week 12, early and monthly induction regimens resulted in higher PASI 75 response rates vs. placebo (54·5% and 42·0% vs. 1·5%; P < 0·001 for both). Among PASI 75 responders at week 12 entering the maintenance period, PASI 75 and PASI 90 achievement at least once from week 20 to week 28 was superior with the fixed‐interval regimen [85% (n = 55) and 58% (n = 38), respectively] vs. the start‐of‐relapse regimen [67% (n = 45), P = 0·020, and 21% (n = 14), respectively]. Fifteen weeks after last study drug administration, < 10% of patients in the fixed‐interval and start‐of‐relapse groups experienced a start of relapse. No immunogenicity was observed, and no injection‐site reactions were reported. Reported cases of neutropenia were mild‐to‐moderate (≤ grade 2); none was associated with clinically significant adverse events or resulted in study discontinuation. Due to the brief duration of the safety assessment, no firm conclusions can be drawn regarding long‐term safety. Conclusions Secukinumab shows efficacy for induction and maintenance treatment of moderate‐to‐severe plaque psoriasis.