Progression of Quality of Life in Patients with Plaque Psoriasis Who Achieved Three or More Years of Complete Skin Clearance with Guselkumab Treatment: a Post hoc Analysis of the VOYAGE 1 Clinical Trial.

INTRODUCTION: The interleukin-23p19 subunit inhibitor, guselkumab, has demonstrated improvements in clinical and patient-reported outcome (PRO) measures in patients with moderate-to-severe psoriasis. Understanding the relationship among clinical response, PRO measures and baseline characteristics could help clinicians individualize treatment plans. The objective of this analysis was to examine changes in signs, symptoms and quality-of-life (QoL) PRO measures in patients who maintained complete skin clearance through ≥ 3 years in the phase 3 VOYAGE 1 trial. METHODS: A descriptive post hoc analysis of data from VOYAGE 1 was conducted to compare baseline characteristics of patients who maintained complete skin clearance (Psoriasis Area and Severity Index [PASI] = 0 for ≥ 156 consecutive weeks) versus patients who did not. Mean scores for individual domains of the Dermatology Life Quality Index (DLQI) and Psoriasis Symptom and Sign Diary (PSSD) were evaluated in patients who maintained complete skin clearance, and baseline characteristics of patients who achieved PRO scores of DLQI = 0/1 and PSSD = 0 were compared with those who did not. RESULTS: Of the 329 patients included in this post hoc analysis, 73 (22.2%) maintained PASI = 0 for ≥ 156 weeks. This group had a numerically lower proportion of patients at baseline with obesity, depression or previous biologic treatment and a higher proportion who had never smoked. Patients who maintained PASI = 0 generally achieved positive DLQI and PSSD outcomes, though some impact of residual disease was observed, largely related to the DLQI "Symptoms and feelings" sub-scale and PSSD components "Dryness," "Redness" and "Itch." Patients reporting continued disease impact (despite sustaining PASI = 0) had greater disease severity at baseline versus those achieving DLQI = 0/1 and PSSD = 0. CONCLUSION: Clinical measures alone do not capture the full patient experience. While both QoL and clinical symptoms are responsive to highly effective treatment, a subset of patients with complete clinical response is still impacted by their psoriasis. Further investigation into this population is warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02207231.

Predictors of initiating biologics in the treatment of psoriasis.

BACKGROUND: Biologics are among the most effective therapies for psoriasis. However, many patients are only introduced to them at advanced stages of the disease course. OBJECTIVES: Our aim was to identify predictors of initiating biologic therapy in patients with psoriasis and compare patients initiating biologics early versus late in their disease course. METHODS: Kaplan-Meier curves visualized time to biologic initiation, while Cox regression models further explored variables as predictors of biologic initiation. Mann-Whitney U and chi-squared tests compared patients who started biologics early with those who began biologics later in the disease course. RESULTS: Our primary analysis included 233 psoriasis patients. Cox regression showed that age at diagnosis (P = 0.007), general physical well-being (P = 0.02), and nail psoriasis severity (P = 0.02) were significantly associated with time to biologic initiation. Our secondary analysis, the comparisons between patients starting biologics early versus later in the disease course, included a total of 378 patients. The median (interquartile range [IQR]) age at diagnosis was 34.5 (25.0-51.2) years for patients initiating biologics within 5 years, compared to 22.0 (15.0-32.8) years for patients initiating biologics later (P < 0.0001). The median (IQR) age at initiation was 37.0 (27.0-53.2) and 45.0 (36.0-55.0) years for patients initiating biologics earlier versus later than 5 years (P = 0.04). CONCLUSIONS: Age at diagnosis, general well-being, and severity of nail psoriasis significantly predicted future initiation of biologic treatment. Patients initiating biologics early in their disease course were generally older at diagnosis but younger at the time of biologic initiation compared to patients initiating biologics later in their disease course.

Targeting IL-1 controls refractory pityriasis rubra pilaris.

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease with a poorly understood pathogenesis. Through a molecularly driven precision medicine approach and an extensive mechanistic pathway analysis in PRP skin samples, compared to psoriasis, atopic dermatitis, healed PRP, and healthy controls, we identified IL-1ß as a key mediator, orchestrating an NF-κB-mediated IL-1ß-CCL20 axis, including activation of CARD14 and NOD2. Treatment of three patients with the IL-1 antagonists anakinra and canakinumab resulted in rapid clinical improvement and reversal of the PRP-associated molecular signature with a 50% improvement in skin lesions after 2 to 3 weeks. This transcriptional signature was consistent with in vitro stimulation of keratinocytes with IL-1ß. With the central role of IL-1ß underscoring its potential as a therapeutic target, our findings propose a redefinition of PRP as an autoinflammatory keratinization disorder. Further clinical trials are needed to validate the efficacy of IL-1ß antagonists in PRP.

Age affects drug survival rates of interleukin (IL)-17 and IL-23 inhibitors in patients with plaque psoriasis: Results from a retrospective, multicentric, multi-country, cohort study.

BACKGROUND: Scarce data related to the drug survival of biologic agents in psoriasis patients aged ≥65 years is available. OBJECTIVES: To evaluate the drug survival of interleukin (IL)-23 or the IL-17 inhibitors approved for the treatment of moderate-to-severe psoriasis in elderly patients (aged ≥65 years), compared with younger adult patients (aged <65 years), and to identify clinical predictors that can influence the drug survival. METHODS: This retrospective multicentric cohort study included adult patients with moderate-to-severe psoriasis, dissecting two-patient subcohorts based on age: elderly versus younger adults. Kaplan-Meier estimator and proportional hazard Cox regression models were used for drug survival analysis. RESULTS: We included 4178 patients and 4866 treatment courses; 934 were elderly (1072 treatment courses), and 3244 were younger patients (3794 treatment courses). Drug survival, considering all causes of interruption, was higher in patients aged <65 years than in elderly patients overall (log-rank p < 0.006). This difference was significant for treatment courses involving IL-23 inhibitors (p < 0.001) but not for those with IL-17 inhibitors (p = 0.2). According to both uni- and multi-variable models, elder age was associated with an increased risk of treatment discontinuation (univariable analysis: HR: 1.229, 95% CI 1.062-1.422; p < 0.006; multivariable analysis: HR: 1.199, 95% CI 1.010-1.422; p = 0.0377). Anti-IL-23 agents were associated with a reduced likelihood of treatment discontinuation after adjusting for other variables (HR: 0.520, 95% CI 0.368-0.735; p < 0.001). Being previously treated with IL-17 inhibitors increased the probability of discontinuation. CONCLUSION: Elderly patients with psoriasis have an increased risk of biologic treatment discontinuation compared with younger adult patients, particularly, if being treated with IL-23 inhibitors. However, in stratified analyses conducted in elderly patients, IL-23 inhibitors showed higher drug survival rates than IL-17 inhibitors.

[Treatment of childhood psoriasis: present and future]. / Thérapie du psoriasis pédiatrique : présent et futur.

Psoriasis may present in childhood with skin, nail and scalp lesions but sometimes also articular involvement. It has an import impact on the quality of life of young patients. In this article we present an overview of the treatments that may be used in children according to skin area involved and severity of lesions with special interest for the biological treatments, already available and under investigation.

Le psoriasis peut déjà se manifester dans l'enfance avec des lésions cutanées, des ongles, du scalp, mais parfois aussi une atteinte articulaire. Cette maladie a un impact important sur la qualité de vie de l'enfant. Dans cet article, nous présentons une revue des traitements en ce moment possibles chez les enfants, selon la surface de peau atteinte, la sévérité des lésions, en mettant surtout en lumière les traitements par biologiques déjà possibles et en étude.

Human neutrophils drive skin autoinflammation by releasing interleukin (IL)-26.

Autoinflammation is a sterile inflammatory process resulting from increased neutrophil infiltration and overexpression of IL-1 cytokines. The factors that trigger these events are, however, poorly understood. By investigating pustular forms of psoriasis, we show that human neutrophils constitutively express IL-26 and abundantly release it from granular stores upon activation. In pustular psoriasis, neutrophil-derived IL-26 drives the pathogenic autoinflammation process by inducing the expression of IL-1 cytokines and chemokines that further recruit neutrophils. This occurs via activation of IL-26R in keratinocytes and via the formation of complexes between IL-26 and microbiota DNA, which trigger TLR9 activation of neutrophils. Thus our findings identify neutrophils as an important source of IL-26 and point to IL-26 as the key link between neutrophils and a self-sustaining autoinflammation loop in pustular psoriasis.

Response Types and Factors Associated with Response Types to Biologic Therapies in Patients with Moderate-to-Severe Plaque Psoriasis from Two Randomized Clinical Trials.

INTRODUCTION: This study aimed to understand treatment response dynamics, including factors associated with favorable response, among patients with moderate-to-severe psoriasis who received guselkumab, adalimumab, or secukinumab. METHODS: These post hoc analyses used data from the phase III clinical trials ECLIPSE and VOYAGE 1, which were conducted between September 2021 and November 2022. On the basis of absolute Psoriasis Area and Severity Index (aPASI) scores, patients were divided into short-term response types (SRT1-6, based on week 20-48 response) and long-term response types (LRT1-4, based on week 52-252 response). Response types (RTs) were based on aPASI cutoffs deemed clinically relevant by the investigators; SRT1/LRT1 were the most favorable response types. Baseline characteristics were compared across RTs, and logistic regression analyses established factors associated with SRT1/LRT1. RESULTS: Overall, 1045, 662, and 272 patients were included in the ECLIPSE short-term, VOYAGE 1 short-term, and VOYAGE 1 long-term analyses, respectively. Mean age, body mass index (BMI), baseline aPASI score, and body surface area were lower in SRT1 than SRT6. In VOYAGE 1, adalimumab treatment, high BMI, and current/former smoking status resulted in less favorable responses. In the VOYAGE 1 long-term analysis, patients in LRT4 had the highest baseline aPASI score, were older, and were more often obese compared with other LRT groups. Regression analyses showed that SRT1 (both treatments) in VOYAGE 1 and ECLIPSE, and LRT1 (guselkumab group) in the VOYAGE 1 long-term analysis, were associated with week 16 aPASI response. In VOYAGE 1, SRT1 was associated with psoriasis duration and smoking status. CONCLUSIONS: Early treatment response and baseline characteristics, including smoking, psoriasis duration, and obesity, may be associated with longer-term response to biologics. TRIAL REGISTRATION NUMBERS: ECLIPSE: NCT03090100, VOYAGE 1: NCT02207231.

Guselkumab-Treated Patients with Plaque Psoriasis Who Achieved Complete Skin Clearance for ≥ 156 Consecutive Weeks: A Post-Hoc Analysis From the VOYAGE 1 Clinical Trial.

BACKGROUND: Treatment of moderate-to-severe plaque psoriasis with biologics, such as guselkumab, has demonstrated greater efficacy over traditional non-biologic treatments. However, given patient diversity, greater understanding of the relationship between patient characteristics, positive clinical outcomes, and long-term response to biologics is crucial for optimizing treatment choices. MATERIALS AND METHODS: This post-hoc analysis of the 5-year VOYAGE 1 clinical trial compares baseline characteristics of patients maintaining a Psoriasis Area and Severity Index (PASI) score of 0 at all visits for ≥ 156 consecutive weeks (PASI = 0 group) with those that never achieve PASI = 0 (comparator group), using descriptive statistics and a multiple logistic regression model. Guselkumab plasma trough concentrations in both response groups were assessed from Weeks 4-156. RESULTS: Of patients who started guselkumab treatment at Week 0 or at Week 16 after switching from placebo, 22.7% (112/494) maintained PASI = 0 for ≥ 156 consecutive weeks. Numerical differences in baseline characteristics, including age, obesity, diabetes, PASI score, disease duration, smoking status, and psoriatic arthritis comorbidity, were identified between the PASI = 0 group and comparator group. Plasma guselkumab levels were consistently higher in the PASI = 0 group. Multiple logistic regression analysis revealed absence of diabetes, lower Dermatology Life Quality Index score at baseline, and higher Week 4 guselkumab plasma concentration as significantly (p < 0.05) associated with the PASI = 0 group. CONCLUSION: A substantial (22.7%) number of guselkumab-treated patients in the VOYAGE 1 clinical trial maintained complete skin clearance for a consecutive period of ≥ 156 weeks. Factors associated with this outcome may suggest clinical benefits of holistic treatment approaches. TRIAL REGISTRATION: NCT02207231.

Sex differences in adverse events from systemic treatments for psoriasis: A decade of insights from the Swiss Psoriasis Registry (SDNTT).

BACKGROUND: Psoriasis is a disease that often requires prolonged systemic treatment. It is important to determine the safety of available therapies. There is currently little insight into sex-specific differences in the safety of systemic psoriasis therapies. OBJECTIVES: To examine the real-world, long-term safety of systemic psoriasis therapies with sex stratification in drug-related adverse events (ADRs). METHODS: Ten-year data from adults with moderate-to-severe psoriasis requiring systemic treatment (conventional systemic therapies [CST], biologics) were obtained from the Swiss psoriasis registry (SDNTT). ADRs were categorized according to the international terminology Medical Dictionary for Regulatory Activities (MedDRA). Safety was assessed by calculating event rates per 100 patient-years (PY). We used descriptive statistics for patient and disease characteristics, and binomial and t-tests to compare treatment groups and sex. RESULTS: In total, 791 patients (290 females) were included with a mean age of 46 years. 358 (45%) received CSTs and 433 (55%) biologics; both groups had similar baseline characteristics except for more joint involvement in patients using biologics (26.86% vs. 14.8%, p < 0.0001). CSTs were associated with a 2.2-fold higher ADR rate (40.43/100 PY vs. 18.22/100 PY, p < 0.0001) and an 8.0-fold higher drug-related discontinuation rate than biologics (0.16/PY vs. 0.02/PY, p < 0.0001). Trends showed non-significant higher serious adverse event rates per 100 PY for biologics (8.19, CI 6.87-9.68) compared to CSTs (7.08, CI 5.39-9.13) (p = 0.3922). Sex stratification revealed a significantly higher overall ADR rate for all treatments in females (1.8-fold for CSTs [57.30/100 PY vs. 31.69/100 PY] and 2.0-fold for biologics [27.36/100 PY vs. 13.9/100 PY], p < 0.0001), and drug-related discontinuation rates for most CSTs in females. CONCLUSION: Females were associated with a significantly higher rate of ADRs and drug-related discontinuation rates. Sex stratification should be taken into consideration when designing studies in the patient-tailored management of psoriasis.

Phase 3 Trial of Nemolizumab in Patients with Prurigo Nodularis.

BACKGROUND: Prurigo nodularis is a chronic, debilitating, and severely pruritic neuroimmunologic skin disease. Nemolizumab, an interleukin-31 receptor alpha antagonist, down-regulates key pathways in the pathogenesis of prurigo nodularis. METHODS: In this phase 3, double-blind, multicenter, randomized trial, we assigned adults with moderate-to-severe prurigo nodularis to receive an initial 60-mg dose of nemolizumab followed by subcutaneous injections of 30 mg or 60 mg (depending on baseline weight) every 4 weeks for 16 weeks or matching placebo. The primary end points were an itch response (a reduction of ≥4 points on the Peak Pruritus Numerical Rating Scale [PP-NRS; scores range from 0 to 10, with higher scores indicating more severe itch]) and an Investigator's Global Assessment (IGA) response (a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4] and a reduction from baseline to week 16 of ≥2 points). There were five key secondary end points. RESULTS: A total of 274 patients underwent randomization; 183 were assigned to the nemolizumab group, and 91 to the placebo group. Treatment efficacy was shown with respect to both primary end points at week 16; a greater percentage of patients in the nemolizumab group than in the placebo group had an itch response (56.3% vs. 20.9%; strata-adjusted difference, 37.4 percentage points; 95% confidence interval [CI], 26.3 to 48.5), and a greater percentage in the nemolizumab group had an IGA response (37.7% vs. 11.0%; strata-adjusted difference, 28.5 percentage points; 95% CI, 18.8 to 38.2) (P<0.001 for both comparisons). Benefits were observed for the five key secondary end points: itch response at week 4 (41.0% vs. 7.7%), PP-NRS score of less than 2 at week 4 (19.7% vs. 2.2%) and week 16 (35.0% vs. 7.7%), and an improvement of 4 or more points on the sleep disturbance numerical rating scale (range, 0 [no sleep loss] to 10 [unable to sleep at all]) at week 4 (37.2% vs. 9.9%) and week 16 (51.9% vs. 20.9%) (P<0.001 for all comparisons). The most common individual adverse events were headache (6.6% vs. 4.4%) and atopic dermatitis (5.5% vs. 0%). CONCLUSIONS: Nemolizumab monotherapy significantly reduced the signs and symptoms of prurigo nodularis. (Funded by Galderma; ClinicalTrials.gov number, NCT04501679; EudraCT number, 2019-004789-17.).

Differentiation of IL-26+ TH17 intermediates into IL-17A producers via epithelial crosstalk in psoriasis.

Interleukin (IL)-26 is a TH17 cytokine with known antimicrobial and pro-inflammatory functions. However, the precise role of IL-26 in the context of pathogenic TH17 responses is unknown. Here we identify a population of blood TH17 intermediates that produce high levels of IL-26 and differentiate into IL-17A-producing TH17 cells upon TGF-ß1 exposure. By combining single cell RNA sequencing, TCR sequencing and spatial transcriptomics we show that this process occurs in psoriatic skin. In fact, IL-26+ TH17 intermediates infiltrating psoriatic skin induce TGF-ß1 expression in basal keratinocytes and thereby promote their own differentiation into IL-17A-producing cells. Thus, our study identifies IL-26-producing cells as an early differentiation stage of TH17 cells that infiltrates psoriatic skin and controls its own maturation into IL17A-producing TH17 cells, via epithelial crosstalk involving paracrine production of TGF-ß1.

A severe case of neuroleukemiosis caused by B cell chronic lymphocytic leukemia, presenting as mononeuritis multiplex.

AIMS: To report an exceptional case of nerve infiltration by an otherwise benign chronic B cell leukemia, inducing severe mononeuritis multiplex. METHODS: The patient underwent extensive evaluation, including nerve conduction study and myography, brain and plexus MRI, and nerve biopsy. RESULTS: The clinical and electrophysiological diagnosis was a mononeuritis multiplex with severe motor and sensory involvement; only the nerve biopsy allowed definite diagnosis and introduction of chemotherapy, leading to resolution of sensory deficit and progressive motor improvement. DISCUSSION: Neuroleukemiosis caused by chronic lymphoid leukemia is an exceptional diagnosis. The presence of other possible causes like cryoglobulinemia could induce avoidance of nerve biopsy thus undertreating patient, since steroid treatment is not expected to be efficient on lymphocytic proliferation. Our case stretches the importance of nerve biopsy and raises neuromuscular specialist's awareness of this rare entity.

A plain language summary of what freedom from disease means to people with psoriasis according to doctors, nurses, and people with psoriasis.

What is this summary about? This summary presents findings from recent research involving people with psoriasis, based on an article originally published in the Journal of the European Academy of Dermatology and Venereology. Psoriasis is a condition that primarily affects the skin. However, it can also influence people's mental health, social activities, work, and relationships too. Current assessment tools used by doctors and nurses do not cover the complete experience of people with psoriasis, which often include other medical conditions and can leave these individuals feeling that treatment has not been successful. Researchers conducted a study in which people with psoriasis, doctors, and nurses were asked in virtual meetings and via questionnaires what freedom from disease in psoriasis means to them. What were the results? In addition to skin symptoms, the areas of mental health, well-being, treatment, and relationships with healthcare teams were found to be important aspects to be addressed. What do the results of the study mean? Focusing on all five aspects of freedom from disease will help people with psoriasis manage their psoriasis with confidence.

Safety and efficacy of bimekizumab through 2 years in patients with moderate-to-severe plaque psoriasis: longer-term results from the BE SURE randomized controlled trial and the open-label extension from the BE BRIGHT trial.

BACKGROUND: BE SURE 1-year results demonstrated the superior efficacy of bimekizumab compared with adalimumab with no unexpected safety findings. OBJECTIVES: To provide efficacy and safety data over 2 years of bimekizumab treatment compared with adalimumab from BE SURE and the BE BRIGHT open-label extension (OLE) in patients with moderate-to-severe plaque psoriasis. METHODS: The 56-week double-blinded BE SURE phase III randomized controlled trial randomized patients 1 : 1 : 1 to bimekizumab 320 mg every 4 weeks (Q4W), bimekizumab 320 mg Q4W to week 16 then every 8 weeks (Q8W), or adalimumab 40 mg every 2 weeks to week 24 then bimekizumab 320 mg Q4W. After completing BE SURE, patients could enter the ongoing BE BRIGHT OLE, with possible dosing adjustments based on Psoriasis Area and Severity Index (PASI). The primary outcome in BE BRIGHT was incidence of treatment-emergent adverse events (TEAEs); safety data are reported by study period through week 104. Efficacy data are reported for the intention-to-treat population through week 104 by initial randomization group, with ≥ 90% improvement from baseline PASI (PASI 90) and 100% improvement (PASI 100) as key outcomes. RESULTS: Of the patients randomized to bimekizumab, 158 were assigned to Q4W, and 161 to Q4W/Q8W. At week 104, PASI 90 was achieved by 91.2% and 89.7%, and PASI 100 was achieved by 72.3% and 68.1%, for Q4W and Q4W/Q8W, respectively; comparable to week 16 results. Among the 159 patients randomized to adalimumab, responses rapidly and substantially increased after the week 24 bimekizumab switch; at week 104, 96.9% and 70.2% of patients achieved PASI 90 and PASI 100 respectively. Through weeks 24-104, the three most common TEAEs in any bimekizumab-treated group were nasopharyngitis, oral candidiasis and upper respiratory tract infection. Rates of serious TEAEs were low. CONCLUSIONS: Clinical responses observed through week 16 of BE SURE in patients randomized to bimekizumab were sustained through 104 weeks of treatment, regardless of Q4W or Q8W maintenance dosing. Response rates were also sustained through week 104 in patients who switched from adalimumab to bimekizumab at week 24, and were similar to those observed in the bimekizumab groups. Bimekizumab was well tolerated with no new safety signals.

Secukinumab demonstrates superiority over narrow-band ultraviolet B phototherapy in new-onset moderate to severe plaque psoriasis patients: Week 52 results from the STEPIn study.

BACKGROUND: Biologic treatments have been studied mainly in patients with a long-term history of psoriasis and previous treatment failures. OBJECTIVES: The purpose of this primary analysis of the STEPIn study is to determine whether early intervention with secukinumab in patients with new-onset moderate to severe plaque psoriasis is superior to standard of care treatment with narrow band ultraviolet B (nb-UVB) phototherapy. METHODS: The STEPIn study is a randomized, open-label, multicentre study to investigate early intervention with 52 weeks of secukinumab 300 mg administered subcutaneously versus standard treatment with nb-UVB phototherapy in patients with new-onset (≤12 months) moderate to severe plaque psoriasis (NCT03020199). The primary and additional secondary endpoints were ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) at Week 52 and Investigator's Global Assessment (IGA mod 2011) 0/1 response at Week 52, respectively. RESULTS: In the secukinumab and nb-UVB study arms, 77/80 and 76/80 randomized patients received at least one dose of study treatment, respectively. The primary endpoint was achieved: 91.1% (70/77) of patients achieved a PASI 90 response at Week 52 in the secukinumab arm versus 42.3% (32/76) in the nb-UVB arm (p < 0.0001, odds ratio [OR] estimate [95% confidence intervals, CI] = 16.3 [5.6, 46.9]). The additional secondary endpoint was also achieved: 85.7% of patients achieved an IGA 0/1 response at Week 52 in the secukinumab arm versus 36.8% in the nb-UVB arm (p < 0.0001). The safety data were consistent with the safety profiles of secukinumab and nb-UVB with no new or unexpected safety signals. CONCLUSIONS: Secukinumab was superior to nb-UVB in treating patients with new-onset moderate to severe plaque psoriasis. The high and sustained skin clearance observed indicates that biologic treatment for psoriasis may be more effective if used early in the disease course.