Review of ustekinumab, an interleukin-12 and interleukin-23 inhibitor used for the treatment of plaque psoriasis

The pathogenesis of psoriasis is unknown, although it is generally accepted that this chronic inflammatory skin disorder is a complex autoimmune condition similar to other T-cell mediated disorders. Psoriasis imposes a heavy burden on the lifestyle of those affected due to the psychological, arthritic, and cutaneous morbidities; thus significant research has focused on the genetic and immunologic features of psoriasis in anticipation of more targeted, efficacious, and safe therapies. Recently, CD4+ T helper (Th) 17 cells and interleukins (IL)-12 and -23 have been important in the pathogenesis of T-cell mediated disorders such as psoriasis and has influenced the development of medications that specifically target these key immunological players. Ustekinumab is a monoclonal antibody belonging to a newly developed class of biological, anti-cytokine medications that notably targets the p40 subunit of both IL-12 and -23, both naturally occurring proteins that are important in regulating the immune system and are understood to play a role in immune-mediated inflammatory disorders. Ustekinumab’s safety and efficacy has been evaluated for the treatment of moderate-to-severe plaque psoriasis in 3 phase III clinical trials, 2 placebo-controlled (PHOENIX 1 and 2), and 1 comparator-controlled (ACCEPT) study which proved advantageous in patients who were treatment-naive, previously failed other immunosuppressive medications including cyclosporine or methotrexate, were unresponsive to phototherapy, or were unable to use or tolerate other therapies. Ustekinumab has also been investigated for other indications such as psoriatic arthritis, Crohn’s disease, and relapsing/remitting multiple sclerosis. We present a concise review evaluating the evidence that supports the use of ustekinumab in the treatment of plaque psoriasis and other conditions

Fixed-Combination Halobetasol Propionate and Tazarotene in the Treatment of Psoriasis: Narrative Review of Mechanisms of Action and Therapeutic Benefits

Psoriasis is a lifelong disease associated with cycles of remission and relapse. Topical treatments are the front line of psoriasis therapy for most patients and have antiproliferative, anti-inflammatory, and immunosuppressive mechanisms of action. Novel fixed-dose combinations of topical therapeutic agents are becoming increasingly available, leveraging multiple mechanisms of action to improve safety and efficacy with formulations that are easier to use and may allow for the use of lower doses of active ingredients. A fixed-combination lotion containing the potent-to-super-potent corticosteroid halobetasol propionate (HP) and the retinoid tazarotene (HP 0.01%/TAZ 0.045%) was recently developed using polymeric emulsion technology. This new formulation technology allows for more uniform and efficient delivery of the active ingredients at lower doses than conventional monotherapy formulations of either ingredient while providing enhanced hydration and moisturization. This review provides an up-to-date overview of the therapeutic mechanisms of action of HP and TAZ, the rationale behind the development of HP 0.01%/TAZ 0.045% lotion, and clinical trials data on the efficacy, safety and tolerability, and maintenance of therapeutic effect with HP 0.01%/TAZ 0.045% lotion in the treatment of moderate-to-severe plaque psoriasis

Difelikefalin suppresses itch and reduces scratching independent of inflammation in a murine model of atopic dermatitis

BACKGROUND: Therapies specifically targeting nonhistaminergic pruritus are largely lacking. Difelikefalin (DFK) has been found to reduce itch in various chronic pruritic conditions, including atopic dermatitis (AD). OBJECTIVE: We sought to investigate the ability of DFK to impact scratching behavior, inflammatory mediators, and neuronal signaling in a murine model of AD. METHODS: The ears of C57BL/6 mice were topically treated with MC903 for 12 consecutive days to induce AD-like inflammation and itch. Before MC903 treatment, mice were treated with either DFK (0.5 mg/kg, intraperitoneal injection twice daily) or vehicle (saline). Skin ear thickness, histological analysis, flow cytometry, RNA-sequencing, and differential gene expression analyses of mouse ear skin were used to examine the effect of DFK on skin inflammation. Scratching behavior was quantified to measure itch behavior in mice that were topically treated with MC903 for 6 consecutive days; then, mice received a single injection of either DFK (1.0 mg/kg, intraperitoneal injection) or saline. Calcium imaging and single-cell RNA-sequencing were used in mouse dorsal root ganglia neurons to determine the size of the neurons activated with DFK treatment. Statistical significance was determined by Mann-Whitney test, unless otherwise noted. RESULTS: DFK rapidly suppressed itch without altering AD-like skin inflammation in MC903 (calcipotriol)-treated mice. In vitro Ca CONCLUSIONS: These studies support a potential neuromodulatory role of DFK for reducing itch associated with AD in mice

Efficacy of ruxolitinib cream in vitiligo by patient characteristics and affected body areas: Descriptive subgroup analyses from a phase 2, randomized, double-blind trial

To the Editor: Vitiligo is a chronic autoimmune disease resulting in patches of depigmented skin and reduced quality of life. In a randomized, dose-ranging phase 2 study (NCT03099304) in 157 adult patients, the Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib cream produced substantial repigmentation of facial and total body vitiligo lesions after 24 weeks, with continued improvement through week 52, and was well tolerated.3 Here, we present treatment response subanalyses from the phase 2 trial

Rapid and sustained improvements in Generalized Pustular Psoriasis Physician Global Assessment scores with spesolimab for treatment of generalized pustular psoriasis flares in the randomized, placebo-controlled Effisayil 1 study

BACKGROUND: Effisayil 1 was a randomized, placebo-controlled study of spesolimab, which is an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis flare. OBJECTIVE: To assess the effects of spesolimab over the 12-week study. METHODS: The primary endpoint of the study was Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 at week 1. Patients (N = 53) were randomized (2:1) to receive a single intravenous dose of 900 mg spesolimab or placebo on day 1. Patients could receive open-label spesolimab for persistent flare symptoms on day 8. RESULTS: Most patients receiving spesolimab achieved a GPPGA pustulation subscore of 0 (60.0%) and GPPGA total score of 0 or 1 (60.0%) by week 12. In patients randomized to placebo who received open-label spesolimab on day 8, the proportion with GPPGA pustulation subscore of 0 increased from 5.6% at day 8 to 83.3% at week 2. No factors predictive of spesolimab response were identified in patient demographics or clinical characteristics. LIMITATIONS: The effect of initial randomization was not determined conventionally beyond week 1 due to patients receiving open-label spesolimab. CONCLUSION: Rapid control of generalized pustular psoriasis flare symptoms with spesolimab was sustained over 12 weeks, further supporting its potential use as a therapeutic option for patients

Evolution of Patient Perceptions of Psoriatic Disease : Results from the Understanding Psoriatic Disease Leveraging Insights for Treatment (UPLIFT) Survey

Since the 2012 Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) survey, several systemic treatments for psoriasis (PsO) and/or psoriatic arthritis (PsA) have been approved. The population-based UPLIFT survey was conducted to understand how perceptions of treatment-related outcomes have evolved, particularly for patients with mild to moderate PsO and/or PsA and their dermatologists. This population- and web-based survey was conducted from 2 March to 3 June 2020, in North America, Europe, and Japan. Adults with self-reported healthcare practitioner (HCP)-diagnosed PsO and/or PsA and dermatologists who spent > 50% of time treating patients and treated ≥ 20 patients with PsO, including plaque PsO, per month were included. Patient participants were recruited at random from online panels; dermatologists were recruited randomly from representative physician panels. Of 264,054 patient responses, 3806 who self-reported an HCP diagnosis of PsO and/or PsA were included in the final sample; 67% had PsO alone, 28% had PsO and PsA, and 5% had PsA alone. The estimated population prevalence of psoriatic disease was 7% (PsO only: 4%; PsO and PsA: 2%; PsA only: 1%). Most patients (78%) reported PsO-involved body surface area (BSA) ≤ 3 palms, and ~ 90% or more reported itching, redness, flaking, and scales. Many PsO patients without diagnosed PsA reported musculoskeletal symptoms suggestive of PsA (63%). Across BSA categories, approximately one in four patients was not currently receiving treatment and > 50% had Dermatology Life Quality Index score > 5. Patients and dermatologists had different perceptions of PsO severity, office visit discussions, treatment goals, and treatment satisfaction. The survey was conducted during the coronavirus disease 2019 (COVID-19) pandemic, which could have affected assessments of patient-reported outcomes and ability to have in-person HCP visits. Patients with PsO and PsA in UPLIFT reported high disease burden, including patients with limited skin involvement. An opportunity exists to align patient and dermatologist perceptions to optimize management of PsO and PsA. The online version contains supplementary material available at 10.1007/s13555-021-00635-4. The online version contains supplementary material available at 10.1007/s13555-021-00635-4

27874 Correlation of itch response to roflumilast cream with disease severity and patient-reported outcomes in patients with chronic plaque psoriasis

Roflumilast cream is a nonsteroidal, selective phosphodiesterase-4 inhibitor in development for plaque psoriasis (PsO). A Phase 2b, double-blinded trial randomized adults with PsO (2-20% body surface area) to once daily roflumilast 0.3%, roflumilast 0.15%, or vehicle for 12 weeks (NCT03638258). Throughout the trial, itch and its impact were evaluated via patient reported outcomes (PROs): Worst Itch Numeric Rating Scale (WI–NRS), Itch related Sleep Loss (IRSL), and Dermatology Life Quality Index (DLQI). This posthoc analysis reports correlation of WI–NRS with other PROs and with disease severity. Overall, 331 patients were randomized (109 to roflumilast 0.3%, 113 to 0.15%, and 109 to vehicle). At baseline, the mean WI–NRS score was 5.87. Throughout the trial, both roflumilast doses showed similar improvements in WI–NRS starting at Week 2 and were significantly superior to vehicle (P ≤.002). At baseline, Pearson correlation coefficients (PCCs) for WI–NRS and Psoriasis Area and Severity Index (PASI) were 0.189, 0.282, 0.205 for roflumilast 0.3%, roflumilast 0.15%, and vehicle, respectively (P ≤.033 for all correlations); for WI–NRS and IRSL: 0.548, 0.646, 0.652 (P ˂.001); for WI–NRS and DLQI: 0.445, 0.617, 0.422 (P ˂.001). At Week 8, PCCs for WI–NRS and PASI were 0.420, 0.409, 0.365 (P ˂.001); for WI–NRS and IRSL: 0.673, 0.725, 0.696 (P ˂.001); for WI–NRS and DLQI: 0.607, 0.823, 0.529. Treatment with roflumilast resulted in rapid and robust improvement in the severity of itch associated with PsO. Itch response to roflumilast was independent of disease severity and positively correlated with patient-reported sleep loss and quality of life improvement

28043 Roflumilast cream significantly improves chronic plaque psoriasis in patients with steroid-sensitive area involvement

Roflumilast cream is a nonsteroidal, selective phosphodiesterase-4 inhibitor in development for plaque psoriasis (PsO). A double-blind, phase 2b trial randomized adults with PsO to once daily roflumilast 0.3%, 0.15%, or vehicle for 12 weeks (NCT03638258).(1) Efficacy was assessed using Investigator Global Assessment (IGA), Worst Itch Numeric Rating Scale (WI–NRS), and Psoriasis Symptom Diary (PSD). This posthoc analysis reports efficacy and safety in patients with steroid-sensitive area involvement (plaques on the face, neck, or in intertriginous areas). Of 331 patients, 160 had steroid-sensitive area involvement. The primary endpoint in the study, IGA status clear/almost clear at Week 6 was met by 27.2% patients with steroid sensitive areas (P =.007 vs vehicle), 22.3% (P =.026), and 6.3% on roflumilast 0.3%, roflumilast 0.15%, and vehicle, respectively; relative to 30.1% (P =.026), 24.1% (P =.098), and 12.0% patients without steroid-sensitive areas. Among patients with baseline WI–NRS score ≥4, 73.5%, 55.6%, and 32.6% of those with steroid-sensitive areas and 45.9%, 72.7%, and 23.7% of those without steroid-sensitive areas achieved a 4-point reduction with roflumilast 0.3%, 0.15%, or vehicle at Week 12. PSD improvement from baseline at Week 12 for patients with steroid-sensitive areas was -48.3 (P ˂.001), -43.1 (P =.012), and -24.9, and for patients without steroid-sensitive areas -35.7 (P =.003), -44.6 (P ˂.001), and -17.1. Most treatment emergent adverse events were mild to moderate and there was no evidence of local irritation. Once-daily roflumilast cream was well tolerated with significant improvements in investigator and patient assessed PsO outcomes in patients with steroid-sensitive area involvement on the face, neck, or intertriginous areas