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BACKGROUND: Efficacy and/or safety profiles limit topical psoriasis treatments. OBJECTIVE: Evaluate long-term effects of once-daily roflumilast cream 0.3% in patients with psoriasis. METHODS: In this open-label phase 2 trial, adult patients (N = 332) with psoriasis who completed the phase 2b parent trial or were newly enrolled applied roflumilast once-daily for 52 weeks. Safety and effectiveness were assessed. RESULTS: Overall, 244 patients (73.5%) completed the trial; 13 patients (3.9%) discontinued due to adverse events (AEs) and 3 (0.9%) due to lack of efficacy. Twelve patients (3.6%) reported treatment-related AEs; none were serious. ≥97% of patients had no irritation. No tachyphylaxis was observed with 44.8% of the patients achieving Investigator Global Assessment (IGA) Clear or Almost Clear at Week 52. LIMITATIONS: Intertriginous-IGA and Psoriasis Area and Severity Index (PASI) were not evaluated in all patients. CONCLUSIONS: In this long-term trial, once-daily roflumilast cream was well-tolerated and efficacious up to 64 weeks in patients in the earlier trial, suggesting it is suitable for chronic treatment, including the face and intertriginous areas.
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Aminopiridinas , Benzamidas , Ciclopropanos , Inhibidores de Fosfodiesterasa 4 , Psoriasis , Índice de Severidad de la Enfermedad , Crema para la Piel , Humanos , Ciclopropanos/administración & dosificación , Ciclopropanos/efectos adversos , Ciclopropanos/uso terapéutico , Psoriasis/tratamiento farmacológico , Aminopiridinas/administración & dosificación , Aminopiridinas/efectos adversos , Benzamidas/efectos adversos , Benzamidas/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Adulto , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Inhibidores de Fosfodiesterasa 4/efectos adversos , Resultado del Tratamiento , Crema para la Piel/administración & dosificación , Crema para la Piel/efectos adversos , Enfermedad Crónica , Anciano , Esquema de Medicación , Factores de Tiempo , Adulto JovenRESUMEN
Cytokines in the interleukin (IL)-23/IL-17 axis are central to psoriasis pathogenesis. Janus kinase (JAK) signal transducer and activator of transcription (STAT) regulates intracellular signalling of several cytokines (including IL-12, 23, 22, 6, 17, and interferon (IFN)-γ) in the IL-23/IL-17 axis, and, as a result, has become a therapeutic target for psoriasis treatment. Although several JAK1-3 inhibitors, with varying degrees of selectivity, have been developed for immune-mediated inflammatory diseases, use in psoriasis is limited by a low therapeutic index as anticipated by signals from other disease indications. More selective inhibition of the JAK family is an area of interest. Specifically, selective tyrosine kinase (TYK)2 inhibition suppresses IL-23/IL-17 axis signalling, and at therapeutic doses, has a favorable safety profile compared to therapeutic doses of JAK1-3 inhibitors. Phase III efficacy and safety data for the selective allosteric TYK2-inhibitor, deucravacitinib, in adult patients with moderate-to-severe plaque psoriasis is promising. Furthermore, phase II clinical trials for ropsacitinib (PF-06826647), a selective TYK2 inhibitor, and brepocitinib (PF-06700841), a JAK1/TYK2 inhibitor, have also demonstrated efficacy and an acceptable safety profile in adult patients with moderate-to-severe plaque psoriasis. Other novel TYK2 allosteric inhibitors, NDI-034858 and ESK-001, are currently being investigated in adult patients with plaque psoriasis. This article reviews the details of the JAK-STAT pathway in psoriasis pathophysiology, the rationale for selective targeting of JAKs in the treatment of psoriasis, and provides clinical perspective on clinical trial data for JAK and TYK2 inhibitors.
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Inhibidores de las Cinasas Janus , Psoriasis , Adulto , Humanos , Quinasas Janus/metabolismo , Quinasas Janus/uso terapéutico , Interleucina-17/metabolismo , Transducción de Señal , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/uso terapéutico , TYK2 Quinasa/metabolismo , TYK2 Quinasa/uso terapéutico , Psoriasis/patología , Interleucina-23 , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/uso terapéuticoRESUMEN
BACKGROUND: Atopic dermatitis is a common skin disorder for which there remains an unmet need for topical pharmacotherapies that are safe and effective. This phase 2 study assessed the efficacy and safety of 3 dosages of PUR 0110 (Thykamine; Devonian Health Group Inc.) cream (0.05%, 0.1%, and 0.25%) compared to vehicle for treatment of adults with mild to moderate atopic dermatitis. The primary efficacy endpoint was the proportion of patients with an Investigator’s Global Assessment (IGA) of clear/almost clear and with a decrease from baseline score of at least 2 grades at day 29. Key secondary efficacy endpoints included change from baseline to day 29 in IGA, percent body surface area (%BSA) affected, Eczema Area and Severity Index (EASI) score, pruritus, and quality of life. Safety outcomes included the incidence of local and systemic adverse events. The primary efficacy endpoint was met with PUR 0110 cream 0.10% compared to vehicle (30.8% vs 6.7%, respectively, P=.014). Most secondary endpoints also favored PUR 0110 cream 0.10% vs vehicle, including change from baseline to day 29 in IGA score, %BSA affected, pruritus, and patient-reported quality of life. Adverse events occurred at a similar rate in all treatment groups; most were mild to moderate in intensity and were infrequently associated with study withdrawal. PUR 0110 cream 0.10% demonstrated rapid improvement in signs and symptoms of atopic dermatitis. This observation, along with its favorable safety and tolerability profile, could make it a useful therapeutic option for the treatment of atopic dermatitis. J Drugs Dermatol. 2022;21(10):1091-1097. doi:10.36849/JDD.6729.
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Dermatitis Atópica , Emolientes , Adulto , Dermatitis Atópica/tratamiento farmacológico , Emolientes/efectos adversos , Humanos , Inmunoglobulina A/uso terapéutico , Prurito/etiología , Calidad de Vida , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
INTRODUCTION: Receptor-interacting protein kinase 1 (RIPK1), a key mediator of inflammation through necroptosis and proinflammatory cytokine production, may play a role in the pathogenesis of immune-mediated inflammatory diseases such as chronic plaque psoriasis. An experimental medicine study of RIPK1 inhibition with GSK2982772 immediate-release formulation at doses up to 60 mg three times daily in mild to moderate plaque psoriasis indicated that efficacy may be improved with higher trough concentrations of GSK2982772. METHODS: This multicenter, randomized, double-blind, placebo-controlled, repeat-dose study (NCT04316585) assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of 960 mg GSK2982772 (once-daily modified-release formulation) in patients with moderate to severe plaque psoriasis. Twenty-nine patients were randomized 2:1 to GSK2982772 (N = 19) or placebo (N = 10) for 12 weeks. RESULTS: GSK2982772 was well tolerated with trough concentrations greater than tenfold higher than the previous phase 1 study with immediate release. Despite near complete RIPK1 target engagement in blood and modest reduction in circulating inflammatory cytokines, the proportion of patients achieving 75% improvement from baseline in Psoriasis Area Severity Index score at week 12 was similar between GSK2982772 and placebo (posterior median 1.8% vs 4.9%, respectively), with an estimated median treatment difference of - 2.3%. This analysis incorporated historical placebo data through the use of an informative prior distribution on the placebo arm. Week 4 changes in skin biopsy gene expression suggested sufficient local drug exposure to elicit a pharmacodynamic response. CONCLUSION: Administration of the RIPK1 inhibitor GSK2982772 to patients with moderate to severe plaque psoriasis did not translate into meaningful clinical improvements.
Psoriasis is thought to be caused by problems with the immune system, including possibly receptor-interacting protein kinase 1 (RIPK1), which plays an important role in the development of inflammation. A previous study suggested that the drug, GSK2982772, which interferes with RIPK1, might improve symptoms in patients with psoriasis. This study examined whether higher doses of GSK2982772 than previously studied would be beneficial for patients with psoriasis. The study found that the severity of psoriasis was similar in patients treated with GSK2982772 for 12 weeks as in those who did not receive the drug, indicating that GSK298772 did not improve psoriasis.
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Background: Prurigo nodularis is a chronic skin disease characterised by intensely pruritic, hyperkeratotic nodules. Vixarelimab, a human monoclonal antibody, binds to the beta subunit of the oncostatin M receptor, inhibiting signalling of both interleukin 31 and oncostatin M, two cytokine pathways that contribute to pruritus and nodule formation in prurigo nodularis. Methods: This double-blind, placebo-controlled, phase 2a trial was done at both private and academic dermatology outpatient research clinics across the United States and Canada (n = 40). Patient eligibility criteria included age 18-75 years, physician-documented diagnosis of prurigo nodularis minimum 6 months duration of prurigo nodularis, presence of at least 10 pruritic nodules approximately 0.5-2 cm in size on at least two different anatomical locations (excluding face and scalp) and involving the extremities, and presence of normal-appearing skin between nodules; atopic dermatitis as a comorbidity was exclusionary. Patients were required to have moderate-to-severe pruritus, defined as Worst Itch-Numeric Rating Scale (WI-NRS) score ≥7 at screening and LS-mean weekly WI-NRS score ≥5 for each of the 2 consecutive weeks immediately before randomisation. Participants were randomly assigned (1:1) to receive weekly subcutaneous vixarelimab 360 mg (720 mg loading dose) or placebo using stratification factors (sex and presence of atopy) and block size 4 through the IWRS system. Stratification by atopy status was based on the reported high prevalence of atopy in this population and the potential impact of atopy in the immunopathologic process in prurigo nodularis. Patients, investigators, study sponsor, and site staff were masked to study treatment. The primary efficacy endpoint was least squares (LS)-mean percent change from baseline (PCFB) at Week 8 in weekly average Worst Itch-Numeric Rating Scale (WI-NRS) score. The primary efficacy endpoint was analysed with ANCOVA including treatment as fixed effect, with baseline WI-NRS, and randomisation stratification factor as covariates. All randomised patients who had at least 1 dose of study drug or placebo were included in the Safety Analysis Set. This trial is registered at ClinicalTrials.gov, NCT03816891. Findings: Of 50 patients randomised between March 11, 2019 and January 31, 2020, 23 vixarelimab recipients and 26 placebo recipients comprised the modified intent-to-treat analysis population (baseline LS-mean [SD] WI-NRS score, 8.3 [1.05]). Outcomes at Week 8 for vixarelimab versus placebo included LS-mean PCFB in WI-NRS score, -50.6% versus -29.4% (LS-mean difference [95% CI], -21.2% [-40.82, -1.60]; p = 0.03); ≥4-point reduction in WI-NRS score, 52.2% (12/23) versus 30.8% (8/26) (p = 0.11); PN-IGA score of 0 or 1, 30.4% (7/23) versus 7.7% (2/26) (p = 0.03); LS-mean PCFB in pruritus VAS score, -54.4% versus -32.6% (p = 0.03); and LS-mean PCFB sleep loss reduction (improvement), -56.3% versus -30.0% (p = 0.02). No deaths, serious TEAEs, or TEAEs leading to dose interruption were reported. The percentage of vixarelimab recipients reporting any TEAE was 91.3% (21/23) versus 76.9% (20/26) of placebo recipients; drug-related TEAEs generally were similar between the two groups (vixarelimab, 43.5% [10/23]; placebo, 38.5% [10/26]). Interpretation: Vixarelimab demonstrated rapid reduction of pruritus and achievement of clear/almost clear skin in one-third of the patients by Week 8. Relief of itch and clearing of skin nodules represent two important potential therapeutic advances in the management of patients suffering from the debilitating disease Prurigo Nodularis. Funding: Kiniksa Pharmaceuticals, Ltd.
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Senescence of the skin immunological system may explain why the elderly population has an increased susceptibility to certain autoimmune skin disorders. These disorders are characterised by the production of either antibodies that react with host tissue or immune effector T cells that are autoreactive. Bullous pemphigoid is the most common autoimmune blistering disease in the elderly. Although oral corticosteroids are the best established therapy, high-potency topical corticosteroids are very useful as initial treatment and, in the elderly, should be used instead of oral prednisolone wherever possible. Pemphigus is a chronic blistering disease of which there are two main subtypes: vulgaris and foliaceous. Paraneoplastic pemphigus is a unique clinical, histological and immunologically distinct autoimmune mucocutaneous disease which tends to be relentlessly progressive. Lichen sclerosus presents specific complications and a small but definite increased risk of squamous cell carcinoma in elderly patients. It is important to be aware of practical issues such as the difficulty in applying topical corticosteroids, the mainstay treatment of this condition. Dermatomyositis is an autoimmune systemic disorder where the skin and muscles are the most commonly affected organs. Tumour-associated disease occurs more commonly in elderly patients and has a poorer prognosis. Management of the disease includes sunscreens, topical or systemic corticosteroids, antimalarials, oral immunosuppressants or intravenous immunoglobulins. It is important to bear in mind that old age modifies the management of skin diseases because of physical and social circumstances as well as the unwanted adverse effects of medications. Polypharmacy results in an increased risk of drug interactions and, therefore, drug regimens need to be kept as simple as possible. Drug-induced autoimmune skin eruptions are common amongst the elderly and usually resolve when the offending drug is discontinued.
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Corticoesteroides/uso terapéutico , Enfermedades Autoinmunes , Dermatomiositis/fisiopatología , Eritema/inducido químicamente , Liquen Escleroso y Atrófico/patología , Penfigoide Ampolloso/tratamiento farmacológico , Pénfigo/tratamiento farmacológico , Anciano , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/fisiopatología , Eritema/inmunología , Femenino , Geriatría , Humanos , Liquen Escleroso y Atrófico/inmunología , Masculino , Persona de Mediana Edad , Penfigoide Ampolloso/inmunología , Pénfigo/inmunología , Pénfigo/patologíaRESUMEN
Modernisation has brought down outpatient waits and did-not-attends at Addenbrooke Hospital's dermatology department. A 360-degree review of services has led to continuous service Improvement. GPs and hospital nurses have received specialist training, freeing up consultant time and enabling more consultants to be seen.
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Dermatología/organización & administración , Departamentos de Hospitales/normas , Hospitales Públicos/normas , Cambio Social , Departamentos de Hospitales/estadística & datos numéricos , Hospitales Públicos/estadística & datos numéricos , Humanos , Satisfacción del Paciente , Gestión de la Calidad Total , Reino Unido , Listas de EsperaRESUMEN
BACKGROUND: Psoriasis and vitiligo are both autoimmune diseases with an increased incidence noted in genetic relatives. They share similar trigger factors and have been observed to coexist in individuals. OBJECTIVE: The purpose was to review the literature on the coexistence of psoriasis and vitiligo and to determine if there is a higher than expected prevalence of psoriasis in patients with vitiligo and vice versa. METHODS: A literature review was conducted using Medline, EMBASE, and the Cochrane Library from 1968 to 2010. All articles that included reports of individuals with both psoriasis and vitiligo in the English language were documented. RESULTS: We identified 338 articles, among which 35 case reports and 7 case series were mentioned. For each case series, the prevalence of psoriasis in patients with vitiligo, or vice versa, falls within the prevalence range of the background population on which the study was based. CONCLUSION: An increase in the expected prevalence of psoriasis in individuals with vitiligo, or vice versa, was not found in our study, suggesting that the coexistence of the two diseases appears to be due to chance alone. Large epidemiologic studies are required to address with certainty whether psoriasis is more common in individuals with vitiligo and vice versa.