Brodalumab Versus Guselkumab in Patients with Moderate-to-Severe Psoriasis with an Inadequate Response to Ustekinumab: A Randomized, Multicenter, Double-Blind Phase 4 Trial (COBRA).

INTRODUCTION: Despite improved treatment options for plaque psoriasis within the last decades, some patients still have an inadequate response to treatment. Direct clinical evaluation between therapies used after biologic failure could facilitate physicians' choice of treatment. METHODS: COBRA (NCT04533737) was a randomized (1:1), blinded (patient and assessor), 28-week, active-comparator trial conducted in Europe from December 2020 to December 2022. The objective was to compare the efficacy and safety of brodalumab versus guselkumab in adults with moderate-to-severe plaque psoriasis and inadequate response to ustekinumab. Patients received either brodalumab 210 mg or guselkumab 100 mg. The primary [having Psoriasis Area and Severity Index (PASI)-100 response at week 16] and key secondary (time to PASI-100 response) endpoints were tested in a fixed sequence. RESULTS: Due to delays and enrollment challenges, recruitment was terminated with 113 patients enrolled of 240 planned. The proportion of patients having PASI-100 at week 16 for brodalumab was 53.4% compared with 35.9% for guselkumab [odds ratio (OR) 2.05; 95% confidence interval (CI) 0.95, 4.44; p = 0.069]. As this was not statistically significant, the hierarchical testing procedure was stopped. All other secondary PASI endpoints had nominal p-values below 0.05 in favor of brodalumab. In the time to PASI response analyses, brodalumab separated from guselkumab in estimated cumulative incidence of patients achieving a response from week 2 onward, suggesting fast onset of action with brodalumab. Quality of life measures improved in both treatment groups. The safety findings were consistent with the known safety profiles. CONCLUSIONS: Brodalumab showed a tendency toward better and earlier effect than guselkumab in patients who had failed ustekinumab. Thus, this trial provides important information in assisting physicians in their choice of therapy for patients who have failed their prior anti-interleukin (IL)-12/23 treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04533737.

[Aspects of sustainability of topical therapy]. / Aspekte der Nachhaltigkeit in der topischen Therapie.

BACKGROUND: Topical compounds are an important treatment option in dermatology. Many ingredients and packaging do not yet sufficiently fulfill sustainable criteria. OBJECTIVES: This article aims to provide a compact overview of sustainability criteria of topical compounds and packaging. MATERIALS AND METHODS: Based on a selective literature search and personal experience, common ingredients and packaging of topical preparations are summarized. RESULTS: Topical preparations often contain mineral oils, acrylates, silicones and polyethylene glycols (PEG), which show poor biodegradability and may accumulate in the environment. As an alternative to these non-renewable substances, plant-based fats, oils, and waxes can be used. Biopolymers such as plant-based gum, agar-agar, pectin, and biologically produced hyaluronic acid are an alternative to plastic polymers. The environmental footprint of glass as packaging material is overestimated. Currently, plastics and aluminum may be preferable when recycled correctly. CONCLUSION: The production of topical formulations without using mineral oils, silicones, acrylates, and PEGs is technically challenging. A sustainable packaging material that fulfills all relevant functionalities is not yet available. Packaging should meet high requirements regarding ecological, economic, and social factors. Better performance with respect to new opportunities in recycling and waste management should be incorporated. Overall, the legislative authorities should provide relevant incentives for more sustainable topical compounds and packaging.

Anti-Psoriatic Effects of Antimony Compounds In Vitro.

Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation of keratinocytes and a pro-inflammatory milieu in the skin. While patients with moderate to severe psoriasis are treated using targeted therapies (small molecules and monoclonal antibodies), patients suffering from milder forms are still in need of effective topical products without adverse effects. Antimony compounds (ACs) are regularly used as anti-inflammatory compounds in traditional and anthroposophic medicine and as antiprotozoan drugs. Here, we examined the effect of metallic antimony, natural antimony(III) sulfide and potassium antimonyl(III) tartrate in vitro on psoriasis-like keratinocytes and the human dendritic cell line THP-1 using qPCR, immunocytochemistry, ELISA and flow cytometry. In psoriatic keratinocytes, ACs inhibited the overexpression of the antimicrobial peptide ß-defensin 2 and glucose transporter 1, as well as the hyperproliferation marker keratin 17. Furthermore, ACs mediated anti-inflammatory effects by reducing nuclear translocation of the p65 subunit of NF-κB and pSTAT3 and inhibited pro-inflammatory cytokine secretion by keratinocytes. In addition, ACs displayed anti-psoriatic effects by reducing the activation of IFN-α-treated THP-1 cells as well as the expression of the psoriasis-promoting master cytokine IL-23 by these cells. While all ACs showed anti-psoriatic effects, the most prominent results were seen with potassium antimonyl(III) tartrate. In summary, ACs display numerous anti-psoriatic effects in vitro at subtoxic concentrations. We conclude that ACs are interesting compounds for the topical treatment of psoriasis that warrant further investigation in clinical studies.

The Effect of Herbal Medicinal Products on Psoriasis-Like Keratinocytes.

Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation of keratinocytes and expression of pro-inflammatory cytokines in the epidermis. New biological drugs were developed for the systemic treatment of moderate to severe psoriasis. However, products for the topical treatment of mild psoriasis are still required. Here, we examined the effect of natural compounds on psoriasis-like keratinocytes in vitro and ex vivo. Psoriasis-like keratinocytes were generated by treating human primary keratinocytes with the psoriasis-associated cytokines IL-17A, TNF-α and IL-22. Initially, 10 botanical extracts from Ayurvedic Medicine, Traditional Chinese Medicine, Northern American traditional medicine and Occidental Monastic Medicine were investigated using BrdU assays and IL-6 and IL-8 ELISAs. Curcuma amada, Humulus lupulus and Hypericum perforatum turned out to be the most effective plant extracts. In vitro, the plant extracts inhibited the expression of anti-microbial peptides (ß-defensin 2), the hyperproliferation marker keratin 17, the glucose transporter 1 and downregulated the nuclear translocation of NF-κB and pSTAT3. In an ex vivo psoriasis model, Humulus lupulus displayed the most prominent anti-proliferative and anti-inflammatory effect. In conclusion, among the plant extracts investigated, Humulus lupulus showed the most promising anti-psoriatic effect. It is an interesting candidate for topical psoriasis treatment that should be further studied in clinical trials.

Luteolin as a modulator of skin aging and inflammation.

Luteolin belongs to the group of flavonoids and can be found in flowers, herbs, vegetables and spices. It plays an important role in defending plants, for example against UV radiation by partially absorbing UVA and UVB radiation. Thus, luteolin can also decrease adverse photobiological effects in the skin by acting as a first line of defense. Furthermore, anti-oxidative and anti-inflammatory activities of luteolin were described on keratinocytes and fibroblasts as well as on several immune cells (e.g., macrophages, mast cell, neutrophils, dendritic cells and T cells). Luteolin can suppress proinflammatory mediators (e.g., IL-1ß, IL-6, IL-8, IL-17, IL-22, TNF-α and COX-2) and regulate various signaling pathway (e.g., the NF-κB, JAK-STAT as well as TLR signaling pathway). In this way, luteolin modulates many inflammatory processes of the skin. The present review summarizes the recent in vitro and in vivo research on luteolin in the field of skin aging and skin cancer, wound healing as well as inflammatory skin diseases, including psoriasis, contact dermatitis and atopic dermatitis. In conclusion, luteolin might be a promising molecule for the development of topic formulations and systemic agents against inflammatory skin diseases.

Gentiana lutea Extract Modulates Ceramide Synthesis in Primary and Psoriasis-Like Keratinocytes.

Gentiana lutea is a bitter herb that is traditionally used to improve gastric disorders. Recently, we have shown that Gentiana lutea extract (GE) also modulates the lipid metabolism of human keratinocytes in vitro and in vivo. In the present study, we investigated the role of GE on ceramide synthesis in human primary keratinocytes (HPKs) and psoriasis-like keratinocytes. We could demonstrate that GE increased the concentrations of glucosylceramides and the ceramide AS/AdS subclass without affecting the overall ceramide content in HPKs. The expression of ceramide synthase 3 (CERS3) and elongases (ELOVL1 and 4) was reduced in psoriasis lesions compared to healthy skin. Psoriasis-like HPKs, generated by stimulating HPKs with cytokines that are involved in the pathogenesis of psoriasis (IL-17, TNF-α, IL-22 and IFN-γ) showed increased levels of IL-6, IL-8 and increased expression of DEFB4A, as well as decreased expression of ELOVL4. The treatment with GE partly rescued the reduced expression of ELOVL4 in psoriasis-like HPKs and augmented CERS3 expression. This study has shown that GE modulates ceramide synthesis in keratinocytes. Therefore, GE might be a novel topical treatment for skin diseases with an altered lipid composition such as psoriasis.

Skin inflammation associated with arthritis, synovitis and enthesitis. Part 2: rheumatoid arthritis, reactive arthritis, Reiter's syndrome, Lyme borreliosis, dermatomyositis and lupus erythematosus.

Syndromes associated with concurrent skin and joint inflammation frequently pose a therapeutic challenge for both dermatologists and rheumatologists. In part 1 of this review, we discussed psoriatic arthritis as well as the autoinflammatory disorders SAPHO syndrome, Still's disease and Behçet's disease. Part 2 will address rheumatoid arthritis, reactive arthritis, Reiter's syndrome and Lyme borreliosis. In addition, we will discuss dermatomyositis and lupus erythematosus, two common autoimmune disorders that frequently present with both cutaneous and joint involvement. For each of the aforementioned disorders, we will highlight aspects of epidemiology, pathogenesis, clinical presentation, diagnosis and treatment.

Skin inflammation associated with arthritis, synovitis and enthesitis. Part 1: psoriatic arthritis, SAPHO syndrome, Still's disease, Behçet's disease.

The coincidence of skin and joint inflammation poses a challenge for both dermatologists and rheumatologists. Adequate management of such disorders requires that physicians of both specialties have sound knowledge of the other discipline. In case of suspected joint involvement, familiarity with the diagnostic options available to rheumatologists enables dermatologists to selectively refer their patients for a rheumatology consult. The objective of the present review is to familiarize the reader with the stepwise diagnostic workup performed by rheumatologists today, including laboratory tests, musculoskeletal ultrasound, X-ray studies, and magnetic resonance imaging. Subsequently, we will discuss a number of disorders characterized by the concurrence of skin and joint inflammation, highlighting aspects of epidemiology, etiology and pathogenesis, clinical presentation, diagnosis and treatment. These disorders include psoriatic arthritis as well as autoinflammatory disorders such as SAPHO syndrome, Still's disease and Behçet's disease.

Hop Extract Acts as an Antioxidant with Antimicrobial Effects against Propionibacterium Acnes and Staphylococcus Aureus.

Acne is associated with hyperkeratosis, elevated levels of skin sebum and growth of Propionibacterium acnes (P. acnes) and Staphylococcus aureus (S. aureus). Furthermore, P. acnes promotes inflammation by inducing IL-6 production and oxidative stress. The aim of this study was to assess the antioxidant, anti-inflammatory and antibacterial potential of a hop-CO2-extract with 50% humulone and lupulone. The susceptibility of P. acnes and S. aureus to the hop extract was tested by using the broth microdilution technique. The minimal inhibitory concentrations (MIC) for P. acnes and S. aureus were 3.1 and 9.4 µg/mL, respectively. In addition, the hop extract showed an antioxidative effect with a half maximal inhibitory concentration (IC50) of 29.43 µg/mL as well as additional anti-inflammatory effects by reducing the IL-6 expression (IC50: 0.8 µg/mL). In addition, a gel formulation with 0.3% hop extract (w/w) had antibacterial activity against P. acnes and S. aureus (inhibition zone value: 5.5 mm and 3 mm, respectively) which was significantly superior to the placebo gel. The positive control (a gel with the antibiotic clindamycin) showed an inhibition zone of 9 mm. Due to its antioxidant, anti-inflammatory and antibacterial effects hop extract might be a treatment option for acne-prone skin.

Effect of a botanical cleansing lotion on skin sebum and erythema of the face: A randomized controlled blinded half-side comparison.

BACKGROUND: Elevated levels of skin sebum are associated with the growth of Propionibacterium acnes. Intensive degreasing of the skin reduces Propionibacterium acnes but also may cause skin irritation. AIMS: We assessed the degreasing effect and skin tolerability of a botanical face cleanser with hops and willow bark extract and disodium cocoyl glutamate as mild cleansing agent compared to a standard face cleanser with sodium laureth sulfate (SLES). MATERIALS AND METHODS: A total of 21 healthy volunteers with normal to oily skin were enrolled in this study. Both cleansers were applied twice a day on the left or right side of the forehead for 15 days in a standardized manner. Bioengineering measurements were performed on day 8 and 15 and on day 17 after an application break of 48 hours. The sebum level was determined using a Sebumeter® , and skin redness was measured using a Mexameter® . RESULTS: The botanical face cleanser significantly reduced the sebum level (P < .01) in the test area on day 17. The SLES containing cleanser showed a statistically relevant degreasing effect already on day 15, but after the application break the sebum level increased again on day 17. None of the cleansers caused skin irritation as determined by skin redness measurements. CONCLUSIONS: In contrast to the SLES containing cleanser, the botanical skin cleanser with hops and willow bark extract had a continuous degreasing effect without reactive seborrhoe after the treatment break. Skin cleansing without SLES might be advantageous for sensitive skin.

The Herbal Bitter Drug Gentiana lutea Modulates Lipid Synthesis in Human Keratinocytes In Vitro and In Vivo.

Gentiana lutea is a herbal bitter drug that is used to enhance gastrointestinal motility and secretion. Recently we have shown that amarogentin, a characteristic bitter compound of Gentiana lutea extract (GE), binds to the bitter taste receptors TAS2R1 and TAS2R38 in human keratinocytes, and stimulates the synthesis of epidermal barrier proteins. Here, we wondered if GE also modulates lipid synthesis in human keratinocytes. To address this issue, human primary keratinocytes were incubated for 6 days with GE. Nile Red labeling revealed that GE significantly increased lipid synthesis in keratinocytes. Similarly, gas chromatography with flame ionization detector indicated that GE increases the amount of triglycerides in keratinocytes. GE induced the expression of epidermal ceramide synthase 3, but not sphingomyelinase. Lipid synthesis, as well as ceramide synthase 3 expression, could be specifically blocked by inhibitors of the p38 MAPK and PPARγ signaling pathway. To assess if GE also modulates lipid synthesis in vivo, we performed a proof of concept half side comparison on the volar forearms of 33 volunteers. In comparison to placebo, GE significantly increased the lipid content of the treated skin areas, as measured with a sebumeter. Thus, GE enhances lipid synthesis in human keratinocytes that is essential for building an intact epidermal barrier. Therefore, GE might be used to improve skin disorders with an impaired epidermal barrier, e.g., very dry skin and atopic eczema.

Anti-inflammatory and vasoconstrictive properties of Potentilla erecta - A traditional medicinal plant from the northern hemisphere.

ETHNOPHARMACOLOGICAL RELEVANCE: Potentilla erecta (L.) Raeusch is a medicinal plant of the Northern hemisphere belonging to the plant family of roses (Rosaceae). It has traditionally been used to treat inflammatory disorders of the skin and mucous membranes as well as chronic diarrhea. AIM OF THE STUDY: In the present study we analyzed the anti-inflammatory and vasoconstrictive effect of a Potentilla erecta extract (PE) and questioned if PE is similar effective as mild corticosteroids. Then we analyzed if PE acts in the skin via a similar mode of action as corticosteroids. MATERIAL AND METHODS: The anti-inflammatory effect of PE was analyzed in irradiated HaCaT keratinocytes by measuring the formation of IL-6 and PGE2. Additionally the effect of PE on TNF-α induced NF-κB activation was determined. As the anti-inflammatory effect of corticosteroids correlates with their vasoconstrictive properties we tested if PE displays also vasoconstriction. Therefore we performed an occlusive patch test and a collagen contraction assay. Furthermore the binding of PE to the glucocorticoid receptor was determined with stainings and reporter assays. The interaction of PE on the nitric oxide (NO) content was examined with radical scavenging and endothelial NO synthase (eNOS) reporter assays. RESULTS: In irradiated or TNF-α stimulated HaCaT cells the formation of IL-6 and PGE2 or NF-κB activation was strongly reduced by PE. Furthermore PE showed a blanching effect comparable to hydrocortisone. However, in contrast to glucocorticoids, PE did not cause nuclear translocation of the glucocorticoid receptor in HaCaT cells. The blanching effect of PE was at least partly attributable to a scavenging effect of NO and inhibition of eNOS. CONCLUSIONS: PE displays anti-inflammatory and vasoconstrictive effects and might therefore be beneficial for the topical treatment of inflammatory skin disorders.