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Prague Medical Report 2023Alopecia areata is a disease of autoimmune origin which causes non scarring hair loss. The extent of alopecia varies from a small patch to complete scalp and body hair... (Review)
Review
Alopecia areata is a disease of autoimmune origin which causes non scarring hair loss. The extent of alopecia varies from a small patch to complete scalp and body hair loss, which can have huge psychosocial impact for those affected. Treatment modalities which have been used so far included nonspecific immunosuppressive medications, such as corticosteroids, cyclosporine, and methotrexate, or topical immunomodulators, such as diphencyprone, dithranol, and squaric acid dibutylester. The recognition of the importance of Janus kinase pathway in alopecia areata pathogenesis enabled more specific approaches in treatment. Positive outcomes of Janus kinase inhibitors in several trials granted approval for baricitinib which became the first on-label treatment for alopecia areata. The aim of this review is to summarize the role, efficacy and safety of several Janus kinase inhibitors in alopecia areata.
Topics: Humans; Alopecia Areata; Janus Kinase Inhibitors; Janus Kinases; Adjuvants, Immunologic
PubMed: 36763827
DOI: 10.14712/23362936.2023.1 -
JAMA Dermatology Jan 2020Treatment of psoriasis is associated with improved quality of life (QOL) in those with the disease. However, in daily clinical practice, the association between the...
IMPORTANCE
Treatment of psoriasis is associated with improved quality of life (QOL) in those with the disease. However, in daily clinical practice, the association between the degree of psoriasis clearance and QOL has not been studied to date, especially in the pediatric population.
OBJECTIVES
To identify the association between the degree of psoriasis improvement (as measured by the Psoriasis Area Severity Index [PASI] and body surface area [BSA] response) and QOL (as measured by the Children's Dermatology Life Quality Index [CDLQI]) in pediatric psoriasis, and to assess the association of treatment type with QOL, independent of psoriasis improvement.
DESIGN, SETTING, AND PARTICIPANTS
Data used in this single-center cohort study were extracted from the Child-CAPTURE (Continuous Assessment of Psoriasis Treatment Use Registry), a prospective, observational, daily clinical practice cohort of all children (aged <18 years) with a psoriasis diagnosis who attended the outpatient clinic of the Department of Dermatology at the Radboud University Medical Center in Nijmegen, the Netherlands, between September 3, 2008, and May 4, 2018. All records of treatment episodes with CDLQI, PASI, and BSA scores were included in the analysis.
EXPOSURES
Patients were treated according to daily clinical care. Treatments were clustered into topical, dithranol, conventional systemic, and biological treatments. Because of low numbers of UV-B phototherapy, this treatment was not assessed.
MAIN OUTCOMES AND MEASURES
Primary outcomes were mean change of CDLQI scores per PASI and BSA response categories (0 to <50, 50 to <75, 75 to <90, and ≥90) and mean CDLQI change per treatment categories.
RESULTS
In total, 319 patients (median [interquartile range] age, 10.0 [7.0] years; 183 female [57.4%]) were analyzed for PASI score improvement (399 treatment episodes) and improvement in BSA involvement (366 treatment episodes). The greatest improvements in CDLQI scores were seen in the PASI ≥90 response category, with an estimated marginal mean change in CDLQI score of -6.6 (95% CI, -7.5 to -5.7). The greatest improvements in CDLQI scores were also observed in the BSA ≥90 response category, with an estimated marginal mean change in CDLQI score of -6.8 (95% CI, -7.5 to -6.1). Systemic treatment demonstrated a greater degree of improvement of CDLQI compared with topical treatment, independent of PASI response categories.
CONCLUSIONS AND RELEVANCE
This cohort study in a real-world setting found that the greatest improvements in QOL were associated with PASI 90 or greater, a decrease in BSA involvement of 90% or greater, and systemic treatments. These findings suggest that reaching PASI 90 or greater and decreasing BSA involvement by at least 90% may be clinically meaningful treatment goals that will help pediatric patients with psoriasis reach optimal QOL.
Topics: Administration, Oral; Administration, Topical; Adolescent; Biological Products; Child; Child, Preschool; Dermatologic Agents; Female; Follow-Up Studies; Humans; Injections; Male; Netherlands; Prospective Studies; Psoriasis; Quality of Life; Severity of Illness Index; Treatment Outcome; Ultraviolet Therapy
PubMed: 31774449
DOI: 10.1001/jamadermatol.2019.3717 -
The Journal of Biological Chemistry Oct 2020A sterilizing or functional cure for HIV is currently precluded by resting CD4 T cells that harbor latent but replication-competent provirus. The "shock-and-kill"...
A sterilizing or functional cure for HIV is currently precluded by resting CD4 T cells that harbor latent but replication-competent provirus. The "shock-and-kill" pharmacological ap-proach aims to reactivate provirus expression in the presence of antiretroviral therapy and target virus-expressing cells for elimination. However, no latency reversal agent (LRA) to date effectively clears viral reservoirs in humans, suggesting a need for new LRAs and LRA combinations. Here, we screened 216 compounds from the pan-African Natural Product Library and identified knipholone anthrone (KA) and its basic building block anthralin (dithranol) as novel LRAs that reverse viral latency at low micromolar concentrations in multiple cell lines. Neither agent's activity depends on protein kinase C; nor do they inhibit class I/II histone deacetylases. However, they are differentially modulated by oxidative stress and metal ions and induce distinct patterns of global gene expression from established LRAs. When applied in combination, both KA and anthralin synergize with LRAs representing multiple functional classes. Finally, KA induces both HIV RNA and protein in primary cells from HIV-infected donors. Taken together, we describe two novel LRAs that enhance the activities of multiple "shock-and-kill" agents, which in turn may inform ongoing LRA combination therapy efforts.
Topics: Anthracenes; Anthralin; Drug Evaluation, Preclinical; HIV Infections; HIV-1; Humans; Jurkat Cells; Virus Latency
PubMed: 32788215
DOI: 10.1074/jbc.RA120.013031 -
NPJ Vaccines Sep 2022Transcutaneous immunization (TCI) utilizing the TLR7 agonist imiquimod (IMQ-TCI) induces T cell-driven protective immunity upon application onto intact skin. In our...
Transcutaneous immunization (TCI) utilizing the TLR7 agonist imiquimod (IMQ-TCI) induces T cell-driven protective immunity upon application onto intact skin. In our present work, we combine the anti-psoriatic agent dithranol with IMQ-TCI to boost vaccination efficacy (Dithranol/IMQ-based transcutaneous vaccination (DIVA)). Using ovalbumin-derived peptides as model antigens in mice, DIVA induced superior cytolytic CD8 T cells and CD4 T cells with a T cytokine profile in the priming as well as in the memory phase. Regarding the underlying mechanisms, dithranol induced an oxidant-dependent, monocyte-attracting inflammatory milieu in the skin boosting TLR7-dependent activation of dendritic cells and macrophages leading to superior T cell priming and protective immunity in vaccinia virus infection. In conclusion, we introduce the non-invasive vaccination method DIVA to induce strong primary and memory T cell responses upon a single local treatment. This work provides relevant insights in cutaneous vaccination approaches, paving the way for clinical development in humans.
PubMed: 36153349
DOI: 10.1038/s41541-022-00530-9 -
International Journal of Nanomedicine 2024Improving the treatment of psoriasis is a serious challenge today. Psoriasis is an immune-mediated skin condition affecting 125 million people worldwide. It is commonly...
Revolutionizing Psoriasis Topical Treatment: Enhanced Efficacy Through Ceramide/Phospholipid Composite Cerosomes Co-Delivery of Cyclosporine and Dithranol: In-Vitro, Ex-Vivo, and in-Vivo Studies.
PURPOSE
Improving the treatment of psoriasis is a serious challenge today. Psoriasis is an immune-mediated skin condition affecting 125 million people worldwide. It is commonly treated with cyclosporine-A (CsA) and dithranol (DTH). CsA suppresses the activation of T-cells, immune cells involved in forming psoriatic lesions. Meanwhile, DTH is a potent anti-inflammatory and anti-proliferative drug that effectively reduces the severity of psoriasis symptoms such as redness, scaling, and skin thickness. CsA and DTH belong to BCS class II with limited oral bioavailability. We aim to develop a drug delivery system for topical co-delivery of CsA and DTH, exploring its therapeutic potential.
METHODS
Firstly, we developed a niosomal drug delivery system based on ceramide IIIB to form Cerosomes. Cerosomes were prepared from a mixture of Ceramide, hyaluronic acid, and edge activator using a thin-film hydration technique. To co-deliver CsA and DTH topically for the treatment of psoriasis. These two hydrophobic drugs encapsulated into our synthesized positively charged particle cerosomes.
RESULTS
Cerosomes had an average particle size of (222.36 nm± 0.36), polydispersity index of (0.415±0.04), Entrapment Efficiency of (96.91%± 0.56), and zeta potential of (29.36±0.38mV) for selected formula. In vitro, In silico, in vivo, permeation, and histopathology experiments have shown that cerosomes enhanced the skin penetration of both hydrophobic drugs by 66.7% compared to the CsA/DTH solution. Imiquimod (IMQ) induced psoriatic mice model was topically treated with our CsA/DTH cerosomes. We found that our formulation enhances the skin penetration of both drugs and reduces psoriasis area and severity index (PASI score) by 2.73 times and 42.85%, respectively, compared to the CsA/DTH solution. Moreover, it reduces the levels of proinflammatory cytokines, TNF-α, IL-10, and IL-6 compared to CsA/DTH solution administration.
CONCLUSION
The Cerosomes nano-vesicle-containing CsA/DTH represents a more promising topical treatment for psoriasis, giving new hope to individuals with psoriasis, compared to commercial and other conventional alternatives.
Topics: Humans; Animals; Mice; Anthralin; Cyclosporine; Phospholipids; Ceramides; Administration, Cutaneous; Psoriasis; Skin; Disease Models, Animal
PubMed: 38344440
DOI: 10.2147/IJN.S443812 -
In Vivo (Athens, Greece) 2023This study aimed to research the effects of Harkány healing water on oxidative stress. The study was performed in a randomized, placebo-controlled, double-blind setup. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND/AIM
This study aimed to research the effects of Harkány healing water on oxidative stress. The study was performed in a randomized, placebo-controlled, double-blind setup.
PATIENTS AND METHODS
Twenty patients with psoriasis who underwent a 3-week-long inward balneotherapy-based rehabilitation were enrolled. Psoriasis Area and Severity Index (PASI) score and Malondialdehyde (MDA) - a marker of oxidative stress - were determined, on admission and before discharge. Patients were treated with dithranol.
RESULTS
The mean PASI score - determined on admission and before discharge - decreased significantly after the 3-week-long rehabilitation 8.17 vs. 3.51 (p<0.001). The baseline MDA value of patients with psoriasis was significantly higher compared to controls (3.0±3.5 vs. 8.4±7.4) (p=0.018). MDA levels of patients receiving placebo water increased significantly compared to MDA levels of patients receiving healing water (p=0.049).
CONCLUSION
The effectiveness of dithranol resides in the formation of reactive oxygen species. No increased oxidative stress was found in the patients treated with healing water, thus healing water seems to be protective against oxidative stress. However, further research is needed to confirm these preliminary results.
Topics: Humans; Pilot Projects; Anthralin; Oxidative Stress; Balneology; Psoriasis; Water
PubMed: 36881082
DOI: 10.21873/invivo.13153 -
Frontiers in Medicine 2021SARS-Cov2 has raised concerns among dermatologists regarding psoriasis and its respective treatments. Comorbidities, which induce the expression of the proprotease...
SARS-Cov2 has raised concerns among dermatologists regarding psoriasis and its respective treatments. Comorbidities, which induce the expression of the proprotease furin have been associated with severe course of COVID-19. Furin and angiotensin converting enzyme 2 (ACE2) play a major role in viral host cell entry of SARS-Cov2. To evaluate mRNA expression of Furin and ACE2 from blood cells in psoriasis patients, and whether systemic or topical treatment reduces expression levels. This observational translational study analyzed blood samples from patients from a clinical trial and samples retrieved from the biobank of the Psoriasis Registry Austria (PsoRA). Furin and ACE2 expression levels were analyzed prior to as well as 3 and 12-24 months after start of biologic treatment with either ustekinumab or secukinumab. Additionally, the study analyzed expression levels prior to, 6 days after start of dithranol treatment and 4-6 weeks after end of dithranol treatment. Furin mRNA expression was significantly increased at baseline in the biologic (4.9 ± 2.6 fold, < 0.0001) and in the dithranol group (2.7 ± 1.4 fold, < 0.001) compared to controls. There was a trend for arthritis patients to express more furin than patients with psoriatic skin involvement only (5.26 ± 2.30 vs. 3.48 ± 2.27, = 0.078). Analyzing furin mRNA expression after treatment initiation with secukinumab or ustekinumab revealed a normalization of levels after 3 and 12 to 24 months. Similar findings were obtained for patients treated with dithranol, with significantly decreased expression levels 6 days after start of dithranol treatment and also at follow-up, (4-6 weeks after dithranol treatment had been terminated). ACE2 expression levels did not differ from controls at any timepoint, regardless of biologic or topical treatment. Significantly overexpressed levels of furin were observed in untreated patients, and, thus, these patients may be at risk for infection and a severe course of COVID-19. However, the data indicate that successful therapeutic intervention in psoriasis, by systemic biologic or topical treatment, can efficiently reduce furin levels in blood cells, possibly limiting the risk of psoriasis patients for a severe COVID-19 course. ClinicalTrials.gov, identifier NCT02752672.
PubMed: 33644099
DOI: 10.3389/fmed.2021.624462 -
Experimental Dermatology Jun 2021Topical dithranol is effective in autoimmune conditions like alopecia areata, inducing hair regrowth in a high percentage of cases. Exact mechanisms of dithranol in...
Topical dithranol is effective in autoimmune conditions like alopecia areata, inducing hair regrowth in a high percentage of cases. Exact mechanisms of dithranol in alopecia areata, with seemingly healthy epidermis besides altered hair follicles, are not well understood. To better understand dithranol's mechanisms on healthy skin, we analysed its effect on normal murine as well as xenografted human skin. We found a strong increase in mRNA expression of anti-microbial peptides (AMPs) (eg Lcn2, Defb1, Defb3, S100a8, S100a9), keratinocyte differentiation markers (eg Serpinb3a, Flg, Krt16, Lce3e) and inflammatory cytokines (eg Il1b and Il17) in healthy murine skin. This effect was paralleled by inflammation and disturbed skin barrier, as well as an injury response resulting in epidermal hyperproliferation, as observed in murine and xenografted adult human skin. This contact response and disturbed barrier induced by dithranol might lead via a vicious loop between AMPs such as S100a8/a9 (that led to skin swelling itself after topical application) and cytokines such as IL-1β to an immune suppressive environment in the skin. A better understanding of the skin's physiologic response to dithranol may open up new avenues for the establishment of novel therapeutics (including AMP-related/interfering molecules) for certain skin conditions, such as alopecia areata.
Topics: Alopecia Areata; Animals; Anthralin; Antimicrobial Peptides; Cytokines; Dermatologic Agents; Humans; Interleukin-1beta; Keratinocytes; Mice; Mice, Inbred BALB C
PubMed: 33629779
DOI: 10.1111/exd.14310 -
International Journal of Nanomedicine 2020Reactive oxygen species (ROS)-induced oxidative stress plays a key role in the pathogenesis and progression of psoriasis by causing inflammation. Antioxidative...
PURPOSE
Reactive oxygen species (ROS)-induced oxidative stress plays a key role in the pathogenesis and progression of psoriasis by causing inflammation. Antioxidative strategies eradicating ROS may serve as effective and easy treatment options for psoriasis, while nanozymes with intrinsic antioxidant enzyme-like activity have not been explored for psoriasis treatment. The aim of this study is to fabricate β-cyclodextrins (β-CDs)-modified ceria nanoparticles (β-CDs/CeO NPs) with drug-loaded and multimimic-enzyme activities for combinational psoriasis therapy.
METHODS
The β-CDs/CeO NPs were synthesized by a hydrothermal method using unmodified β-CDs as a protecting agent. The structure, size and morphology were analyzed by dynamic light scattering, transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectroscopy. Considering the superoxide dismutase (SOD)- and catalase-mimetic activities, the in vitro antioxidant activity of the β-CDs/CeO2 NPs was investigated. After dithranol (DIT) was loaded, the drug-loading capacity and release profile were determined by UV-visible light spectrophotometer and high-performance liquid chromatography. The anti-psoriatic efficacy was studied in the imiquimod (IMQ)-induced mouse model on the basis of morphological evaluation, psoriasis area and severity index calculation (PASI), and inflammatory cytokine expression.
RESULTS
The average particle size of the blank β-CDs/CeO NPs was 60.89±0.32 nm with a polydispersity index (PDI) of 0.12, whereas that of the DIT-loaded NPs was 79.38±1.06 nm with a PDI of 0.27. TEM results showed the as-prepared NPs formed a uniform quasi-spherical shape with low polydispersity. XPS indicates synthesized NPs have a mixed Ce/Ce valence state. FTIR spectroscopy confirmed the presence of β-CDs and DIT in the NPs. Inhibition of superoxide anion rate by NPs could be reached to 79.4% in the presence of 200 µg/mL, and elimination of HO efficiency reached about 50% in the presence of 40 µg/mL, demonstrating excellent superoxide dismutase- and catalase-mimicking activities, thereby providing remarkable cryoprotection against ROS-mediated damage. Furthermore, β-CDs on the surface endowed the NPs with drug-loading function via host-guest interactions. The entrapment efficiency and drug loading of DIT are 94.7% and 3.48%, respectively. The in vitro drug release curves revealed a suitable release capability of DIT@β-CDs/CeO NPs under physiological conditions. In IMQ-induced psoriatic model, the DIT@β-CDs/CeO NPs exhibited excellent therapeutic effect.
CONCLUSION
This study may pave the way for the application of nanozyme β-CDs/CeO NPs as a powerful tool for psoriasis therapy.
Topics: Animals; Catalase; Cell Line; Cell Survival; Cerium; Combined Modality Therapy; Free Radical Scavengers; Hydrodynamics; Imiquimod; Male; Mice, Inbred BALB C; Nanoparticles; Particle Size; Photoelectron Spectroscopy; Psoriasis; Reactive Oxygen Species; Skin; Spectroscopy, Fourier Transform Infrared; Superoxide Dismutase; Tumor Necrosis Factor-alpha; beta-Cyclodextrins
PubMed: 32368038
DOI: 10.2147/IJN.S246783 -
JAAD Case Reports Jul 2020
PubMed: 32743037
DOI: 10.1016/j.jdcr.2020.05.022