A Promising Approach to Treat Psoriasis: Inhibiting Cytochrome P450 3A4 Metabolism to Enhance Desoximetasone Therapy.

(1) Background: Human keratinocytes and murine skin express various cytochrome P450 enzymes. These include cytochrome P450 3A4, which may participate in the metabolism of cytochrome P450 3A4 substrate drugs. Desoximetasone, a topical corticosteroid and cytochrome P450 3A4 substrate, is used to treat skin conditions such as skin allergies, atopic dermatitis, and psoriasis. In this study, we aimed to investigate the anti-psoriatic effect of a low dose of desoximetasone by inhibiting cytochrome P450 3A4 metabolism in the epidermis. (2) Methods: Psoriasis-like skin was induced in BALB/c mice via the topical administration of imiquimod. The mice were then topically treated with 0.01-0.05% desoximetasone loaded into a cytochrome P450 3A4 enzyme inhibitor excipient base emollient microemulsion, 0.25% commercial desoximetasone ointment, or 0.5 mg/gm clobetasol ointment. (3) Results: The topical application of 0.05% desoximetasone loaded into a cytochrome P450 3A4 enzyme inhibitor excipient base emollient formulation restored the imiquimod-induced skin barrier disruption and resulted in fewer severe clinical and pathological features compared with the treatments with 0.25% commercial desoximetasone ointment and 0.5 mg/gm clobetasol ointment. (4) Conclusions: The cytochrome P450 3A4 enzyme inhibitor excipient base emollient formulation improved and prolonged the therapeutic effect of cytochrome P450 3A4 substrate drugs and may be a promising approach for psoriasis treatment.

Magnolol may contribute to barrier function improvement on imiquimod-induced psoriasis-like dermatitis animal model via the downregulation of interleukin-23.

Psoriasis is a chronic, recurrent, immune-mediated disease involving the skin and joints. Epidermal hyperproliferation, abnormal keratinocyte differentiation, angiogenesis with blood vessel dilatation, and excess T helper type-1 (Th-1) and Th-17 cell infiltration are the main histopathological features of psoriasis. Magnolol is a polyphenolic compound that exerts its biological properties through a variety of mechanisms such as the NF-κB/MAPK, Nrf2/HO-1 and PI3K/Akt pathways. Magnolol has been demonstrated to exert a number of therapeutic effects on dermatological processes, including acting as an anti-inflammation, antiproliferation and antioxidation agent. However, few studies have been published on the effect of magnolol on psoriasis. Therefore, the present study aimed to elucidate the mechanism of action of magnolol on psoriasis. BALB/c mice were treated topically with imiquimod (IMQ) to induce psoriasis-like dermatitis, and were randomly assigned to the control, vehicle control, low- and high-dose magnolol, and 0.25% desoximetasone ointment treatment groups in order to investigate skin barrier function, any changes in the levels of cytokines and for the histological assessment. High doses of magnolol were indicated to be able to improve the barrier function following IMQ-induced barrier disruption. Magnolol activated peroxisome proliferator-activated receptor-γ, and also significantly inhibited the protein expression of interleukin (IL)-23, IL-1ß, IL-6, tumor necrosis factor-α and interferon-γ. However, administering a high dose of magnolol did not lead to any improvement in the clinical and pathological features of the psoriasis severity Taken together, these results demonstrated that downregulation of IL-23 may contribute to barrier function improvement in a psoriatic skin model.

Salvianolic Acid B in Microemulsion Formulation Provided Sufficient Hydration for Dry Skin and Ameliorated the Severity of Imiquimod-Induced Psoriasis-Like Dermatitis in Mice.

Psoriasis is a chronic inflammatory skin disorder with a pathogenesis involving the interleukin-23/interleukin-17 axis. Salvianolic acid B exerts several pharmacological effects, such as antioxidation, anti-inflammation, and antitumor effects. The anti-psoriatic effects of salvianolic acid B have not been reported. In this study, we aimed to determine the optimum vehicle for salvianolic acid B, investigate its therapeutic effect on psoriatic-like skin conditions, and explore its underlying mechanisms of action. BALB/c mice were administered topical imiquimod to induce psoriasis-like skin and were then randomly assigned to control, vehicle control, salvianolic acid B in vehicles, and 0.25% desoximetasone ointment treatment groups. Barrier function, cytokine expression, histology assessment, and disease severity were evaluated. The results showed that salvianolic acid B-containing microemulsion alleviated disease severity, reduced acanthosis, and inhibited interleukin-23/interleukin-17 (IL-23/IL-17) cytokines, epidermal proliferation, and increased skin hydration. Our study suggests that salvianolic acid B represents a possible new therapeutic drug for the treatment of psoriasis. In addition, such formulation could obtain high therapeutic efficacy in addition to providing sufficient hydration for dry skin.

Wound Healing in Streptozotocin-Induced Diabetic Rats Using Atmospheric-Pressure Argon Plasma Jet.

In this study, we used an argon-based round atmospheric-pressure plasma jet (APPJ) for enhancing wound healing in streptozotocin (STZ) induced diabetic rats. The APPJ was characterized by optical emission spectroscopy. We induced Type 1 and Type 2 diabetes in rats with different amounts of STZ combined with normal and high-fat diets, respectively. The wound area ratio of all the plasma-treated normal and diabetic groups was greatly reduced (up to 30%) compared with that of the untreated groups during healing. Histological analysis revealed faster re-epithelialization, collagen deposition, less inflammation, and a complete skin structure in the plasma-treated groups was found as compared with the untreated control groups. In addition, the new blood vessels of plasma-treated tissues decreased more than untreated tissues in the middle (Day 14) and late (Day 21) stages of wound healing. The plasma-treated wounds demonstrated more transforming growth factor beta (TGF-ß) expression in the early stage (Day 7), whereas they decreased in the middle and late stages of wound healing. The levels of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) increased after plasma treatment. In addition, plasma-treated water had a higher concentration of hydrogen peroxide, nitrite and nitrate when the plasma treatment time was longer. In summary, the proposed argon APPJ based on the current study could be a potential tool for treating diabetic wounds.

Author Correction: Wound Healing in Streptozotocin-Induced Diabetic Rats Using Atmospheric-Pressure Argon Plasma Jet.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Efficacy and Safety of a Low-Level Light Therapy for Androgenetic Alopecia: A 24-Week, Randomized, Double-Blind, Self-Comparison, Sham Device-Controlled Trial.

BACKGROUND: Previous studies have reported the benefits of low-level/light laser therapy (LLLT) for the promotion of hair regrowth. However, the effectiveness of LLLT for the treatment of androgenetic alopecia (AGA) is still a topic of debate. OBJECTIVE: To investigate the efficacy and safety of LLLT on hair regrowth in patients with AGA. METHODS: This 24-week, randomized, double-blind, self-comparison, sham device-controlled trial enrolled 100 patients with AGA. All participants were randomly assigned to receive the investigational LLLT on one side of the head and sham light treatment on the contralateral side, 3 times weekly for 30 minutes each, over a 24-week period. Global scalp photography, phototrichogram assessment, the investigator's global assessment (IGA) of hair regrowth, and the subject's assessment of the treatment satisfaction were used for evaluation. RESULTS: After 24 weeks of treatment, the LLLT-treated scalp exhibited significantly greater hair coverage than the sham light-treated side (14.2% vs. 11.8%, p < .001). A significantly greater improvement from baseline in hair thickness, hair count, hair coverage, and IGA were also observed in the LLLT-treated side than in the sham light-treated side at the 12- and 24-week visits. No serious adverse events were observed. CONCLUSION: The use of LLLT might be an effective, safe, well-tolerated treatment for AGA.

A Case Report and Literature Review of Scrub Typhus With Acute Abdomen and Septic Shock in a Child-The Role of Leukocytoclastic Vasculitis and Granulysin.

Scrub typhus is becoming a clinically important cause of acute undifferentiated febrile illness in Taiwan. The incubation period is between 6 and 21 days after exposure. It is transmitted by chiggers (larva of trombiculid mite) in long grasses and in dirt-floor homes, with infection characterized by a flu-like illness of fever, headache, and myalgia lasting approximately 1 week. It has various systemic manifestations, including GI symptoms. In some, the illness progresses to multiorgan dysfunction syndrome and death. We report on a 13-year-old boy who lived in Taipei City and who had initially tentative diagnosis of acute pyrexia of unknown origin with high fever up to 40.3°C for 1 week, but later had thrombocytopenia and diffuse abdominal pain with peritoneal sign suspected acute appendicitis. During the clinical course, septic shock and disseminated intravascular coagulopathy (DIC) were noted. There were skin rash in his trunk and extremities and an eschar with black crust surrounded by a scaling erythematous rim on his right buttock. In addition, we got the information of his travel history in Green Island and Orchid Island for 10 days.With the correct antibiotics, vancomycin, meropenem, and doxycycline, the patient was getting better and corresponding with high level of granulysin and tumor necrosis factor-alpha. The diagnosis of scrub typhus was confirmed by the biopsy of eschar and high quantitative real-time polymerase chain reaction values of Orientia tsutsugamushi (16sRNA and 56 kDa) tested by Centers for Disease Control and Prevention, Taiwan. Histopathological findings of the eschar revealed the leukocytoclastic vasculitis, crust and thrombus formation with many gram-negative microorganisms, O. tsutsugamushi demonstrated by 47 kDa monoclonal antibody immunohistochemical stain and electromicroscopy. OUTCOMES: After the careful selection of appropriate antibiotics including meropenem, vancomycin, and doxycycline, he recovered and was subsequently discharged 7 days after admission. LESSON SUBSECTIONS: This case highlights that scrub typhus infection can mimic acute abdomen and septic shock with DIC. This rare presentation of acute abdomen and septic shock with thrombocytopenia and DIC caused by scrub typhus should remind physicians to be alert to the possibility of acute abdomen and febrile illness resulting from scrub typhus.

Purpuric Drug Eruptions Caused by Epidermal Growth Factor Receptor Inhibitors for Non-Small Cell Lung Cancer: A Clinicopathologic Study of 32 Cases.

Importance: Purpuric skin lesions have only rarely been reported in patients receiving epidermal growth factor receptor inhibitors. However, their clinical and histopathologic presentations have varied considerably. Objective: To characterize purpuric skin eruptions caused by epidermal growth factor receptor inhibitors. Design, Setting, and Participants: This prospective study enrolled 32 patients who presented to an integrated dermato-oncologic clinic in a tertiary referral medical center with purpuric skin lesions after using epidermal growth factor receptor inhibitors from January 1, 2013, through December 31, 2015. Exposures: Epidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, erlotinib, and afatinib. Main Outcomes and Measures: Clinical presentations, histopathologic features, laboratory examinations, and treatment outcomes of patients with purpuric drug eruptions. Results: Thirty-two patients, 14 with purpuric drug eruptions without pustules (mean [SD] age, 60 [11] years; 12 female and 2 male) and 18 with purpuric drug eruptions with pustules (mean [SD] age, 64 [11] years; 12 female and 6 male), were identified. The median time to development of skin lesions was 3.5 months. The clinical presentations were characterized by purpuric macules, papules, and confluent plaques predominantly on the lower extremities. Pustules in various sizes could be found in 18 patients (56%). Eleven patients (34%) had skin lesions that covered places other than the lower extremities. Eczema craquelé-like features developed in 13 patients (41%). Bacterial pathogens were frequently identified in these skin lesions. Among them, Staphylococcus aureus was the most predominant and was found in 20 patients (63%), commonly in those with cutaneous pustules. Epidermal dysmaturation, neutrophil exocytosis, perivascular infiltration of lymphocytes and neutrophils, red blood cell extravasation, and plumping endothelium were the main histopathologic features. The expressions of filaggrin and human ß-defensin 2 in lesional skin of these patients were markedly reduced. All patients improved after receiving at least 1 week of systemic antibiotic treatment; the doses of epidermal growth factor receptor inhibitors were also changed for 14 patients (44%). Conclusions and Relevance: Purpuric drug eruptions caused by epidermal growth factor receptor inhibitors are uncommon and have characteristic clinical and histopathologic presentations. The role of bacterial pathogens in this reaction is important and requires further exploration.

Presenile diffuse familial sebaceous hyperplasia successfully treated with low-dose isotretinoin: A report of two cases and review of the published work.

Presenile diffuse familial sebaceous hyperplasia (PDFSH) presents as extensive yellowish papules with central umbilication on the face without involvement of periorificial regions and occurs in adolescents or young adults with a positive family history. Thirteen cases of PDFSH have been reported in the English-language published work, 10 of which responded to oral isotretinoin from 0.5 to 1 mg/kg per day but recurrences were often observed. Herein, we report two cases of PDFSH, which were successfully managed without recurrence with prolonged low-dose isotretinoin (0.2 mg/kg per day, a cumulative dose of 41 and 64 mg/kg, respectively). Treatment protocols among different published works were reviewed to verify the efficacy of isotretinoin.

Alopecia Areata After Vaccination: Recurrence with Rechallenge.

Alopecia areata (AA) is the most common form of hair loss in children. We report the case of a child who had two episodes of AA after two different vaccines with complete hair regrowth between the episodes. This case supports the concept that vaccination might be a trigger for the development of AA in genetically predisposed children.

The Association between Clinical Response to Ustekinumab and Immunogenicity to Ustekinumab and Prior Adalimumab.

BACKGROUND: Immunogenicity due to antidrug antibodies (ADA) to tumor necrosis factor (TNF)-α antagonists is known to decrease treatment response. However, few studies have investigated ADA in ustekinumab, an interleukin-12 and -23 antagonist, in a clinical setting. This study aimed to investigate the immunogenicity of ustekinumab and its clinical consequences in psoriasis. METHODS: This prospective observational study enrolled 76 patients with plaque psoriasis who were treated with ustekinumab for a minimum of 7 months. Blood samples were drawn just prior to scheduled ustekinumab injection during clinic visits. Levels of anti-ustekinumab antibody (AUA) and serum ustekinumab concentration were measured respectively by radioimmunoassays and enzyme-linked immunoassays respectively, and correlated to clinical data and Psoriasis Area and Severity Index (PASI). RESULTS: AUA was detected in 6.5% of patients after a mean of 13 months of treatment. Patients with positive AUA had significantly lower serum ustekinumab concentrations (0.01 vs. 0.2 mg/L, p<0.001) and lower PASI 50 response than patients without AUA (0% vs. 69%, p = 0.004).The percentage of AUA formation was comparable between patients who had failed previous adalimumab with or without anti-adalimumab antibodies (AAA) (14.3% vs. 12.5%, p = 1.00). However, a higher proportion of switchers without AAA obtaining PASI50 (71.4% vs. 37.5%) and PASI75 response (42.9% vs.12.5%) within 7 months of ustekinumab treatment than with AAA though this difference did not reach statistical significance. CONCLUSIONS: Our results suggest that presence of AUA was significantly associated with treatment failure for ustekinumab, though limited by a small sample size. Also, determining the presence of ADA to antecedent TNF-α antagonists may assist in choosing an optimized subsequent treatment modality achieving treatment success.

Increased Risk of Chronic Kidney Disease in Rheumatoid Arthritis Associated with Cardiovascular Complications - A National Population-Based Cohort Study.

BACKGROUND AND OBJECTIVES: There have been few large population-based studies of the association between rheumatoid arthritis (RA) and chronic kidney disease (CKD) and glomerulonephritis. This nationwide cohort study investigated the risks of developing CKD and glomerulonephritis in patients with RA, and the associated risks for cardiovascular complications. METHODS: From the Taiwan National Health Insurance Research Database, we identified a study cohort of 12,579 patients with RA and randomly selected 37,737 subjects without RA as a control cohort. Each subject was individually followed for up for 5 years, and the risk of CKD was analyzed using Cox proportional hazards regression models. RESULTS: During the follow-up period, after adjusting for traditional cardiovascular risk factors RA was independently associated with a significantly increased risk of CKD (adjusted hazard ratio [aHR] 1.31; 95% confidence interval [CI] 1.23-1.40) and glomerulonephritis (aHR 1.55; 95% CI 1.37-1.76). Increased risk of CKD was also associated with the use of non-steroidal anti-inflammatory drugs, cyclosporine, glucocorticoids, mycophenolate mofetil, and cyclophosphamide. Patients with comorbidities had even greater increased risk of CKD. Moreover, RA patients with concurrent CKD had significantly higher likelihood of developing ischemic heart disease and stroke. CONCLUSIONS: RA patients had higher risk of developing CKD and glomerulonephritis, independent of traditional cardiovascular risk factors. Their increased risk of CKD may be attributed to glomerulonephritis, chronic inflammation, comorbidities, and renal toxicity of antirheumatic drugs. Careful monitoring of renal function in RA patients and tight control of their comorbid diseases and cardiovascular risk factors are warranted.

Excimer light photototherapy of segmental and non-segmental vitiligo: experience in Taiwan.

PURPOSE: To determine the efficacy of excimer light in the treatment vitiligo and to assess parameters affecting therapeutic results. METHODS: This retrospective study analyzed 227 patches of vitiligo in 142 patients. Treatment was performed twice weekly and treatment efficacy was assessed by two independent dermatologists. Patients who received less than 24 treatment sessions were excluded from the analysis of predictive factors for response. RESULTS: Sixty-eight (30.0%) patches achieved more than 50% repigmentation, and 42 (18.5%) achieved more than 75% repigmentation. The mean treatment numbers to achieve any repigmentation and more than 50% repigmentation were 19.41 and 34.93, respectively. Fewer treatment sessions number, segmental lesions and absence of melasma were significant predictors for poor treatment response in multivariate analysis. Lesions on the hands/feet needed the highest dose and scalp lesions needed the highest number of treatment sessions to produce initial repigmentation. CONCLUSIONS: Excimer light is a valuable treatment modality for both segmental and non-segmental vitiligo even in patients who have failed previous treatments. The number of treatment sessions needed to produce initial pigmentation may be higher than 30 for scalp lesions. There is a need to find other combination methods, both medical and surgical, to enhance its therapeutic efficacy.