Case report: Successful treatment with biologics in a pediatric patient with a severe inflammatory skin disease and novel CARD14 mutation.

CARD14 (caspase activation and recruitment domain) mutations have been associated with psoriasis vulgaris, psoriatic arthritis, generalized and palmoplantar pustular psoriasis, pityriasis rubra pilaris, and atopic dermatitis. We present a pediatric patient with a novel CARD14: c.394A > T/- (Ile123Phe) mutation, diagnosed with CARD14-associated papulosquamous eruption (CAPE), who was successfully treated with biological treatment.

Efficacy and Safety of Candidate Biosimilar CT-P43 Versus Originator Ustekinumab in Moderate to Severe Plaque Psoriasis: 28-Week Results of a Randomised, Active-Controlled, Double-Blind, Phase III Study.

BACKGROUND: CT-P43 is a candidate ustekinumab biosimilar in clinical development. OBJECTIVES: This paper aims to demonstrate equivalent efficacy of CT-P43 to originator ustekinumab in adults with moderate to severe plaque psoriasis. METHODS: This double-blind, phase III trial randomised patients (1:1) to receive subcutaneous CT-P43 or originator ustekinumab (45/90 mg for patients with baseline body weight ≤ 100 kg/> 100 kg) at week 0 and week 4 in Treatment Period I. Prior to week 16 dosing in Treatment Period II, patients receiving originator ustekinumab were re-randomised (1:1) to continue originator ustekinumab or switch to CT-P43; patients initially randomised to CT-P43 continued receiving CT-P43 (at weeks 16, 28 and 40). The primary endpoint of the trial was mean per cent improvement from baseline in Psoriasis Area Severity Index (PASI) score at week 12. Equivalence was concluded if confidence intervals (CIs) for the estimate of treatment difference were within pre-defined equivalence margins: ± 10% [90% CI; modified intent-to-treat set; Food and Drug Administration (FDA) approach] or ± 15% [95% CI; full analysis set for patients only receiving 45 mg doses in Treatment Period I; European Medicines Agency (EMA) approach]. Additional efficacy, pharmacokinetic, safety and immunogenicity endpoints were evaluated through week 52. Results to week 28 are reported here. RESULTS: In Treatment Period I, 509 patients were randomised (CT-P43: N = 256; originator ustekinumab: N = 253). The mean per cent improvement in PASI score at week12 was 77.93% and 75.89% for CT-P43 and originator ustekinumab, respectively (FDA approach); per the EMA approach, corresponding values were 78.26% and 77.33%. Estimated treatment differences were 2.05 (90% CI -0.23, 4.32) and 0.94 (95% CI -2.29, 4.16); equivalence was achieved for both sets of assumptions. Further efficacy parameters and pharmacokinetic, safety and immunogenicity outcomes were comparable between treatment groups, including after switching from originator ustekinumab to CT-P43. CONCLUSIONS: CT-P43 demonstrated equivalent efficacy to originator ustekinumab in patients with moderate to severe plaque psoriasis, with comparable pharmacokinetic, safety and immunogenicity profiles. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04673786; date of registration: 17 December, 2020.

The Assessment of Activity of Antiseptic Agents against Biofilm of Staphylococcus aureus Measured with the Use of Processed Microscopic Images.

Staphylococcal biofilms are major causative factors of non-healing wound infections. Their treatment algorithms recommend the use of locally applied antiseptic agents to counteract the spread of infection. The efficacy of antiseptics against biofilm is assessed in vitro by a set of standard quantitative and semi-quantitative methods. The development of software for image processing additionally allowed for the obtainment of quantitative data from microscopic images of biofilm dyed with propidium iodine and SYTO-9 reagents, differentiating dead cells from live ones. In this work, the method of assessment of the impact of antiseptic agents on staphylococcal biofilm in vitro, based on biofilms' processed images, was proposed and scrutinized with regard to clinically relevant antiseptics, polyhexanide, povidone-iodine and hypochlorite. The standard quantitative culturing method was applied to validate the obtained data from processed images. The results indicated significantly higher activity of polyhexanide and povidone-iodine than hypochlorite against staphylococcal biofilm. Taking into account the fact that in vitro results of the efficacy of antiseptic agents against staphylococcal biofilm are frequently applied to back up their use in hospitals and ambulatory units, our work should be considered an important tool; providing reliable, quantitative data in this regard.

The In Vitro Ability of Klebsiella pneumoniae to Form Biofilm and the Potential of Various Compounds to Eradicate It from Urinary Catheters.

Urinary infections related to the presence of bacterial biofilm on catheters are responsible for loss of patients' health and, due to their high frequency of occurrence, generate a significant economic burden for hospitals. Klebsiella pneumoniae is a pathogen frequently isolated from this type of infection. In this study, using a cohesive set of techniques performed under stationary and flow conditions, we assessed the ability of 120 K. pneumoniae strains to form biofilm on various surfaces, including catheters, and evaluated the usefulness of clinically applied and experimental compounds to remove biofilm. The results of our study indicate the high impact of intraspecies variability with respect to K. pneumoniae biofilm formation and its susceptibility to antimicrobials and revealed the crucial role of mechanical flushing out of the biofilm from the catheter's surface with use of locally active antimicrobials. Therefore, our work, although of in vitro character, may be considered an important step in the direction of efficient reduction of K. pneumoniae biofilm-related hospital infections associated with the presence of urine catheters.

Bullous diseases caused by KRT1 gene mutations: from epidermolytic hyperkeratosis to a novel variant of epidermolysis bullosa simplex.

INTRODUCTION: Mutations in the KRT1 gene encoding keratin 1 cause epidermolytic hyperkeratosis characterized by blistering in the neonatal period followed by ichthyotic hyperkeratosis in childhood and adolescent life. We observed a spectrum of clinical manifestations of blistering disorders caused by different mutations in the same KRT1 gene. AIM: To analyse the phenotypic spectrum of blistering disorders caused by the KRT1 mutations. MATERIAL AND METHODS: Four patients with an epidermal barrier defect manifesting as blistering with the KRT1 mutations were included to the study. The clinical course of the disease was analysed, histology, immunofluorescence and electron microscopic examinations were performed. RESULTS: An adult patient with severe ichthyosis with p.Asn188Lys mutation in exon 1 of KRT1 who occasionally develops blisters in adolescence represents epidermolytic hyperkeratosis, a newborn child who died 4 days after birth due to disruption of the epidermal barrier (extensive blister and erosions) with mutation p.Ser193Pro in the KTR1 gene and two adult sisters harbouring heterozygous mutation c.591+1A>G in the KRT1 gene who present superficial blisters induced by mild trauma from the birth up to adolescent life without ichthyosis suggesting the diagnosis of epidermolysis bullosa simplex. Histopathology in all adult patients showed cytoplasm disruption in keratinocytes of the stratum spinosum with keratohyalin granule-like structures and, on the ultrastructural level, the presence of keratin clumping confirming the pathology of keratin intermediate filaments. CONCLUSIONS: This study extends the knowledge of the clinical spectrum for the KRT1 gene mutations. This is the first description of familial dominant epidermolysis bullosa simplex linked to the KRT1 mutation.

Usefulness of three-dimensional digital image analysis for objective evaluation of the efficacy of non-facial port-wine stain treatment with large spot 532 nm laser.

INTRODUCTION: New devices such as the large spot KTP laser are being introduced for the treatment of port-wine stains (PWS). AIM: To assess the efficacy of the large spot 532 nm laser for non-facial PWS with 3D image analysis and compare it with subjective evaluation. MATERIAL AND METHODS: Twenty PWS were photographed with a 3D photo unit before and after 532 nm large spot KTP laser treatment. Fifteen lesions were previously treated by different devices and five were not. Objective analysis of percentage improvement based on a 3D digital assessment of combined color and area improvement was performed and rates of improvement were determined as well as subjective evaluation of before and after images by a physician on a 5-grade scale. RESULTS: Mean objective response was 57.0%. A poor response was observed in 5% with the objective method and with no patient with the subjective method. A moderate response was achieved by 25% and 30% with the objective and subjective assessment respectively. A significant response was obtained by 55% objectively and 10% subjectively. 75-100% was achieved by 15% and 60% in the objective and subjective analysis respectively. The two methods significantly correlated with each other but the average subjective improvement rates were higher than the objective rates. CONCLUSIONS: Both objective and subjective analysis indicated that the large spot 532 nm laser is highly effective in the treatment of the neck and trunk. 3D color and area objective analysis provides an accurate tool to measure the efficacy of PWS treatment.

Age-related changes in elastographically determined strain of the facial fat compartments: a new frontier of research on face aging processes.

INTRODUCTION: Our study goal was verification of shear-wave elastography (SWE) as an assessment tool enabling quantitative analysis of facial fat tissue elasticity, using the example of the deep medial cheek fat compartment (DMCFC), due to its major role in pseudoptosis etiology. AIM: Furthermore, we determined the age-specific reference values for DMCFC elasticity and analyzed its correlation with body mass index (BMI) and DMCFC thickness. MATERIAL AND METHODS: The study included 89 female patients (age: 18-63 years, mean: 45.9 ±14.2 years) with intact facial skin. Prior to the procedure, all participants were subjected to SWE of the DMCFC. Reference ranges for elastographic parameters were defined as ± 2 standard deviations (SD), or estimated by means of ROC analysis. RESULTS: The DMCFC elasticity correlated inversely with DMCFC thickness (R = -0.292, p < 0.001), age (R = -0.838, p < 0.001) and BMI of the study subjects (R = -0.258, p = 0.001). Age was found to be the only independent determinant of DMCFC elasticity on multiple linear regression analysis (ß = -0.837, p < 0.001). The cut-off values for DMCFC elasticity estimated during ROC analysis provided excellent accuracy in distinguishing between women from various age categories, and to a large degree overlapped with the reference intervals defined as ± 2 SD. CONCLUSIONS: Shear-wave elastography enables quantitative evaluation of facial fat pad elasticity, creating a new frontier in research on age-related processes. The results indicate that elasticity of the DMCFC decreases significantly with age. Tissue elasticity might be an indirect indicator of metabolic and structural properties of facial adipose tissue and its extracellular matrix.

Intra-rater reproducibility of shear wave elastography in the evaluation of facial skin.

INTRODUCTION: Recently, esthetic medicine has been gaining its momentum worldwide, mostly due to the development of minimally invasive techniques. In our opinion, elastography can be a candidate for an objective quantitative method to evaluate facial skin condition. The aim of this study was to determine intra-rater reproducibility of shear wave elastography (SWE) in the evaluation of facial skin in patients qualified for minimally invasive nonsurgical facial rejuvenation treatment. AIM: To determine intra-rater reproducibility of shear wave elastography (SWE) in the evaluation of facial skin in patients qualified for minimally invasive nonsurgical facial rejuvenation treatment. MATERIAL AND METHODS: The study included 57 women between 40 and 67 years of age (mean: 51.5 ±7.3 years). Prior to the laser treatment, all participants were subjected to ultrasonographic examination and elastography of the skin. Upon visualization of the area of interest, the thickness of the dermis, subcutaneous tissue and superficial muscular aponeurotic system (SMAS) in millimeters was measured. Then, SWE was performed. RESULTS: No statistically significant differences were found in intraclass coefficient values (ICC) for elastographic parameters of the skin on the right and left side of the face (0.953 ±0.001 vs. 0.953 ±0.001, p = 0.992). Moreover, no significant differences were observed in the ICC values for the SWE parameters of various skin layers: dermis, subcutaneous tissue and SMAS (0.945 ±0.001 vs. 0.953 ±.001 vs. 0.961 ±0.001, p = 0.597). Women with normal body weight and overweight did not differ significantly in terms of their elastographic parameters of facial skin. CONCLUSIONS: Shear wave elastography is a reliable method for the evaluation of facial skin elasticity, providing highly reproducible results in all patients, regardless of their age and body weight.

Predictive value of dermoscopy for the treatment of port-wine stains with large spot 532 nm laser.

OBJECTIVE: We wanted to evaluate dermoscopy as a tool to predict the efficacy of port-wine stain (PWS) laser treatment. STUDY DESIGN AND METHODS: Large spot 532 nm laser was used for the treatment of 67 PWS. Efficacy was assessed with an objective 3D digital imaging analysis. Dermoscopy images were taken before the treatment and analyzed semi quantitatively for features and patterns. RESULTS: The following dermoscopic features: "superficial vessels," "deep vessels," "deep lakes," "superficial lakes," and "thick vessels total" were identified as positive determinants of maximal global clearance effect (GCEmax), whereas "thin long vessels," "bright background total," "whitish veil," "white circles," and "perifollicular erythema" were found to be negative determinants. Rapid response correlated positively with "superficial vessels," "superficial lakes," and "thick vessels total" scores and showed inverse correlations with "bright-red background," "bright background total," "white circles," "peacock eyes," and "perifollicular erythema" scores. "Superficial vessels," "thick vessels total," and "pale-pink patchy background" were predictors of the lack of response. Dominance of "deep vessels" was a predictor of 75% of responses and dominance of "brown areas" feature was the predictor of clearance. Patients responded to treatment differently, depending on the dermoscopic pattern of PWS. CONCLUSION: Dermoscopy may be useful to predict the response of PWS to laser treatment: its rapidity, the risk of no response, and 75% response and clearance. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

General Characteristics and Comorbidities in Patients with Palmoplantar Pustulosis.

The aim of this prospective study was to analyze comorbidities in patients with palmoplantar pustulosis (PPP). The current study comprised 63 consecutive patients with palmoplantar pustulosis. The control group consisted of 37 patients with psoriasis vulgaris (PSV). The study included a standardized anamnesis, a clinical examination, blood tests for thyroid hormones, as well as calcium, magnesium, antiendomysial antibody, and patch tests. Hypertension was observed in 28/63 (44.44%) patients with PPP. Eight (12.7%) had ischaemic heart disease, and 7/63 (11.11%) had type 2 diabetes mellitus. There was no statistically significant difference between the patients with PPP and those in the control group. Metabolic syndrome was diagnosed in 19/63 (30.16%) patients with PPP and in 12/37 (32.43%) patients with PSV. Thyroid disease was more prevalent among patients with PPP in comparison to patients with PSV (31.75% vs. 13.51%; p=0.0421). Body mass index was statistically significantly higher in patients with PSV (28.25 vs. 25.86 kg/m², p=0.0144). BMI was higher than 25 kg/m2 in 18.03% patients with PPP and 26.47% patients with PSV (p=0.333). Positive patch tests were observed in 12/39 (30.77%) patients with PPP. The most common allergens were nickel chloride (5/12, 41.67%) and fragrances (5/12, 41.67%). In the control group, patch tests were positive in 2/11 (18.18%) cases (p<0.05). Patients with PPP, like patients with PSV, often presented with hypertension and metabolic syndrome. Given that many studies have focused on cardiovascular risk in PSV, there is a need for further research on the association between PPP and cardiovascular risk. In addition, patients resistant to PPP treatment should be screened for contact allergies.

Treatment of Previously Treated Facial Capillary Malformations: Results of Single-Center Retrospective Objective 3-Dimensional Analysis of the Efficacy of Large Spot 532 nm Lasers.

BACKGROUND: Current treatment of facial capillary malformations (CM) has limited efficacy. OBJECTIVE: To assess the efficacy of large spot 532 nm lasers for the treatment of previously treated facial CM with the use of 3-dimensional (3D) image analysis. PATIENTS AND METHODS: Forty-three white patients aged 6 to 59 were included in this study. Patients had 3D photography performed before and after treatment with a 532 nm Nd:YAG laser with large spot and contact cooling. Objective analysis of percentage improvement based on 3D digital assessment of combined color and area improvement (global clearance effect [GCE]) were performed. RESULTS: The median maximal improvement achieved during the treatment (GCE) was 59.1%. The mean number of laser procedures required to achieve this improvement was 6.2 (range 1-16). Improvement of minimum 25% (GCE25) was achieved by 88.4% of patients, a minimum of 50% (GCE50) by 61.1%, a minimum of 75% (GCE75) by 25.6%, and a minimum of 90% (GCE90) by 4.6%. Patients previously treated with pulsed dye lasers had a significantly less response than those treated with other modalities (GCE 37.3% vs 61.8%, respectively). CONCLUSION: A large spot 532 nm laser is effective in previously treated patients with facial CM.

Novel Therapeutic Approaches to Atopic Dermatitis.

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. The number of people affected by AD is relatively high and seems to be rising. Although mild and moderate forms of the disease can be well controlled by the use of emollients, topical corticosteroids, and topical calcineurin inhibitors, treatment of severe is still a huge challenge. The new hope is biologic drugs, magic bullets in allergy, targeted at different points of the complex pathomechanism of inflammation in AD. In this review, novel biologic therapies are discussed, including recombinant monoclonal antibodies directed against various interleukin pathways (such as IL-4, IL-13, TSLP, IL-31, and IL-12/23), on immunoglobulin E, molecules acting as T cells, B cells, etc. Of biological drugs, the most promising seems to be anti-IL-4/IL-13 therapy (dupilumab-the biological agent) and phosphodiesterase-4 inhibitor (crisaborole-a small molecule). A deep understanding of the AD pathomechanism provides a new perspective for tailor-made treatment of severe atopic dermatitis.

Long-term treatment of chronic plaque psoriasis with biological drugs can control platelet activation: targeting the bridge between inflammation and atherothrombosis.

INTRODUCTION: Platelet activation is elevated in moderate to severe psoriasis, and the reduction in platelet activation during short-term treatment has already been demonstrated. Soluble P-selectin is a well-established marker of platelet activation. AIM: To show whether the long-term treatment of psoriasis with biological drugs can reduce elevated platelet activation. MATERIAL AND METHODS: An observational study of 27 patients with chronic plaque psoriasis, treated with infliximab, adalimumab, etanercept, or ustekinumab for up to 12 months was conducted. Psoriasis area and severity index (PASI), serum P-selectin and interleukin (IL)-6 were monitored throughout the treatment. RESULTS: There was no significant correlation between PASI and platelet activation in our patients. After 3 months of treatment, a significant reduction in PASI and IL-6 was found, while P-selectin was not significantly reduced. When a cohort of patients who had shown elevated P-selectin prior to the treatment was evaluated, a significant reduction in P-selectin was observed in all 8 patients following 3 months; a reduction that was sustained after 6 and 12 months of therapy. CONCLUSIONS: We conclude that PASI is not a good predictor of platelet activity in patients with PASI near to 10. Biological drugs reduce platelet activation in patients who have increased platelet activation prior to treatment, and this effect is stable during chronic therapy.

Retrospective single center study of the efficacy of large spot 532 nm laser for the treatment of facial capillary malformations in 44 patients with the use of three-dimensional image analysis.

OBJECTIVE: We wanted to asses the efficacy of large spot 532 nm laser for the treatment of facial capillary malformations with the use of three-dimensional (3D) image analysis. STUDY DESIGN AND METHODS: Retrospective single center study on previously non-treated patients with facial capillary malformations (CM) was performed. A total of 44 consecutive Caucasian patients aged 5-66 were included. Patients had 3D photography performed before and after and had at least one single session of treatment with 532 nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser with contact cooling, fluencies ranging from 8 to 11.5 J/cm2 , pulse duration ranging from 5 to 9 milliseconds and spot size ranging from 5 to 10 mm. Objective analysis of percentage improvement based on 3D digital assessment of combined color and area improvement (global clearance effect [GCE]) were performed. RESULTS: Median maximal improvement achieved during the treatment (GCEmax ) was 70.4%. Mean number of laser procedures required to achieve this improvement was 7.1 (ranging from 2 to 14)). Improvement of minimum 25% (GCE 25) was achieved by all patients, of minimum 50% (GCE 50) by 77.3%, of minimum 75% (GCE 75) by 38.6%, and of minimum 90% (GCE 90) by 13.64. CONCLUSION: Large spot 532 nm laser is highly effective in the treatment of facial CM. 3D color and area image analysis provides an objective method to compare different methods of facial CM treatment in future studies. Lasers Surg. Med. 49:743-749, 2017. © 2017 Wiley Periodicals, Inc.

Keratoacanthoma (KA): An update and review.

Keratoacanthoma (KA) is a common but underreported tumor of the skin. Two striking features of KA are its clinical behavior with spontaneous regression after rapid growth and its nosological position on the border between benignity and malignancy. We review current knowledge on the clinical, histopathological, and dermoscopic features of KA to ensure a proper diagnosis and describe its variants, including different types of multiple KAs. We highlight current concepts of KA ethiopathogenesis with special emphasis on the genetic background of multiple familial KA, the role of Wnt signaling pathway, and induction of KA by BRAF inhibitors and procedures of esthetic dermatology. Finally, treatment strategies are presented with surgical excision as a first option, followed by other modalities, including intralesional chemotherapy, topical and systemic agents, lasers, cryotherapy, and photodynamic therapy.

Lack of prolidase causes a bone phenotype both in human and in mouse.

The degradation of the main fibrillar collagens, collagens I and II, is a crucial process for skeletal development. The most abundant dipeptides generated from the catabolism of collagens contain proline and hydroxyproline. In humans, prolidase is the only enzyme able to hydrolyze dipeptides containing these amino acids at their C-terminal end, thus being a key player in collagen synthesis and turnover. Mutations in the prolidase gene cause prolidase deficiency (PD), a rare recessive disorder. Here we describe 12 PD patients, 9 of whom were molecularly characterized in this study. Following a retrospective analysis of all of them a skeletal phenotype associated with short stature, hypertelorism, nose abnormalities, microcephaly, osteopenia and genu valgum, independent of both the type of mutation and the presence of the mutant protein was identified. In order to understand the molecular basis of the bone phenotype associated with PD, we analyzed a recently identified mouse model for the disease, the dark-like (dal) mutant. The dal/dal mice showed a short snout, they were smaller than controls, their femurs were significantly shorter and pQCT and µCT analyses of long bones revealed compromised bone properties at the cortical and at the trabecular level in both male and female animals. The differences were more pronounce at 1 month being the most parameters normalized by 2 months of age. A delay in the formation of the second ossification center was evident at postnatal day 10. Our work reveals that reduced bone growth was due to impaired chondrocyte proliferation and increased apoptosis rate in the proliferative zone associated with reduced hyperthrophic zone height. These data suggest that lack of prolidase, a cytosolic enzyme involved in the final stage of protein catabolism, is required for normal skeletogenesis especially at early age when the requirement for collagen synthesis and degradation is the highest.

Tacrolimus and TGF-beta act synergistically on the generation of Langerhans cells.

BACKGROUND: The proportion of dendritic cell subpopulations in the skin is important for the severity of atopic dermatitis because topical treatment with tacrolimus leads to rapid depletion of inflammatory dendritic epidermal cells, whereas Langerhans cells (LCs) predominate in cured sites. OBJECTIVES: The effects of tacrolimus and TGF-beta1 on LC differentiation and the idea of tacrolimus skewing the differentiation of epidermal precursors to LCs were evaluated. METHODS: The presence of LC markers, MHC, and costimulatory molecules and stimulatory capacity toward T cells of monocyte-derived LCs were analyzed. Skin samples of patients with atopic dermatitis were assessed by means of immunofluorescence microscopy before and after tacrolimus treatment. TGF-beta production of skin cells was analyzed. RESULTS: Tacrolimus and TGF-beta1 act synergistically on the generation of LCs and the expression of CD40, CD80, CD86, CD83, and MHC II; stabilize TGF-beta receptor II expression; and decrease the stimulatory capacity of LCs toward T cells. In vivo the number of epidermal LCs in tacrolimus-treated skin increased. CONCLUSION: The synergism between TGF-beta1 and tacrolimus leads to the generation of LCs, reduced expression of costimulatory and MHC II molecules, and reduced stimulatory activity. Shifting the balance of the dendritic cell population to LCs might be of major importance for the therapeutic effect of tacrolimus.