[A woman with bumps in the eyebrows]. / Een vrouw met bultjes in haar wenkbrauwen.

A 28-year-old woman was seen at our clinic with asymptomatic bumps in the eyebrows which arose 3 months after microblading, a cosmetic procedure to make the eyebrows appear fuller. Physical examination showed red-brown confluent papules. A skin biopsy revealed a non-necrotizing granulomatous reaction with sarcoid granulomas. Blood test and a chest X-ray showed no abnormalities and histopathological stains were negative. We diagnosed her with a granulomatous reaction in response to pigment. The skin lesions eventually disappeared spontaneously within 6 months.

Mobile e-diary application facilitates the monitoring of patient-reported outcomes and a high treatment adherence for clinical trials in dermatology.

BACKGROUND: Assessment of treatment effects in clinical trials requires valid information on treatment adherence, adverse events and symptoms. Paper-based diaries are often inconvenient and have limited reliability, particularly for outpatient trials. OBJECTIVES: To investigate the utility of an electronic diary (e-diary) application for patients with skin diseases in outpatient clinical trials. METHODS: An e-diary application was developed and technically validated. Treatment adherence was defined as topical administration by the patient, and patient-reported outcomes, i.e. pain and itch, were evaluated by the e-diary in six clinical trials on newly tested topical drugs. Additionally, the proportion of patients capturing the applied topical drug by camera and filling in the pain and itch scores was defined as e-diary adherence, and patients' perception of usefulness and acceptability of the e-diary were evaluated. RESULTS: Treatment adherence rates of the included 256 patients were high (median 98%, range 97-99%). E-diary adherence was also high with a median of 93% (range 87-97%) for capturing the applied drug by camera, and 89% (range 87-96%) and 94% (range 87-96%) for entering respectively the itch and pain score. Daily symptom scores provided good insights into the disease burden, and patients rated the e-diary as good to excellent with respect to user acceptability. CONCLUSIONS: The results suggest that the e-diary is an excellent way to ensure proper treatment administration, indicated by both the high user acceptability scores and high treatment adherence. Moreover, the e-diary may also be valuable for frequent and reliable monitoring of patient-reported outcomes in daily clinical practice.

Apremilast for moderate hidradenitis suppurativa: no significant change in lesional skin inflammatory biomarkers.

BACKGROUND: Treatment with apremilast has recently demonstrated clinically meaningful improvement in moderate hidradenitis suppurativa (HS). OBJECTIVE: To evaluate the change in expression of inflammatory markers in lesional skin of HS patients receiving apremilast 30 mg twice daily (n = 15) for 16 weeks compared with placebo (n = 5). METHODS: At baseline, 5-mm punch biopsies were obtained from an index lesion (HSL) and non-lesional (HSN) skin in the same anatomical area. Subsequent HSL samples were taken as close as possible to the previously biopsied site at week 4 and week 16. After sampling, biopsies were split; one half was processed for in vivo mRNA analysis using real-time quantitative PCR; the other half was cultured for ex vivo protein analysis using a proximity extension assay (Olink). Linear mixed effects models were calculated to compare the levels of inflammatory markers in HSL skin between apremilast and placebo over time. RESULTS: At baseline, 17 proteins with a fold change >2 in HSL vs. HSN skin were identified in 20 patients. The top five were IL-17A (5), S100A12, CST5, IL-12/23p40, CD6 (1) with fold changes ranging from 6.6 to 1638, respectively (FDR <0.044). Linear mixed effects models for 75 assays were calculated. Protein levels of S100A12 decreased during treatment in the apremilast group compared with the placebo group (p = 0.014, FDR = 0.186). None of the 14 genes exhibited significant changes in expression over time. However, an evident downward trend in relative mRNA expression of IL-17A and IL-17F was demonstrated in patients receiving apremilast. CONCLUSION: We did not detect statistically significant changes in inflammatory markers in HSL skin of HS patients receiving apremilast compared with placebo, despite clinical improvement in the apremilast group. Nonetheless, S100A12 and IL-17A were significantly elevated in HSL skin and showed a decrease in response to apremilast. The translational model in clinical trials involving HS clearly needs further improvement.

A systematic literature review of the human skin microbiome as biomarker for dermatological drug development.

AIMS: To explore the potential of the skin microbiome as biomarker in six dermatological conditions: atopic dermatitis (AD), acne vulgaris (AV), psoriasis vulgaris (PV), hidradenitis suppurativa (HS), seborrhoeic dermatitis/pityriasis capitis (SD/PC) and ulcus cruris (UC). METHODS: A systematic literature review was conducted according to the PRISMA guidelines. Two investigators independently reviewed the included studies and ranked the suitability microbiome implementation for early phase clinical studies in an adapted GRADE method. RESULTS: In total, 841 papers were identified and after screening of titles and abstracts for eligibility we identified 42 manuscripts that could be included in the review. Eleven studies were included for AD, five for AV, 10 for PV, two for HS, four for SD and 10 for UC. For AD and AV, multiple studies report the relationship between the skin microbiome, disease severity and clinical response to treatment. This is currently lacking for the remaining conditions. CONCLUSION: For two indications - AD and AV - there is preliminary evidence to support implementation of the skin microbiome as biomarkers in early phase clinical trials. For PV, UC, SD and HS there is insufficient evidence from the literature. More microbiome-directed prospective studies studying the effect of current treatments on the microbiome with special attention for patient meta-data, sampling methods and analysis methods are needed to draw more substantial conclusions.

[A man with severe skin rash]. / Een man met heftige huiduitslag.

A 31-year-old man visited the outpatient clinic Dermatology with an exacerbation of his atopic eczema. Since a few day vesicles and crusts had appeared and his eyelids were swollen. He was known to have eczema, for which he was treated with ciclosporin 200 mg 2 times a day (4 mg/kg per day) since four months. Under this treatment the eczema used to be under control. There were no neurological symptoms or vision problems. At physical examination we saw erythematous papules, vesicles, superficial erosions and crusts on all body regions, but especially on the trunk and in the main neck region. The patient was diagnosed with eczema herpeticum and he was treated with intravenous aciclovir 1000 mg 3 times a day (10 mg/kg 3 dd) and flucloxacillin 1000 mg 4 times a day for seven days.

Non-invasive anaesthetic methods for dermatological laser procedures: a systematic review.

Pain is a common side-effect of dermatological laser procedures. Non-invasive anaesthetic drugs and anaesthetic procedures can be used to provide pain relief and increase patient satisfaction and treatment efficacy. However, it remains unclear which method provides the best pain relief. The objective of this systematic review was therefore to assess the efficacy and safety of non-invasive anaesthetic methods during dermatological laser procedures. A systematic literature search was conducted. Randomized and non-randomized controlled clinical trials (RCTs and CCTs) were included. Two authors independently assessed study eligibility, extracted data and assessed the risk of bias. The quality of evidence was rated using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Twenty RCTs and 12 CCTs were included, involving nine different laser indications: hair removal (n = 9), resurfacing/rejuvenation (n = 5), port wine stains (n = 8), leg telangiectasia (n = 3), facial telangiectasia (n = 2), tattoo removal (n = 2), naevus of Ota (n = 1), solar lentigines (n = 1) and HPV lesions (n = 1). The non-invasive anaesthetic methods (i.e. topical anaesthetic drugs, skin cooling, and pneumatic skin flattening [PSF]), types of lasers, laser settings, application time, and types of pain scales varied widely among the included studies. All of the studies had an unclear or high risk of bias, and the overall quality of evidence was rated as low. In general, active non-invasive anaesthetic methods seemed to provide favourable results compared to placebo or no anaesthesia, and topical anaesthetic drugs and PSF seemed to result in a better pain reduction than skin cooling. However, the current evidence is insufficient to provide recommendations for daily clinical practice. There is a need for more high-quality (head-to-head) RCTs. Future studies should also evaluate sex differences in pain perception, have uniformity with regard to validated pain measurement scales and address clinically significant differences in pain reduction besides statistically significant differences.

Lentigo maligna - anatomic location as a potential risk factor for recurrences after non-surgical treatment.

BACKGROUND: A higher incidence of lentigo maligna (LM) recurrences on the nose was previously observed in our cohort after non-surgical treatment. OBJECTIVES: To determine histological parameters that might be related to the previously observed higher incidence of LM recurrences on the nose after non-surgical treatment. METHODS: We randomly selected 22 surgical specimens of LM on the nose and 22 on the cheek. Histopathological analysis was performed on haematoxylin and eosin stained and microphthalmia transcription factor immunohistochemically stained slides. The number of pilosebaceous units (PSU) per mm, maximum depth of atypical melanocytes along the skin appendages and maximum depth of the PSU itself were determined. RESULTS: The nose had a significantly higher density of PSU than the cheek. The atypical melanocytes extended deeper along the PSU on the nose with a mean (SD) depth of 1.29 mm (0.48) vs. a mean depth of 0.72 mm (0.30) on the cheek (P < 0.001). The maximum depth of the PSU on the nose was greater than on the cheek, mean (SD) depth of 2.28 mm (0.41) vs. 1.65 mm (0.82) (P = 0.003). CONCLUSIONS: The higher recurrence risk of LM on the nose after non-surgical treatment that we previously observed in our cohort is most likely based on a higher density of atypical melanocytes and also their deeper extension into the follicles. These results shed more light on our previous findings and learn that anatomical location is relevant for the risk of recurrence of LM after non-surgical treatment.

Recurrence rate of lentigo maligna after micrographically controlled staged surgical excision.

BACKGROUND: Lentigo maligna is a slowly growing melanoma in situ. Current guidelines advise wide local excision with a margin of 5 mm as the treatment of first choice, which has recurrence rates ranging from 6% to 20%. OBJECTIVES: To determine retrospectively the recurrence rate of lentigo maligna after staged surgical excision. METHODS: Records of all patients with lentigo maligna treated with our method of staged surgical excision between 2002 and 2011 were retrieved. To identify recurrences we used the computer program Sympathy, which is linked to PALGA, a nationwide network and registry of histo- and cytopathology in the Netherlands. RESULTS: We identified 100 patients, who were treated with staged surgical excision with 100% immunohistopathological control of lateral margins. Digital pictures were used to facilitate orientation during the several stages of surgery. After a mean follow-up of 60 months, four patients had a recurrence, after 37, 58, 74 and 77 months of follow-up. CONCLUSIONS: Staged surgical excision is superior in clearance and recurrence rates to wide local excision for lentigo maligna and should be considered as the treatment of first choice in national and international guidelines.

Clinical relevance of immunogenicity of biologics in psoriasis: implications for treatment strategies.

Biological drugs such as the tumour necrosis factor inhibitors have revolutionized the treatment of psoriasis, but some have the potential to induce an unwanted immune response. This immunogenicity may be associated with low trough drug levels, reduced clinical efficacy, reduced drug survival and an increased risk for adverse events. This article presents a literature review of the evidence on immunogenicity of biologics used in the treatment of psoriasis and considers the implications for therapeutic decision-making in the management of patients with moderate-to-severe psoriasis.

Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families.

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition caused by germline FLCN mutations, and characterised by fibrofolliculomas, pneumothorax and renal cancer. The renal cancer risk, cancer phenotype and pneumothorax risk of BHD have not yet been fully clarified. The main focus of this study was to assess the risk of renal cancer, the histological subtypes of renal tumours and the pneumothorax risk in BHD. METHODS: In this study we present the clinical data of 115 FLCN mutation carriers from 35 BHD families. RESULTS: Among 14 FLCN mutation carriers who developed renal cancer 7 were <50 years at onset and/or had multifocal/bilateral tumours. Five symptomatic patients developed metastatic disease. Two early-stage cases were diagnosed by surveillance. The majority of tumours showed characteristics of both eosinophilic variants of clear cell and chromophobe carcinoma. The estimated penetrance for renal cancer and pneumothorax was 16% (95% minimal confidence interval: 6-26%) and 29% (95% minimal confidence interval: 9-49%) at 70 years of age, respectively. The most frequent diagnosis in families without identified FLCN mutations was familial multiple discoid fibromas. CONCLUSION: We confirmed a high yield of FLCN mutations in clinically defined BHD families, we found a substantially increased lifetime risk of renal cancer of 16% for FLCN mutation carriers. The tumours were metastatic in 5 out of 14 patients and tumour histology was not specific for BHD. We found a pneumothorax risk of 29%. We discuss the implications of our findings for diagnosis and management of BHD.

MK-0873, a PDE4 inhibitor, does not influence the pharmacokinetics of theophylline in healthy male volunteers.

BACKGROUND: MK-0873 is a novel selective phosphodiesterase-4 inhibitor, which has been in development for the treatment of chronic obstructive pulmonary disease (COPD). In this indication, theophylline is still an important treatment, despite its relatively small therapeutic window. In view of this, it is important to investigate whether MK-0873 could affect the pharmacokinetics, safety and tolerability of theophylline, when both drugs are given concomitantly. AIM: The objective of this study was to investigate the effect of multiple doses of oral MK-0873, a selective phosphodiesterase-4 inhibitor, on the pharmacokinetics, safety and tolerability profile of orally administered theophylline in healthy volunteers. METHODS: Eight healthy, non-smoking male subjects participated in this randomized, open-label, 2-period, cross-over study. In one period subjects received an oral dose of 2.5mg MK-0873 for 6 days co-administered with a single oral dose of 250 mg theophylline on day 5. The other period consisted of a single dose of 250 mg theophylline on day 1. In each period, blood samples were collected at predefined time points to evaluate theophylline pharmacokinetics. RESULTS: All subjects completed the study. The study medications were generally well tolerated and no clinically relevant changes were observed in either treatment periods. No significant difference was found in the AUC 0-infinity (77.7 vs. 83.8h ng/ml; p=0.280) and Cmax (6.70 vs. 7.77 ng/ml; p=0.125) of theophylline between the MK-0873+theophylline and theophylline only treatment, and bioequivalence was demonstrated for AUC0-infinity (geometric mean ratio with 90% confidence interval: 0.930 (0.826, 1.047)). CONCLUSION: In this study, in a limited number of subjects, co-administration of oral MK-0873 did not affect the pharmacokinetics, safety, and tolerability of oral theophylline in non-smoking healthy male subjects.

Pharmacokinetic differences between Caucasian and Japanese subjects after single and multiple doses of a potential combined oral contraceptive (Org 30659 and EE).

OBJECTIVES: To compare the pharmacokinetic parameters and safety of the progestagen, Org 30659, (17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one), and ethinyl estradiol (EE) in Caucasian and Japanese women after single and multiple doses. METHODS: This was an open-label parallel design of a single dose followed by a multiple dose period in healthy young Japanese and Caucasian subjects. RESULTS: The area under the curve (AUC) of Org 30659 after single dosing was increased by a factor of 1.75 [90% confidence interval (CI): 1.48-2.08] in Japanese women compared to Caucasian women. At steady state, this difference increased to a factor of 1.90 (90% CI: 1.60-2.25). The AUC of EE after single dosing was similar in Caucasian and Japanese women, but at steady state it was increased by a factor 1.38 (90% CI: 1.15-1.64) in the Japanese group. Weight normalization reduced, but did not remove, all the observed differences. Sex hormone binding globulin played no significant role in the differences between Caucasian and Japanese subjects. Both the single- and multiple-dose treatments with Org 30659/EE were generally well tolerated by all subjects. The Japanese population reported more and different treatment-related adverse events than the Caucasian population. CONCLUSIONS: The peak concentration and extent of exposure of Org 30659, and to a lesser extent of EE, in Japanese women are higher than in Caucasian women. Furthermore, the peak concentration and extent of exposure at steady state of Org 30659, and to a lesser extent of EE, are higher than would be predicted assuming linear pharmacokinetics over time. No major safety issues were observed.