Compromising human skin in vivo and ex vivo to study skin barrier repair.

Ex vivo regenerated stratum corneum (SC) after tape-stripping can be used as a model to study the barrier function of compromised skin. Yet, details about how close the regenerated SC model mimics the lipid properties (e.g. lipid composition and lipid ordering) of the in vivo situation are not known. Here, we examined using a comprehensive ceramide analysis whether human ex vivo regenerated SC showed similar lipid properties as human in vivo regenerated SC. Both in vivo and ex vivo regenerated SC had an altered ceramide subclass composition, with increased percentages of sphingosine-based subclass and decreased percentages of phytosphingosine-based subclass ceramides, a reduced mean ceramide chain length, and a higher percentage of unsaturated ceramides. Overall, regenerated SC ex vivo showed more pronounced but similar changes compared to the in vivo response. One of the purposes of these models is to use them to mimic compromised skin of inflammatory skin diseases. The altered lipid properties in regenerated SC were comparable to those observed in several inflammatory skin diseases, which makes them a valuable model for the barrier properties in inflammatory skin diseases.

[Chloroquine retinopathy]. / Retinopathie door chloroquine.

BACKGROUND: Chloroquine (CQ) and hydroxychloroquine (HCQ) can induce retinopathy. The risk of this severe, irreversible ophthalmological complication significantly increases with duration of treatment (> 5 years) and dosage of medication (for CQ > 2.3 mg/kg/day and HCQ > 5.0 mg/kg/day). Other important risk factors are renal failure, concomitant tamoxifen use and pre-existing retinopathy or maculopathy. CASE DESCRIPTION: We describe a 46-year old woman with chronic discoid lupus erythematosus who developed bull's-eye maculopathy as a consequence of treatment with CQ in varying doses of 100-300 mg/day for five years. Treatment with CQ was subsequently discontinued. CONCLUSION: All patients treated with CQ or HCQ should be referred to the ophthalmologist for baseline testing within 1 year after starting treatment. If there are no risk factors, patients who are treated with CQ or HCQ should undergo annual ophthalmological testing from 1 year, respectively 5 years after start of treatment. The risk factors need to be rechecked at each outpatient check-up because these factors can affect the required frequency of ophthalmological check-ups.

Attentional processing of itch.

Itch is a prevalent somatosensory symptom that can be highly disabling, because it is likely to draw attention and, as a result, may interfere with the performance of daily activities. Yet, research experimentally investigating attention to itch is lacking. In this study we aimed to investigate attentional processing of itch using multiple behavioral attention tasks. Forty-one healthy participants performed (1) a modified Stroop task with itch-related words, (2) a dot-probe task with itch-related pictures, and (3) a recently developed somatosensory attention task in which the effect of experimentally induced itch on the localization of visual targets was examined. Additionally, a number of self-report questionnaires related to somatosensory attentional processing were administered. Results indicated that participants' attention was biased toward itch-related words and pictures assessed by means of the dot-probe and modified Stroop task, respectively. For the somatosensory attention task, results showed that itch did not significantly influence the allocation of attention. However, when taking into account the time course of attention during the itch stimulus, data suggested that participants tended to disengage attention away during the itch stimulus. This is the first study that indicates an attentional bias for itch, using methods that have previously been validated for other sensations such as pain. In addition, the newly developed somatosensory attention task may reflect the time course of attention toward a tonic itch stimulus.

Cellulitis: current insights into pathophysiology and clinical management.

Cellulitis is a bacterial skin and soft tissue infection which occurs when the physical skin barrier, the immune system and/or the circulatory system are impaired. Diabetes, obesity and old age are associated with defects in all of these areas and as a result are major predisposing factors for cellulitis. In this review, we summarise current insights into the pathophysiology of cellulitis and place the Dutch guidelines on the clinical management of cellulitis of the lower extremities in perspective. Recent evidence on diagnostic strategies is discussed, the importance of which is underscored by findings that venous insufficiency, eczema, deep vein thrombosis and gout are frequently mistaken for cellulitis. Empiric antibiotic choices are designed against the background of a low prevalence of multi-resistant Staphylococcus aureus. Novel antimicrobial agents registered for cellulitis are also discussed. Relapses occur frequently due to a high prevalence of risk factors associated with cellulitis in combination with the ccurrence of persistent post-inflammatory lymphatic damage. Lastly, we identify knowledge gaps which, if addressed, will advance our understanding of the pathophysiology of cellulitis and improve its clinical management.

[A man with skin lesions of his face]. / Een man met huidafwijkingen in zijn gezicht.

A 69-year-old man with rheumatoid arthritis developed a discoid rash on his face years after the initiation of treatment with adalimumab. Serological tests were positive for antinuclear antibodies (ANA) and autoantibodies against Sjögren's syndrome-related antigen A (SSA). We diagnosed him with 'lupus-like syndrome'. After discontinuation of the adalimumab therapy and the use of topical corticosteroids, his symptoms resolved quickly.

Lipid to protein ratio plays an important role in the skin barrier function in patients with atopic eczema.

BACKGROUND: The barrier function of the skin is primarily provided by the stratum corneum (SC), the outermost layer of the skin. Skin barrier impairment is thought to be a primary factor in the pathogenesis of atopic eczema (AE). Filaggrin is an epidermal barrier protein and common mutations in the filaggrin gene strongly predispose for AE. However, the role of filaggrin mutations in the decreased skin barrier in AE is not fully understood. It was recently shown that changes in SC lipid composition and organization play a role in the reduced skin barrier in AE. OBJECTIVES: To determine whether the lipid/protein ratio and the total dry SC mass per surface area are related to the skin barrier function of controls and patients with AE. METHODS: A case-control study was performed to compare nonlesional and lesional skin of AE with skin of controls. The dry SC mass was determined by tape-stripping and Squamescan(™) . The ratio between lipid and protein bands in the Raman spectrum was used to determine the lipid/protein ratio. Skin barrier function was assessed by transepidermal water loss. RESULTS: The results show that the dry SC mass per skin area is altered only in lesional SC of patients with AE compared with control subjects. The observed reduction in the lipid/protein ratio in SC of patients with AE was more pronounced, both in lesional and nonlesional SC and correlated strongly with the skin barrier function and disease severity. CONCLUSIONS: The lipid/protein ratio plays a role in the reduced skin barrier function in AE.

Electron diffraction study of lipids in non-lesional stratum corneum of atopic eczema patients.

Skin barrier impairment is thought to be an important factor in the pathogenesis of atopic eczema (AE). The skin barrier is located in the stratum corneum (SC), consisting of corneocytes embedded in lipids. Ceramides, cholesterol and free fatty acids are the major lipid classes and are crucial for the skin barrier function, but their role in relation to AE is indistinct. Filaggrin is an epidermal barrier protein and common mutations in the filaggrin gene strongly predispose for AE. However, there is no strong evidence that filaggrin mutations are related to the reduced skin barrier in AE. In this study, electron diffraction is used in order to study the lipid organization of control SC and non-lesional SC of AE patients in vivo. An increased presence of the hexagonal lipid organization was observed in non-lesional SC of AE patients, indicating a less dense lipid organization. These changes correlate with a reduced skin barrier function as measured with transepidermal water loss but do not correlate with the presence of filaggrin mutations. These results are indicative for the importance of the lipid organization for a proper skin barrier function.

Point and period prevalences of eczema in rural and urban schoolchildren in Ghana, Gabon and Rwanda.

BACKGROUND: Eczema is a growing problem in Africa, particularly amongst children. OBJECTIVES: To investigate the point-prevalences of eczema by physical examination in schoolchildren living in rural and urban areas and with different socioeconomic backgrounds in Ghana, Gabon and Rwanda. In Ghana period-prevalences were also estimated by questionnaire and compared with the point-prevalences. METHODS: In total, 4839 schoolchildren in Ghana, Gabon and Rwanda were seen by at least one dermatologist. The point-prevalences of eczema were estimated on the basis of physical examination. Period-prevalences were measured in Ghana with questionnaire based-interviews adapted from the International Study of Asthma and Allergies in Childhood (ISAAC). RESULTS: The point-prevalences were 1.5% and 1.6% in the two Ghanaian studies; 4% in Gabon and 0.8% in Rwanda. The period-prevalences were 2.6% and 4.4% in the two Ghanaian studies. The prevalences of eczema were not significantly different when comparing the urban and rural groups as well as the different socioeconomic levels. The sensitivity and positive predictive value to identify eczema cases based on the questionnaires compared to the diagnoses by physical examination were only 33% and 22% in the first Ghanaian study and 10% and 4% in the second Ghanaian study respectively. CONCLUSIONS: The point-prevalences of eczema in the three African countries studied were low compared with industrialized countries. Physical examination by a dermatologist is still the gold standard to identify eczema cases because the sensitivity and the positive predictive value to identify eczema cases with questionnaires were low in the two Ghanaian studies.

Recommendations on management of EGFR inhibitor-induced skin toxicity: a systematic review.

Epidermal growth factor receptor (EGFR) inhibitors, such as the monoclonal antibodies cetuximab and panitumumab, have proven efficacy in various types of cancer. However, these agents frequently result in skin toxicity, due to the expression of the EGFR in the skin. A correlation between the occurrence of skin toxicity and anti-tumor activity has been suggested in several phase III studies. However, since skin toxicity may impair the quality of life, and severe skin toxicity requires dose reduction or interruption, adequate and timely management of skin toxicity is important to maximize the anti-tumor efficacy of the EGFR inhibitor, as well as maintaining the patient's quality of life. Due to the small number of randomized controlled trials conducted in the field of EGFR inhibitor-induced skin toxicity so far, it is not possible yet to generate evidence based guidelines on its management. Here, we review and discuss available trials and case studies reporting on the management of EGFR inhibitor-induced skin toxicity.

Prevalence and causative fungal species of tinea capitis among schoolchildren in Gabon.

Tinea capitis is endemic among schoolchildren in tropical Africa. The objective was to determine the prevalence of symptomatic tinea capitis in schoolchildren in Gabon. A cross-sectional study was conducted with 454 children aged 4-17 years, attending a rural school and an urban school. The diagnosis of tinea capitis was based on clinically manifest infection, direct microscopic examination using 20% potassium hydroxide (KOH) solution and fungal culture. Based on clinical examination, 105 (23.1%) of 454 children had tinea capitis. Seventy-four (16.3%) children were positive by direct examination (KOH) and/or fungal culture. The prevalence of tinea capitis depended on the school studied and ranged from 20.4% in the urban school with a higher socioeconomic status to 26.3% in the rural school with a lower socioeconomic status. Similarly, the spectrum of causative species varied between the different schools. Taken the schools together, Trichophyton soudanense (29.4%) was the most prominent species, followed by Trichophyton tonsurans (27.9%) and Microsporum audouinii (25.0%). Clinically manifest tinea capitis is endemic among schoolchildren in the Lambaréné region in Gabon. The prevalence of tinea capitis and the causative species depended on the type of school that was investigated.

[Mucocutaneous abnormalities in Chlamydia trachomatis-induced reactive arthritis]. / Mucocutane afwijkingen bij reactieve artritis door Chlamydia trachomatis.

Reactive arthritis (previously known as Reiters syndrome) is an inflammatory arthritis that is a type of spondyloarthropathy. The disease consists of the classical triad of arthritis, urethritis and conjunctivitis, but mucocutaneous abnormalities also frequently appear: balanitis circinata, keratoderma blennorrhagicum, aphthous ulcers in the mouth and nail disorders. These skin lesions are mainly found in reactive arthritis induced by Chlamydia trachomatis (Ct). Reactive arthritis is often triggered by a sexually transmitted infection (Chlamydia trachomatis) or an enteric infection (such as Salmonella or Shigella). It is thought that human antibodies against the pathogen cross-react with the HLA antigen (mainly HLA-B27). To distinguish between reactive arthritis and psoriatic arthritis, screening of the urine or synovium for Ct infection should be carried out. Acute reactive arthritis is treated with NSAIDs as the first choice. In addition, patients may receive an intra-articular injection of glucocorticoids. The mucocutaneous abnormalities respond well to topical glucocorticoids. Although in the Netherlands a Ct induced reactive arthritis is not yet treated with antibiotics, a recent published clinical trial in patients with a chronic Ct induced reactive arthritis showed a significant reduction in complaints in the group treated with a combination of antibiotics for 6 months, compared to the placebo group. Active genitourinary Ct infection should be treated with antibiotics, the first choice being azithromycin 1000 mg as a single dose. It is important that the patient's partner is tested at the same time and if necessary treated simultaneously to prevent reinfection.

Allergic characteristics of urban schoolchildren with atopic eczema in Ghana.

BACKGROUND: Atopic eczema is an increasing clinical problem in Africa. OBJECTIVE: To determine allergic characteristics and to identify possible risk factors for eczema among schoolchildren in an urbanized area in Ghana. PATIENTS AND METHODS: Schoolchildren aged 3-16 years with eczema were recruited. For each patient, one to three age- and sex-matched controls were selected. All children completed a questionnaire and were skin prick tested with a panel of allergens. Blood was drawn to determine the total and allergen-specific IgE. Conditional logistic regression models with the matching factors included in the model were used to calculate the odds ratios and to adjust for possible confounders. RESULTS: A total of 52 children with eczema (27 boys and 25 girls) and 99 controls were included. Levels of total IgE were found to be 9.1 (1.1; 78.4) times more often elevated in children with eczema. This association was mainly driven by elevated IgE levels against cockroach antigen. Children with eczema were found to have 2.0 (0.87; 4.7) times more often positive skin prick tests (SPT), but this association diminished to 1.2 (0.40; 3.6) after adjustment for total IgE levels. Frequent washing with soap was identified as a risk factor for the development of eczema among these children. CONCLUSION: Schoolchildren with eczema in Ghana were characterized by elevated IgE levels especially against cockroach antigen. The association between eczema and positive SPT was much weaker suggesting immune hyporesponsiveness of the skin. After adjustment for IgE level, SPT were less suitable to distinguish children with and without eczema.

Diagnosis of common dermatophyte infections by a novel multiplex real-time polymerase chain reaction detection/identification scheme.

BACKGROUND: In the absence of a functional dermatophyte-specific polymerase chain reaction (PCR), current diagnosis of dermatophytoses, which constitute the commonest communicable diseases worldwide, relies on microscopy and culture. This combination of techniques is time-consuming and notoriously low in sensitivity. OBJECTIVES: Recent dermatophyte gene sequence records were used to design a real-time PCR assay for detection and identification of dermatophytes in clinical specimens in less than 24 h. PATIENTS AND METHODS: Two assays based on amplification of ribosomal internal transcribed spacer regions and on the use of probes specific to relevant species and species-complexes were designed, optimised and clinically evaluated. One assay was for detecting the Trichophyton mentagrophytes species complex plus T. tonsurans and T. violaceum. The second assayed for the T. rubrum species complex, Microsporum canis and M. audouinii. RESULTS: The analytical sensitivity of both assays was 0.1 pg DNA per reaction, corresponding to 2.5-3.3 genomes per sample. The protocol was clinically evaluated over 6 months by testing 92 skin, nail and hair specimens from 67 patients with suspected dermatophytosis. Real-time PCR detected and correctly identified the causal agent in specimens from which T. rubrum, T. interdigitale, M. audouinii or T. violaceum grew in culture, and also identified a dermatophyte species in an additional seven specimens that were negative in microscopy and culture. CONCLUSIONS: This highly sensitive assay also proved to have high positive and negative predictive values (95.7% and 100%), facilitating the accurate, rapid diagnosis conducive to targeted rather than empirical therapy for dermatophytoses.

Classification and management of skin, hair, nail and mucosal side-effects of epidermal growth factor receptor (EGFR) inhibitors.

Inhibitors of epidermal growth factor receptor (EGFR) are commonly used as therapeutic agents in oncology. In contrast to currently used oncological treatments, these inhibitors almost always cause skin- and skin adnex toxicity. About 85% of treated patients develop to a more or lesser extent an acneiform eruption. Xerosis cutis and painful nail disorders occur in, respectively, 35% and 10-15% of all treated patients. Also hair and mucosal changes have been reported, although to a lesser extent. These skin- and skin adnex toxicities are reversible after withdrawal of treatment, but are seldom a reason to stop or interrupt therapy. This review outlines the classification, the pathogenesis and therapy of these skin, hair, nail and mucosal changes due to EGFR inhibition. Informing the patient and management of these side-effects is very important to reduce discomfort and as such to increase compliance to therapy.

Prospective controlled study of the diagnostic value of skin biopsy in patients with presumed meningococcal disease.

Microbiological tests for diagnosis of acute meningococcal disease are important for the clinical management of patients with this often-fatal illness, but cultures are frequently negative after antibiotics have been administered. Retrospective studies suggest that examination of skin biopsies may aid a rapid diagnosis and that cultures of skin biopsies are often positive even after antimicrobial treatment has commenced. This prospective controlled study aimed to assess the diagnostic value of skin biopsy compared with investigations of blood and cerebrospinal fluid (CSF) in patients with skin lesions and presumed meningococcal disease. A total of 43 patients, 31 with suspected acute meningococcal infection and 12 controls, were included. All skin biopsies were investigated by Gram stain and routine microbiological culture. In 25 patients, meningococcal infection was diagnosed microbiologically. The clinical diagnosis was meningococcal meningitis in 8 patients, meningococcal sepsis in 11 patients, and a combination of both in 6 patients. The sensitivity of cultures of blood, CSF, and skin biopsies was 56%, 50%, and 36%, respectively. When culture and Gram stain were combined, positive results were obtained in 56%, 64%, and 56%, respectively. There was no correlation between the diagnostic yield of skin biopsies and previous antibiotic treatment. In 14 patients, the diagnosis was based exclusively on one positive sample: CSF in 7 (28%) patients, blood in 4 (16%) patients, and skin biopsy in 3 (12%) patients. The sensitivity of skin biopsies was highest in patients with the least extensive skin lesions. Specificity was 100%. Microbiological investigation of skin biopsies increased the diagnostic yield and could be considered a component of the routine diagnostic work-up in patients with suspected meningococcal infection, even after the initiation of antimicrobial treatment.

[Sharp increase in the number of syphilis cases in The Netherlands: early recognition and treatment is of great importance]. / Sterke toename van het aantal syfilispatiënten in Nederland: vroegtijdige herkenning en behandeling van groot belang.

Syphilis was diagnosed in three men having sex with men, aged 36, 38 and 58 years, who had a variety of skin lesions and other symptoms. In a woman aged 38 years and her 39-year-old husband, syphilis was found during routine pregnancy screening. All patients were successfully treated with intramuscular (benzathin) benzylpenicillin. Early recognition and treatment as well as advice on avoiding high-risk sexual behaviour are important in preventing further spread of the disease. Although generally the risk of HIV transmission during unprotected oral sexual contact is believed to be low, the transmission of Treponema pallidum during this type of contact is possible and is probably the most important transmission route amongst men having sex with men.