Pieter G. M. van der Valk

Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis

Topical application of coal tar is one of the oldest therapies for atopic dermatitis (AD), a T helper 2 (Th2) lymphocyte-mediated skin disease associated with loss-of-function mutations in the skin barrier gene, filaggrin (FLG). Despite its longstanding clinical use and efficacy, the molecular mechanism of coal tar therapy is unknown. Using organotypic skin models with primary keratinocytes from AD patients and controls, we found that coal tar activated the aryl hydrocarbon receptor (AHR), resulting in induction of epidermal differentiation. AHR knockdown by siRNA completely abrogated this effect. Coal tar restored filaggrin expression in FLG-haploinsufficient keratinocytes to wild-type levels, and counteracted Th2 cytokine-mediated downregulation of skin barrier proteins. In AD patients, coal tar completely restored expression of major skin barrier proteins, including filaggrin. Using organotypic skin models stimulated with Th2 cytokines IL-4 and IL-13, we found coal tar to diminish spongiosis, apoptosis, and CCL26 expression, all AD hallmarks. Coal tar interfered with Th2 cytokine signaling via dephosphorylation of STAT6, most likely due to AHR-regulated activation of the NRF2 antioxidative stress pathway. The therapeutic effect of AHR activation herein described opens a new avenue to reconsider AHR as a pharmacological target and could lead to the development of mechanism-based drugs for AD.

The risk of active sensitization to PPD.

Para‐phenylenediamine (PPD) and para‐aminoazobenzene are strong sensitizers. By the patch test procedure, the patient may be sensitized to these agents. Combined testing of para‐compounds may increase the risk of active sensitization. We studied the % of positive patch test reactions and their relevance. In order to assess the risk of active sensitization, we compared the % of relevant reactions of both early (2/3 days) and late (7 days) reactions. We also compared the percentage of positive patch test reactions to PPD and their relevance if simultaneously tested with para‐aminoazobenzene. We studied the patch test reactions to PPD in the routine series in 2058 patients. In a group of 678 patients we tested PPD and para‐aminoazobenzene simultaneously. 4.3% and 3.1% of the patients reacted to PPD, respectively, with and without simultaneous testing with para‐aminoazobenzene. We estimated the reactions as relevant in 21.1% and 39.7%, respectively, with and without simultaneous testing with para‐aminoazobenzene. We considered none of the late reactions as relevant. We found a high proportion of relevant patch test reactions to PPD, but sensitization to PPD by the patch test procedure is a risk. We state that routine series should not contain PPD. The high number of irrelevant late positive reactions strongly suggests active sensitization. Moreover, PPD is not a ubiquitous allergen and can be tested on a non‐routine basis if industrial exposure to para‐compounds is suspected or if a specific localization (e.g., head or feet) prompts the testing of PPD. Testing PPD combined with para‐aminoazobenzene does lead to a slight increase in positive reactions to PPD (p<0.25) and to an increase in irrelevant reactions (p<0.10).

No increased risk of cancer after coal tar treatment in patients with psoriasis or eczema.

Coal tar is an effective treatment for psoriasis and eczema, but it contains several carcinogenic compounds. Occupational and animal studies have shown an increased risk of cancer after exposure to coal tar. Many dermatologists have abandoned this treatment for safety reasons, although the risk of cancer after coal tar in dermatological practice is unclear. This large cohort study included 13,200 patients with psoriasis and eczema. Information on skin disease and treatment, risk factors, and cancer occurrence was retrieved from medical files, questionnaires, and medical registries. Proportional hazards regression was used to evaluate differences in cancer risk by treatment modality. Patients treated with coal tar were compared with a reference category of patients treated with dermatocorticosteroids (assumed to carry no increased cancer risk). The median exposure to coal tar ointments was 6 months (range 1-300 months). Coal tar did not increase the risk of non-skin malignancies (hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.78-1.09), or the risk of skin cancer (HR 1.09; 95% CI 0.69-1.72). This study has sufficient power to show that coal tar treatment is not associated with an increased risk of cancer. These results indicate that coal tar can be maintained as a safe treatment in dermatological practice.

Changes in keratinocyte differentiation following mild irritation by sodium dodecyl sulphate

Although the induction of acute irritant dermatitis by detergents has been studied extensively in recent years, our understanding of the cell biological events in the repair phase, and its relevance for the development of chronic irritant dermatitis is limited. Here we studied the reaction pattern of human skin to short-term application of sodium dodecyl sulphate (SDS) in a model that induced a minimal acute inflammatory reaction (absence of polymorphonuclear leucocytes, PMN) and did not have cytopathic effects on the epidermal keratinocytes as determined by histological investigation. All parameters were measured up to 14 days after exposure to SDS. Application of SDS caused disturbances of barrier function as measured by transepidermal water loss and had vascular effects as judged by erythema. Several cell biological markers for epidermal growth and differentiation were examined by immunohistochemistry. A rapid and strong induction of the cornified envelope precursor protein involucrin was seen in the stratum spinosum, with a peak at 24 h. Within 24 h a strong upregulation of epidermal fatty acid binding protein (E-FABP) was noted, with a peak at 7 days after injury. Cellular proliferation in the basal layer was increased fivefold as assessed by nuclear staining for the Ki-67 antigen, showing a peak at 48 h. Surprisingly, no significant induction of cytokeratin 16 and SKALP/elafin expression, two markers associated with epidermal hyperproliferation and inflammation, was seen. These findings suggest that the cellular changes following exposure to detergent are distinct from those seen in other forms of skin injury. We would speculate that the epidermal response to detergent exposure is primarily directed at restoration of barrier function.

Evidence-based diagnosis in patch testing.

Evidence‐based medicine (EBM) is defined as the integration of the best research evidence with clinical expertise and patient values. Based on the principles of EBM, we can conclude that patch testing is cost‐effective only if patients are selected on the basis of a clear‐cut clinical suspicion of contact allergy and only if patients are tested with chemicals relevant to the problem (high pretest probability). Random patch testing (low pretest probability) should be discouraged. Proper pretest probability assessment can only be done in expert centres, because problem‐based testing requires both a thorough knowledge of the patch‐test procedure and knowledge about potential sensitizers in a specific environment.

Coal tar in dermatology

Coal tar is one of the oldest treatments for psoriasis and eczema. It has anti‐inflammatory, antibacterial, antipruritic and antimitotic effects. The short‐term side effects are folliculitis, irritation and contact allergy. Coal tar contains carcinogens. The carcinogenicity of coal tar has been shown in animal studies and studies in occupational settings. There is no clear evidence of an increased risk of skin tumors or internal tumors. Until now, most studies have been fairly small and they did not investigate the risk of coal tar alone, but the risk of coal tar combined with other therapies. New, well‐designed, epidemiological studies are necessary to assess the risk of skin tumors and other malignancies after dermatological use of coal tar.

Skin diseases in family medicine: prevalence and health care use.

PURPOSE Ongoing care for patients with skin diseases can be optimized by understanding the incidence and population prevalence of various skin diseases and the patient-related factors related to the use of primary, specialty, and alternative health care for these conditions. We examined the recent prevalence of skin diseases in a defined population of family medicine patients, self-reported disease-related quality of life, extent and duration of skin disease, and the use of health care by patients with skin diseases. METHODS We undertook a morbidity registry-based epidemiological study to determine the prevalence of various skin diseases, using a patient questionnaire to inquire about health care use, within a network of family practices in the Netherlands with a practice population of approximately 12,000 citizens. RESULTS Skin diseases accounted for 12.4% of all diseases seen by the participating family physicians. Of the 857 questionnaires sent to patients registered with a skin disease, 583 (68.0%) were returned, and 501 were suitable for analysis. In the previous year, 83.4% of the patients had contacted their family physician for their skin disease, 17.0% had contacted a medical specialist, and 5.2% had consulted an alternative health care practitioner. Overall, 65.1% contacted only their family physician. Patients who reported more severe disease and lower quality of life made more use of all forms of health care. CONCLUSION This practice population-based study found that skin diseases account for 12.4% of diseases seen by family physicians, and that some skin problems may be seen more frequently. Although patients with more extensive skin diseases also obtain care from dermatologists, most patients have their skin diseases treated mainly by their family physician. Overall, patients with more severe disease and a lower quality of life seek more treatment.

Nickel on the Dutch market: 10 years after entry into force of the EU Nickel Directive

dimethylglyoxime test;EUlegislation;nickelallergy;NickelDirective;prevention;TheNetherlands.Theprevalenceofnickelallergyinthegeneralpopulationisapproximately 9%,17%inwoman and 3%inmen(1).Consumer items are important for sensitization to nickeland for elicitation of nickel dermatitis. The EU NickelDirective, limiting nickel release from certain items,may have had beneficial health effects(2–5). Studieson nickel release from consumer items have beenperformed(6–10). The aim of this study was to estimatethe percentage of products in The Netherlands that didnotmeetthecriteriaoftheEUNickelDirective.

A histological and immunohistochemical study on chronic irritant contact dermatitis

BACKGROUND Chronic irritant contact dermatitis (CICD) is characterized by erythema, scaling, hyperkeratosis, chapping and fissures. It may be the result of skin damage evoked by the cumulative effect of a variety of irritant stimuli. The diagnosis of CICD is made on basis of the patients history and clinical features. No specific diagnostic tests are available. OBJECTIVE The histopathologic and cell biological features of CICD have not been extensively studied. Here, we describe the histological and immunohistological changes in CICD. METHODS Punch biopsies were taken from 11 patients with CICD for hematoxylin eosin and immunohistochemical stainings. Four skin biopsies of the palms of the hands of healthy volunteers served as controls. RESULTS The histopathologic pattern was characterized by different grades of hyperkeratosis, parakeratosis, spongiosis, exocytosis, acanthosis, and mononuclear perivascular infiltrates. Mitotic activity, as measured by Ki-67-staining in the epidermis, was increased fourfold in involved skin as compared with normal skin. Involucrin, a structural protein of the cornified envelope, was expressed from the stratum granulosum throughout the stratum spinosum in all patients with CICD and was upregulated in comparison with normal skin. Epidermal fatty-acid binding protein (E-FABP), a terminal differentiation marker, was proportionally unaltered in the CICD as compared with the normal skin and was localized from the stratum granulosum to the upper layers of the stratum spinosum. Cytokeratin 16, a differentiation marker expressed in hyperproliferative epidermis, was markedly increased from the stratum granulosum throughout the stratum spinosum in 5 out of 11 patients with CICD. Skin-derived antiproteinase (SKALP)/elafin, a proteinase inhibitor expressed in inflamed epidermis, was only detected within the stratum granulosum in 3 out of 11 patients. CONCLUSION We conclude that CICD is clinically characterized by features of a chronic dermatitis and, at the histological level, by inflammatory changes, epidermal hyperproliferation and altered differentiation.

Economic evaluation of an integrated care programme for patients with hand dermatitis

Hand dermatitis has a large impact on society as a whole.