Thomas Rustemeyer

European Society of Contact Dermatitis guideline for diagnostic patch testing – recommendations on best practice

The present guideline summarizes all aspects of patch testing for the diagnosis of contact allergy in patients suspected of suffering, or having been suffering, from allergic contact dermatitis or other delayed‐type hypersensitivity skin and mucosal conditions. Sections with brief descriptions and discussions of different pertinent topics are followed by a highlighted short practical recommendation. Topics comprise, after an introduction with important definitions, materials, technique, modifications of epicutaneous testing, individual factors influencing the patch test outcome or necessitating special considerations, children, patients with occupational contact dermatitis and drug eruptions as special groups, patch testing of materials brought in by the patient, adverse effects of patch testing, and the final evaluation and patient counselling based on this judgement. Finally, short reference is made to aspects of (continuing) medical education and to electronic collection of data for epidemiological surveillance.

Allergic contact dermatitis: epidemiology, molecular mechanisms, in vitro methods and regulatory aspects. Current knowledge assembled at an international workshop at BfR, Germany.

Contact allergies are complex diseases, and one of the important challenges for public health and immunology. The German ‘Federal Institute for Risk Assessment’ hosted an ‘International Workshop on Contact Dermatitis’. The scope of the workshop was to discuss new discoveries and developments in the field of contact dermatitis. This included the epidemiology and molecular biology of contact allergy, as well as the development of new in vitro methods. Furthermore, it considered regulatory aspects aiming to reduce exposure to contact sensitisers. An estimated 15–20% of the general population suffers from contact allergy. Workplace exposure, age, sex, use of consumer products and genetic predispositions were identified as the most important risk factors. Research highlights included: advances in understanding of immune responses to contact sensitisers, the importance of autoxidation or enzyme-mediated oxidation for the activation of chemicals, the mechanisms through which hapten-protein conjugates are formed and the development of novel in vitro strategies for the identification of skin-sensitising chemicals. Dendritic cell cultures and structure-activity relationships are being developed to identify potential contact allergens. However, the local lymph node assay (LLNA) presently remains the validated method of choice for hazard identification and characterisation. At the workshop the use of the LLNA for regulatory purposes and for quantitative risk assessment was also discussed.

Hand eczema severity and quality of life: a cross-sectional, multicentre study of hand eczema patients

Background and Objectives:  Hand eczema is a chronic disease with negative impact on quality of life (QoL). In this study, QoL in hand eczema patients is assessed and related to age, sex, severity, and diagnostic subgroups.

The European baseline series in 10 European Countries, 2005/2006 : results of the European Surveillance System on Contact Allergies (ESSCA)

Background: Continual surveillance based on patch test results has proved useful for the identification of contact allergy.

Hand eczema classification: a cross-sectional, multicentre study of the aetiology and morphology of hand eczema.

Background  Hand eczema is a long‐lasting disease with a high prevalence in the background population. The disease has severe, negative effects on quality of life and sometimes on social status. Epidemiological studies have identified risk factors for onset and prognosis, but treatment of the disease is rarely evidence based, and a classification system for different subdiagnoses of hand eczema is not agreed upon. Randomized controlled trials investigating the treatment of hand eczema are called for. For this, as well as for clinical purposes, a generally accepted classification system for hand eczema is needed.

Contact allergies in healthcare workers. Results from the IVDK.

Healthcare workers often suffer from occupational skin disease frequently caused by allergic sensitization. Therefore the patch-test results and important patient history items of 31,849 patients recorded between 1992 and 1995 in the 24 allergy departments participating in the Information Network of Departments of Dermatology (IVDK) were evaluated. Significantly increased sensitization rates common to the healthcare sector as a whole were found for the vaccine preservative thiomersal (12.6% vs. 4.9%), the surface and instrument disinfectants glutardialdehyde (9.9% vs. 2.6%), formaldehyde (3.6% vs. 2.1%) and glyoxal (4.2% vs. 1.4%), and for the compounds of the thiuram mix (6.7% vs. 2.6%) present in protective gloves. Formaldehyde seems to lose its importance, but glyoxal must be added to the list of occupational allergens in the healthcare sector. In addition, occupation-specific sensitization was observed, with fragrances in massage therapists (16.1% vs. 10.6%) and nurses (13.8% vs. 11.4%), as well as with methacrylates in dental technicians. The often assumed importance of drugs as type-IV allergens was not confirmed, at least in terms of quantity. The identification of subgroups of increased risk and of occupation-specific allergens could be the basis of targeted preventive action in the healthcare sector.

Wound-healing factors secreted by epidermal keratinocytes and dermal fibroblasts in skin substitutes

Full‐skin substitutes, epidermal substitutes, and dermal substitutes are currently being used to heal deep burns and chronic ulcers. In this study, we investigated which wound‐healing mediators are released from these constructs and whether keratinocyte–fibroblast interactions are involved. Autologous skin substitutes were constructed from human keratinocytes, fibroblasts, and acellular donor dermis. Full‐thickness skin was used to represent an autograft. Secretion of wound‐healing mediators was investigated by means of protein array, enzyme‐linked immunosorbent assay, neutralizing antibodies, and conditioned culture supernatants. Full‐skin substitutes and autografts produce high amounts of inflammatory/angiogenic mediators (IL‐6, CCL2, CXCL1, CXCL8, and sST2). Epidermal and dermal substitutes produced less of these proteins. Epidermal‐derived proinflammatory cytokines interleukin‐1α (IL‐1α) and tumor necrosis factor‐α (TNF‐α) were found to mediate synergistically the secretion of these wound‐healing mediators (with the exception of sST2) from fibroblasts in dermal substitutes. The secretion of proinflammatory cytokines (IL‐1α, TNF‐α), chemokine/mitogen (CCL5) and angiogenic factor (vascular endothelial growth factor) by epidermal substitutes and tissue remodeling factors (tissue inhibitor of metalloproteinase‐2, hepatocyte growth factor) by dermal substitutes was not influenced by keratinocyte–fibroblast interactions. The full‐skin substitute has a greater potential to stimulate wound healing than epidermal or dermal substitutes. Both epidermal‐derived IL‐1α and TNF‐α are required to trigger the release of dermal‐derived inflammatory/angiogenic mediators from skin substitutes.

Progress on the development of human in vitro dendritic cell based assays for assessment of the sensitizing potential of a compound

Allergic contact dermatitis is the result of an adaptive immune response of the skin to direct exposure to an allergen. Since many chemicals are also allergens, European regulations require strict screening of all ingredients in consumer products. Until recently, identifying a potential allergen has completely relied on animal testing (e.g.: Local Lymph Node Assay). In addition to the ethical problems, both the 7th Amendment to the Cosmetics Directive and REACH have stimulated the development of alternative tests for the assessment of potential sensitizers. This review is aimed at summarising the progress on cell based assays, in particular dendritic cell based assays, being developed as animal alternatives. Primary cells (CD34(+) derived dendritic cells, monocyte derived dendritic cells) as well as dendritic cell-like cell lines (THP-1, U-937, MUTZ-3, KG-1, HL-60, and K562) are extensively described along with biomarkers such as cell surface markers, cytokines, chemokines and kinases. From this review, it can be concluded that no single cell based assay nor single marker is yet able to distinguish all sensitizers from non-sensitizers in a test panel of chemicals, nor is it possible to rank the sensitizing potential of the test chemicals. This suggests that sensitivity and specificity may be increased by a tiered assay approach. Only a limited number of genomic and proteomic studies have been completed until now. Such studies have the potential to identify novel biomarkers for inclusion in future assay development. Although progress is promising, this review suggests that it may be difficult to meet the up and coming European regulatory deadlines.

Dendritic cells: biology of the skin

Allergic contact dermatitis results from a T‐cell‐mediated, delayed‐type hypersensitivity immune response induced by allergens. Skin dendritic cells (DCs) play a central role in the initiation of allergic skin responses. Following encounter with an allergen, DCs become activated and undergo maturation and differentiate into immunostimulatory DCs and are able to present antigens effectively to T cells. The frequency of allergic skin disorders has increased in the past decades. Therefore, the identification of potential sensitizing chemicals is important for skin safety. Traditionally, predictive testing for allergenicity has been conducted in animal models. For regulatory reasons, animal use for sensitization testing of compounds for cosmetic purposes is shortly to be prohibited in Europe. Therefore, new non‐animal‐based test methods need to be developed. Several DC‐based assays have been described to discriminate allergens from irritants. Unfortunately, current in vitro methods are not sufficiently resilient to identify allergens and therefore need refinement. Here, we review the immunobiology of skin DCs (Langerhans’ cells and dermal dendritic cells) and their role in allergic and irritant contact dermatitis and then explore the possible use of DC‐based models for discriminating between allergens and irritants.

T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays

Chemicals can elicit T-cell-mediated diseases such as allergic contact dermatitis and adverse drug reactions. Therefore, testing of chemicals, drugs and protein allergens for hazard identification and risk assessment is essential in regulatory toxicology. The seventh amendment of the EU Cosmetics Directive now prohibits the testing of cosmetic ingredients in mice, guinea pigs and other animal species to assess their sensitizing potential. In addition, the EU Chemicals Directive REACh requires the retesting of more than 30,000 chemicals for different toxicological endpoints, including sensitization, requiring vast numbers of animals. Therefore, alternative methods are urgently needed to eventually replace animal testing. Here, we summarize the outcome of an expert meeting in Rome on 7 November 2009 on the development of T-cell-based in vitro assays as tools in immunotoxicology to identify hazardous chemicals and drugs. In addition, we provide an overview of the development of the field over the last two decades.