Diagnosing lanolin contact allergy with lanolin alcohol and Amerchol L101.

BACKGROUND: The prevalence of lanolin contact allergy in dermatitis patients varies from 1.2% to 6.9%. Different lanolin derivatives are used in patch testing. OBJECTIVES: To determine which combination of lanolin derivatives is most effective in patch testing for the diagnosis of lanolin contact allergy. METHODS: A retrospective analysis of patients patch tested between 2016 and 2017 was performed. Patients were eligible if they had been tested with lanolin alcohol 30% pet., Amerchol L101 50% pet., and a supplementary series containing other lanolin derivatives. Lanolin alcohol and Amerchol L101 were tested in duplicate. RESULTS: Of 594 patients, 28.6% (95% confidence interval [CI]: 25.1%-32.3%) had a positive patch test reaction to at least one lanolin derivative. Reactions to lanolin alcohol (14.7%, 95%CI: 11.3%-18.2%) and Amerchol L101 (15.0%, 95%CI: 11.5%-18.5%) were common in the routinely tested series. Reactions to other test preparations were significantly less frequent (P < 0.05). The addition of Amerchol L101 to lanolin alcohol significantly increased the number of positive cases (odds ratio 1.79, P < 0.001). CONCLUSIONS: The combination of lanolin alcohol and Amerchol L101 is effective in patch testing for the diagnosis of lanolin contact allergy. Routinely testing with other lanolin derivatives may not be worthwhile, as it detects only a few additional patients.

Photopatch testing: recommendations for a European photopatch test baseline series.

In order to establish a consensus recommendation for performing photopatch testing, a photopatch test taskforce group was established under the joint umbrella of the European Society for Contact Dermatitis and the European Society for Photodermatology in 2000. After proposing the most adequate methodology in 2004 and completing a European multicentre photopatch test study in 2011, this taskforce is recommending a list of photoallergens that should form part of a baseline series for photopatch testing in Europe. It contains mainly ultraviolet filters and drugs, mostly non-steroidal anti-inflammatory drugs. The choice of chemicals was based on the results of a recent multicentre study, previous published cases of photoallergy, and use of the substances in the European market. It is suggested that an extended list of photoallergens should be photopatch tested in selected cases, along with patients' own products. Two contact allergens, cinnamyl alcohol and decyl glucoside, should be simultaneously patch tested in order to clarify photopatch and patch test reactions, respectively, to ketoprofen and methylene bis-benzotriazolyl tetramethylbutylphenol (Tinosorb M™).

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.

Do 'cinnamon-sensitive' patients react to cinnamate UV filters?

BACKGROUND: Use of sunscreens has increased dramatically worldwide, and some sunscreen chemicals may be allergens. Ultraviolet (UV) filters are added to various cosmetic products. Cinnamate UV filters are structurally related to cinnamon-related fragrances. OBJECTIVE: The purpose of this study was to determine if 'cinnamon-sensitive' patients show positive photopatch tests to cinnamate UV filters and, therefore, should avoid these UV filters. METHOD: We photopatch tested cinnamon-sensitive patients (n = 18) with cinnamon, cinnamon-related fragrances, Myroxylon pereirae, and two cinnamate UV filters. RESULTS: No positive photopatch test to cinnamate UV filters was found (95% confidence interval 0-13%). DISCUSSION: The risk of developing unwanted allergic contact dermatitis because of cinnamate UV filters in cinnamon-sensitive patients seems to be low, but our study population was small. Therefore, we recommend cinnamon-sensitive patients to perform a use test, for example the repeated open application test, before using cosmetic products containing cinnamate UV filters. In addition, physicians and patients should be aware that many sunscreens contain (cinnamon-related) fragrances and could, therefore, elicit allergic contact dermatitis in cinnamon-sensitive patients, independently from other potential sensitizing components of the sunscreen.

Contact sensitisation in hand eczema patients-relation to subdiagnosis, severity and quality of life: a multi-centre study.

BACKGROUND: Contact sensitisation has been identified as a factor associated with poor prognosis for patients with hand eczema. OBJECTIVES: To study implications of contact sensitisation with respect to severity, quality of life (QoL) and subdiagnosis of hand eczema. METHODS: The study was performed as a multi-centre, cross-sectional study from 10 European clinics. All patients were patch tested, and severity of hand eczema assessed by Hand Eczema Severity Index. A multi-variate analysis was performed to explore which factors influenced severity, QoL and sick leave. RESULTS: A total 416 patients were included, and 63% had contact sensitisation to one or more of the tested allergens. More women (66%) than men (51%) were sensitized. No significant association was found between sensitisation to specific allergens, disease severity, QoL or diagnostic subgroups. High age, male sex, atopic eczema and presence of contact sensitisation were independent risk factors for increased severity as measured by Hand Eczema Severity Index. Furthermore, the severity of hand eczema increased by the number of contact sensitisations detected (P = 0.023). High age and personal history of atopic eczema were independent risk factors for low QoL, as measured by Dermatology Life Quality Index, and atopic eczema as well as allergic contact dermatitis as subdiagnosis was associated with increased sick leave. CONCLUSION: Diagnostic subgroups were not found to be related to specific allergens. Contact sensitisation was found to be a risk factor for increased severity of hand eczema, as did high age, male sex and atopic eczema.

Allergic contact dermatitis from EMLA cream: concomitant sensitization to both local anesthetics lidocaine and prilocaine.

Local anesthetics are widely used drugs. In contrast to the local anesthetics of the ester group, the ones of the amide group (for example prilocaine and lidocaine) are considered to be rare sensitizers. Positive patch test results to both prilocaine and lidocaine in EMLA cream might indicate potential cross-reactivity.

Anogenital allergic contact dermatitis, the role of spices and flavour allergy.

BACKGROUND: In patients with vulval or anogenital dermatitis, irritant contact dermatitis is more common than allergic contact dermatitis. The reported frequency and relevance of contact sensitivity in anogenital dermatitis varies greatly. OBJECTIVE: To determine the frequency and relevance of contact sensitization in a Dutch group of female patients with chronic anogenital complaints. METHODS: We reviewed patch test results of 53 women with chronic anogenital complaints, with sole vulval symptoms in 29 women and sole perianal in 5, in whom inflammatory skin diseases like lichen sclerosus, lichen planus, psoriasis, as well as infectious diseases were unlikely or excluded as a cause of their symptoms. All women were tested with the European baseline series plus additional test series according to their personal history. RESULTS: Thirty-five patients (66%) showed one or more positive test reactions. Seven of these patients (20%) had one or more clinically relevant positive reactions, most often to flavours and spices. CONCLUSION: A considerable number of patients with anogenital dermatitis have a contact sensitization. Clinically relevant reactions were mainly found to spices and flavours. This is in contrast to the data reported in the literature that shows most contact allergies in vulval patients to ingredients of topical medication.

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. METHODS: A total of 416 patients with hand eczema from 10 European patch test clinics participated in the study. Data on QoL were obtained from a self-administered questionnaire using the Dermatology Life Quality Index (DLQI). Severity was assessed by a scoring system (Hand Eczema Severity Index, HECSI) as well as frequency of eruptions and sick leave due to hand eczema. RESULTS: No significant difference was found between males and females with respect to QoL [DLQI median values and 25/75 percentiles for males and females being 7.0 (3-14) and 8.0 (3-13), respectively], although males were more severely affected than females (P < 0.025). A significant positive correlation was found for hand eczema severity and age (P < 0.001), while no significant correlation was found for QoL and age. QoL was found increasingly reduced when sick leave was getting higher (P < 0.001). A statistically significant correlation between QoL (as measured by DLQI) and hand eczema severity as measured by HECSI was found (P < 0.001). No significant difference in QoL was found between diagnostic subgroups. CONCLUSIONS: QoL was found markedly negatively affected in hand eczema patients and was significantly correlated to disease severity. No significant difference in QoL was found between males and females, in spite of significantly more severe eczema in males, indicating that QoL in female patients is more easily affected.

Cytokine gene polymorphisms and susceptibility to chronic irritant contact dermatitis.

BACKGROUND: Cytokines play an important role in skin inflammation. OBJECTIVES: We determined whether polymorphisms in cytokine genes contribute to the occurrence of occupational chronic irritant contact dermatitis (CICD). METHODS: In a case-control study, 9 polymorphisms in the genes coding for interleukin (IL)-1 alpha, IL-1 beta, IL-8, IL-10, and tumour necrosis factor (TNF)-alpha were determined in 197 patients with CICD. 217 apprentices in vocational training for high-risk occupations for CICD served as controls. RESULTS: For all polymorphisms, no differences in genotype distributions were found between patients and controls. However, in patients with self-reported low levels of wet work and irritant exposure, more TNFA -308 variant genotypes (G/A and A/A) were present compared with those exposed to higher levels or controls, which indicates a TNFA-induced increase of susceptibility. In patients with TNFA -308 variant genotypes, the prevalence of flexural eczema was higher (48% and 57%) compared with that in patients presented with wild-type genotype (30%). Regarding IL1A -889, prevalence of symptoms of dermatitis was lower in apprentices with T/T or C/T genotype (32% and 36%) compared with wild-type genotype (54%, C/C). This indicates a protective effect of these variant alleles in acquiring hand dermatitis. CONCLUSIONS: This study provides evidence that some genetic variations alter susceptibility to (chronic) dermatitis. Knowledge of the impact of genetic differences on the risk of CICD is essential in predictive testing of individuals at risk.

Relevance of positive patch-test reactions to fragrance mix.

BACKGROUND: Fragrances are an important cause of allergic contact dermatitis. We presume that the traditional fragrance mix (FM) detects 70 to 80% of fragrance-allergic patients. FM has an irritant potential. Weak positive reactions may have a greater chance of being irrelevant than strong reactions. OBJECTIVE: To improve the appraisal of FM patch-test reactions, we studied the relevance of reactions of different strength. We also studied the predictive value of the following on the relevance of the initial FM patch-test results: patch-test results of a repeated FM test; results of patch tests with balsam of Peru, colophony, and ingredients of the mix; and (history of) atopic dermatitis. METHODS: One hundred thirty-eight patients who had doubtful positive (?+) or positive (+ to +++) reactions were included in the study. We determined relevance by history taking, location and course of the dermatitis, and additional patch testing. Patients were retested with FM and with each ingredient separately. RESULTS: The relevance of reactions to FM increases with the strength of the reactions. Predictors of relevance are the results of retesting with FM, the results of tests with the ingredients, and a history and/or present symptoms of atopic dermatitis. CONCLUSION: Retesting with FM and its ingredients may add to the benefit of patch testing.

Comparison of oral psoralen-UV-A with a portable tanning unit at home vs hospital-administered bath psoralen-UV-A in patients with chronic hand eczema: an open-label randomized controlled trial of efficacy.

OBJECTIVE: To study whether oral psoralen-UV-A (PUVA) with a portable tanning unit at home is as effective as hospital-administered bath PUVA in patients with chronic hand eczema. DESIGN: Open-label randomized controlled trial, with a 10-week treatment period and an 8-week follow-up period. SETTING: Two university hospital dermatology departments in the Netherlands, specializing in hand eczema. PATIENTS: One hundred fifty-eight patients with moderate to severe chronic hand eczema (more than 1 year in duration). INTERVENTIONS: Oral PUVA using methoxsalen capsules and a simple portable commercial facial tanning unit, or hospital-administered bath PUVA with trioxsalen. MAIN OUTCOME MEASURES: The primary outcome was clinical assessment by a hand eczema score (evaluation of desquamation, erythema, vesiculation, infiltration, fissures, itch, and pain, each on a 4-point scale) after 10 weeks of treatment. The secondary outcome was hand eczema score at 8 weeks of follow-up, after completion of treatment. The tertiary outcome was travel cost and time off work. RESULTS: Both groups showed a comparable and substantial decrease in hand eczema score (meaningful clinical improvement). This decrease was maintained during the follow-up period. Patients treated with oral PUVA at home had lower travel costs and less time off work. CONCLUSIONS: Oral PUVA at home has a clinically relevant efficacy, similar to that of hospital-administered bath PUVA. This effect was maintained during an 8-week follow-up period. It resulted in lower travel costs and less time off work.

CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis.

The initial step in Langerhans cell (LC) migration from the epidermis to the lymph node involves migration of maturing LC into the dermis. Here, we investigated the migration of LC out of the epidermis after exposure of the skin to contact allergens. Ex vivo intact human skin, epidermal sheets, and LC derived from the MUTZ-3 cell line (MUTZ-LC) were used to determine whether dermal fibroblasts play a role in mediating LC migration towards the dermis. Exposure of epidermal sheets or MUTZ-LC to allergens (nickel sulphate, 2,4-dinitrochlorobenzene, and cinnamaldehyde) or a cytokine maturation cocktail resulted in LC migration towards dermal fibroblasts. This was due to upregulation of CXCR4 on maturing LC and secretion of CXCL12/stromal derived factor-1 chemokine by fibroblasts. Neutralizing antibodies to either CXCL12 or CXCR4 completely blocked migration. Injection of CXCL12 neutralizing antibodies into intact human skin totally inhibited LC migration into the dermis. In contrast, neutralizing antibodies to CCL19/CCL21 did not inhibit migration into the dermis. We describe a novel and essential role of dermis-derived CXCL12 in initiating migration of maturing human LC to the dermis thus permitting their further journey to the draining lymph nodes.

Allergic contact dermatitis to nickel: modified in vitro test protocols for better detection of allergen-specific response.

To date, no in vitro test is suitable for routine diagnosis of contact allergy. The aim of our study was to establish improved in vitro test protocol for the detection of antigen-specific responses of lymphocytes from patients with allergic contact dermatitis to nickel (Ni-ACD). Blood leucocytes from 14 Ni-ACD patients and 14 controls were cultured in the presence of 'cytokine cocktails' skewing lymphocytes towards 'type 1' [interferon-gamma (IFN-gamma)-secreting] or 'type 2' [interleukin (IL)-5 and IL-13-secreting] phenotypes. The cocktails consisted of IL-7 and, respectively, either IL-12 or IL-4. Cell responses to nickel were measured with enzyme-linked immunospot assay (ELISpot), enzyme-linked immunosorbent assay (ELISA), and lymphocyte proliferation test (LPT). Significant differences between patients with Ni-ACD and controls were found for the 'type 2' cytokines IL-13 and IL-5, with further increase of allergen-specific responses occurring when cultures were supplemented with IL-7 and IL-4. No significant differences were found for IFN-gamma. The best correlate to clinical diagnosis was LPT with 'type 2' skewing (r= 0.739, P < 0.001), followed by IL-13 ELISpot with 'type 2' skewing (r= 0.654, P < 0.001). The non-radioactive method that correlated best with LPT was IL-2 ELISpot (r= 0.809, P < 0.001). Overall, we conclude that combining ELISpot assay with proposed modifications of culture conditions improves detection of specific lymphocyte responses in contact allergy to nickel.

Intrinsic characteristics of contact and respiratory allergens influence production of polarizing cytokines by dendritic cells.

Type 1 and type 2 cytokines are primary mediators in contact allergy and aeroallergen-mediated disorders, respectively. For both types of disease, dendritic cells (DCs) are pivotal in initiating immune hyperresponsiveness. We studied whether contact and respiratory allergens possess intrinsic capacities to polarize DC towards DC1 and DC2 functions, independent of environmental factors. Human monocyte-derived DCs were exposed to the positive controls [type 1: lipopolysaccharide (LPS) + interferon-gamma; type 2: LPS + prostaglandin E(2)], contact allergens [2,4-dinitrochlorobenzene (DNCB), oxazolone (OXA), and nickel sulfate (NiSO(4))], and respiratory allergens [trimellitic anhydride (TMA) and the protein allergen derived from Dermatophagoides pteronyssinus (Der p1)]. The polarizing potentials of the allergens on DCs were determined by the secretion of type 1 [tumour necrosis factor-alpha (TNF-alpha), CXCL10, and interleukin (IL)-12p70] and type 2 (IL-10) cytokines. The contact allergens, DNCB and OXA, induced strict type 1 DC polarization, whereas the respiratory allergens, TMA and Der p1, showed strict type 2 DC polarization. The contact allergen, NiSO(4), induced both DC1 (TNF-alpha and CXCL10 production) and DC2 (decreased IL-12p70/IL-10 ratio) features. These results support the view that allergens have an intrinsic capacity to skew immune responses at the DC level, irrespective of local factors such as those determined by cutaneous or mucosal epithelial microenvironments.

Mercaptobenzothiazole or the mercapto-mix: which should be in the standard series?

Mercaptobenzothiazole (MBT) compounds are well known contact allergens. To detect rubber allergic patients we use both MBT (2% in petrolatum) and a mercapto-mix with 4 constituents of 0.5% each in our standard series. In this article the EECDRG presents data of in total 32,475 consecutive tested patients attending the respective contact dermatitis clinics from 11 centres in Europe to determine if the mix and MBT detected the same allergic patients. We found 327 patients positive to the mix or MBT, or to both. 261 were positive to the mix and 254 to MBT. MBT was negative in 73 patients who were positive to the mix. If the mix had not been in the standard series, on average 22% of patients allergic to a mercapto-compound would have been missed, for MBT this would have been on average 20%. All clinics would have missed a significant number of positive reactions if both compounds had not been tested. We conclude, that both the mercapto mix and MBT are required in the standard series.

Airborne irritant contact dermatitis due to synthetic fibres from an air-conditioning filter.

We describe 8 cases of occupational airborne irritant contact dermatitis in intensive care unit (ICU) employees caused by synthetic (polypropylene and polyethylene) fibres from an air-conditioning filter. Not until a workplace investigation was conducted, was it possible to clarify the unusual sequence of events. High filter pressure in the intensive care air-conditioning system, maintained to establish an outward airflow and prevent microorganisms from entering the ward, probably caused fibres from the filter to become airborne. Upon contact with air-exposed skin, fibres subsequently provoked skin irritation. Test periods in the ICU with varying filter pressures, in an attempt to improve environmental conditions, led to even higher filter pressure levels and more complaints. The sometimes-very-low humidity might have contributed to development of skin irritation. The fact that most patients recovered quickly after treatment with emollients and changing the filters made it most likely that the airborne dermatitis was of an irritant nature.

Improved detection of allergen-specific T-cell responses in allergic contact dermatitis through the addition of 'cytokine cocktails'.

The gold standard for the diagnosis of allergic hypersensitivity is skin patch testing with the suspected allergens. This diagnostic tool, however, has distinct disadvantages, and therefore the development of alternative or complementary in vitro tests is of great importance. In this study, we evaluate the applicability of an in vitro test method, as developed earlier for nickel allergy, to detect allergen-specific T cells in the blood of patients allergic to frequent sensitizers (chromate, cobalt, paraphenylenediamine, fragrances and chloromethyl-isothiazolinone). Peripheral blood mononuclear cells (PBMCs) of allergic patients and healthy controls were cultured in the absence or presence of allergen. Additionally, type 1 (IL-7 and IL-12) or type 2 (IL-7 and IL-4) stimulating cytokines were added; after 6-day proliferation, IFN-gamma and IL-5 secretions were determined. Without the addition of cytokines, consistent allergen-induced proliferation was observed in PBMCs of nickel-allergic patients only. By contrast, the addition of type 1 or type 2 stimulating cytokines resulted in a significantly enhanced allergen-specific proliferation for all allergens tested (sensitivity increased from 26 to 43% or 38%, respectively, P < 0.05). In these cultures, allergen-induced IFN-gamma and IL-5 secretion was also significantly increased, compared to healthy controls (P < 0.05, for IFN-gamma sensitivity 79%, specificity 93%; for IL-5 sensitivity 74%, specificity 81%). In conclusion, these results demonstrate an increased proliferative capacity and cytokine production by allergen-specific T cells from allergic patients, but not of healthy individuals upon stimulation with allergens in combination with type 1 or 2 skewing cytokines. The present data warrant further exploration of the application of this test to a broader set of allergens.

Assessment of contact allergen cross-reactivity by retesting.

At former allergic contact dermatitis reaction sites retesting causes augmented hyper-reactivity, characterized by an accelerated onset within a few hours. This expression of 'local skin memory' has been ascribed to locally persisting allergen-specific effector/memory T cells. To verify this hypothesis, we investigated whether accelerated retest reactivity also occurs with cross-reactive allergens. Guinea pigs were immunized with either or both 2,4-dinitrochlorobenzene (DNCB) and 2-hydroxyethyl methacrylate (HEMA), and primary skin tests to these and cross-reactive methacrylic compounds were performed 12-21 days later. Subsequently, new skin tests were conducted 3 weeks later both at the former test ('retest') and contralateral, non-pretreated test ('control') sites, and skin test readings started 2 h later. Retest reactivity was evaluated by comparing retest and contralateral control reactions. Both contact sensitizers, HEMA and DNCB, induced strong retest reactivity, peaking at 4-6 h. Fully allergen-specific retest reactivity was observed when primary skin tests had been postponed until 21 days after immunization, most probably reflecting loss of accumulation of irrelevant allergen-primed T cells at that time. As hypothesized, retesting with various methacrylate congeners at primary HEMA, but not DNCB, skin test sites showed early hyperreactivity strengths in line with those observed earlier in conventional cross-reactivity studies. These results, therefore, support the view that local skin memory exhibits allergen specificity through residual allergen-primed T cells. Because the retesting procedure is readily applicable in clinical practice, it provides a tool not only for confirmation of doubtful contact allergic skin reactions, but also for distinguishing between true cross-reactivity and coincident multiple sensitization in man.

Increased CCL27-CCR10 expression in allergic contact dermatitis: implications for local skin memory.

Allergic contact dermatitis (ACD) is a T-cell-mediated disease in which expression of a distinct repertoire of chemokines results in the recruitment of effector T cells into the skin. While it is becoming clear which chemokines and receptors determine the development of ACD, the mechanisms involved in the retention of T cells in the skin after resolution of inflammation are still unknown. Unravelling these mechanisms will help us to understand local skin memory as observed in retest reactivity and flare-up reactions. This study was designed to evaluate the role of chemokine-chemokine receptor interactions in local T-cell retention. The results show that expression of the CCR10 targeting ligand CCL27 is not only increased during inflammation, but also remains increased several weeks after clinical responsiveness to patch testing. In parallel with increased CCL27 expression, an increased number of infiltrating cells could still be detected in skin that, clinically, had returned to normal 21 days after patch testing. These persisting cells were characterized as CD4+ cells expressing CCR10, while no CD8+ CCR10+ cells could be detected. The presence of these cells is most likely an allergen-mediated effect, as increased levels of CCL27 and CCR10 could not be detected 21 days after initiating an irritant contact dermatitis reaction. In contrast to CCL27, increased expression of CXCL9, CXCL10, and CXCL11 could only be observed during the clinically inflammatory phase of ACD. In conclusion, local CCL27-mediated retention of CCR10+ CD4+ T cells in sites previously challenged by ACD could be responsible for phenomena such as local skin memory observed in retest reactions and flare-up reactions in which the presence of persisting T cells results in an accelerated inflammatory response upon renewed allergen challenge.