A seven-year retrospective analysis of patch test data in a cohort of patients with contact dermatitis in Sri Lanka.

BACKGROUND: Patch testing with a baseline series is a common tool employed when the sensitizing agent in contact dermatitis is unclear. However, for Asian countries, there are no locally validated baseline series to utilize in screening. METHODS: We completed a retrospective analysis of all patients that had undergone patch testing with the European Baseline series, Shoe Series or Comprehensive International Baseline series, over 7 years from 2012 to 2018 in a tertiary care reference dermatology clinic in Sri Lanka to evaluate the suitability of these investigations to identify causes for contact dermatitis in the local study population. RESULTS: Out of 438 patients tested, 239 (54.8%) reacted to at least one substance in the series. The Shoe Series was significantly more likely to yield a positive result than the European Baseline Series (70.2% vs 46.9%, p < 0.05). The top three sensitizers identified by all series were nickel sulfate (16%, 70/438), p-phenylenediamine (12.3%, 54/438) and 2-mercaptobenzothiazole or mercapto mix (10.5%, 46/438). CONCLUSION: Shoe series has a comparatively high yield in the local population compared to European Baseline series. Since little less than half of the study population did not have any reactivity to any of the allergens tested it is important to develop or modify and validate a locally relevant, more suitable baseline series which is based on the Shoe Series in Sri Lanka. This is further evidence for the continuously changing nature of allergens in the environment and the need to modify existing patch testing standards accordingly.

Cross-elicitation responses to 2-methoxymethyl-p-phenylenediamine in p-phenylenediamine highly allergic volunteers using allergy alert test: the Italian experience.

Summary: Background. Allergic contact dermatitis after exposure to p-phenylenediamine (PPD)-containing hair dye products is a common and important clinical problem. Because there is a high rate of cross-elicitation of allergic contact dermatitis to other important hair dye products (such as p-toluene diamine [PTD] and other aminophenol hair dyes) in PPD allergic patients, safer alternative dyes with excellent hair coloring options are needed. We studied 2-methoxy methyl-PPD (Me-PPD), a chemical derivative of PPD for tolerance versus cross-elicitation in a cohort of eight PPD-allergic volunteers. Objective. To study tolerance to Me-PPD in a PPD highly allergic Italian cohort. Methods. Eight volunteers with a history of contact dermatitis to hair dyes or other PPD-containing chemicals and positive patch tests to 1% PPD in petrolatum, were recruited to study their immediate and delayed skin reactivity to PPD, vehicle control and 2-methoxy-methyl-PPD (Me-PPD), using the allergy alert test (simulating hair dyeing conditions) on volar forearm skin. This is a short-contact open patch test. Results. All eight volunteers reacted to PPD allergy alert test (100%); none reacted to vehicle (0%), and seven of eight reacted to Me-PPD allergy alert test (88%). However, in those seven volunteers who exhibited cross-elicitation to Me-PPD, their aggregate skin test reactivity to Me-PPD was significantly less than that of PPD (figure 3, p minore 0.0062, highly significant, paired two-tailed, students t test). Conclusions. Me-PPD may offer a safer alternative for PPD-allergic patients with an absent or reduced elicitation response in the allergy alert test simulating hair dye use conditions. Even patients with strong patch test reactions, with appropriate selection by allergy alert test and counselling, may be able to tolerate hair dyeing with Me-PPD containing products.

Increased expression of interleukin-9 in patients with allergic contact dermatitis caused by p-phenylenediamine.

BACKGROUND: Allergic contact dermatitis has been described as a type IV reaction caused by antigen-specific T cells. Central roles for CD8+ cytotoxic T cells as effector cells and CD4+ T cells as regulatory cells have been suggested. T helper (Th) 2 and Th1 cytokines have been implicated; however, the nature of the allergen influences the Th response. OBJECTIVE: To determine the types of T cells and cytokines expressed in patients allergic to p-phenylenediamine (PPD). METHODS: Serial skin biopsies of areas with positive patch test reactions in 29 PPD-sensitized patients were collected. T cell markers and cytokine expression were analysed by flow cytometry and quantitative reverse transcription polymerase chain reaction in both skin and peripheral blood mononuclear cells (PBMCs) of sensitized patients. RESULTS: We observed increased expression of T cell markers and Th2/Th9-associated cytokines in both skin and stimulated PBMCs of PPD-allergic patients. Moreover, interleukin (IL)-9 was mainly produced by Th9 cells, in both skin and PBMCs. Further investigations showed that Il9r-deficient mice were more affected in a PPD contact hypersensitivity model than wild-type mice. CONCLUSION: We did not confirm the preclinical presence of CD8+ T cells. However, the expression of different T cell markers positively correlated with patch test reactions. IL-9 expression was strongly upregulated and directly related to patch test severity. In addition, we showed that IL-9 has an anti-inflammatory role in a mouse model of PPD contact hypersensitivity.

Cross-elicitation responses to 2-methoxymethyl-p-phenylenediamine in p-phenylenediamine-allergic individuals: Results from open use testing and diagnostic patch testing.

BACKGROUND: Allergic contact dermatitis caused by p-phenylenediamine (PPD) is a health concern for hair dye users. Because of its lower sensitization potency, the PPD derivative 2-methoxymethyl-p-phenylenediamine (ME-PPD) has been developed as an alternative hair dye for primary prevention. However, cross-elicitation responses can occur in PPD-allergic subjects. OBJECTIVES: To compare cross-elicitation responses to ME-PPD in open use and diagnostic patch testing of PPD-allergic subjects with hair dye-related allergic contact dermatitis. METHODS: Reactions to ME-PPD were investigated in 25 PPD-allergic subjects by performing (1) 45-minute open use testing with a hair dye containing 2.0% of either ME-PPD or PPD, and (2) patch testing with increasing ME-PPD concentrations (0.1%-2.0% pet.). RESULTS: Of the 25 PPD-allergic subjects, 21 (84%) reacted to open use testing with a hair dye containing 2.0% PPD, and testing with 2.0% ME-PPD led to cross-elicitation in 12 (48%). When patch tested with increasing ME-PPD concentrations, 13 (52%) cross-reacted at 0.1% (lowest dose) and 21 (84%) at 2.0% (highest dose), indicating decreased reactivity as compared with published PPD dose-response data. CONCLUSION: In line with the decreased cross-reactivity of ME-PPD in hair dye open use testing, PPD-allergic subjects show an attenuated cross-elicitation dose response to ME-PPD in patch testing.

An Analysis of Skin Prick Tests to Latex and Patch Tests to Rubber Additives and other Causative Factors among Dental Professionals and Students with Contact Dermatoses.

BACKGROUND: Dental workers often experience unwanted allergic and nonallergic skin reactions resulting in different contact dermatoses (e.g., contact urticaria, irritant and allergic contact dermatitis) that are often attributed to rubber gloves. OBJECTIVE: To examine allergic and nonallergic contact dermatoses by different methods amongst dental professionals and dental students, more specifically, reactions to natural rubber latex (NRL), rubber additives, and other causative factors. METHODS: In this cross-sectional study we surveyed a total of 444 subjects (dentists, assistants, technicians, and students); 200 agreed to be tested to latex by the standard skin prick test (SPT) and prick-by-prick test, of whom 107 were patch tested to rubber additives (mercapto mix, thiuram mix, carba mix, and N-isopropyl-N-phenyl-4-phenylenediamine [IPPD]). RESULTS: Skin lesions appeared significantly more frequently with longer work experience (p = 0.002; V = 0.181), frequent glove changes (p < 0.001; V = 0.310), and hand washing (p < 0.001; V = 0.263), and in subjects with a history of allergies (atopic dermatitis, allergic rhinitis, allergic conjunctivitis, and others) (p < 0.001; V = 0.183). Positive SPTs to latex occurred in 14/200 subjects (7%), of whom 5/14 subjects (35.7%) were also positive in prick-by-prick tests. Patch tests were positive in 5/104 subjects (4.8%) (mercapto mix 1%, thiuram mix 1.9%, and carba mix 1.9%). CONCLUSION: Only a small number of our subjects were allergic to latex (7%) or rubber additives (4.8%). Thus, self-reported contact dermatoses (during NRL product use) in dental professionals and students are not commonly caused by allergies to latex and rubber additives, as is often assumed, but by other factors.

Patch-test results using Korean standard series: a 5-year retrospective review.

BACKGROUND: There have been few studies regarding the results of the Korean standard patch test. OBJECTIVES: The purpose of this study was to analyze the type and frequency of common contact allergens in Korea and to compare the results with those of previous reports. METHODS: From June 2009 to June 2014, 330 patients with suspected allergic contact dermatitis who visited our clinic were tested using the Korean standard patch test. RESULTS: The highest sensitization rate was found for nickel sulfate (47.58%). There was a significant gender difference in the prevalence of sensitization to nickel sulfate (OR = 2.41, p = .0004) and wool alcohol (OR = 2.85, p = .0358). Higher sensitization to nickel sulfate (OR = 1.18, p = .0159), 4-phenylenediamine (OR = 1.23, p= .003), tixocortol-21-pivalte (OR 1.48, p = .0212) and lower sensitization to thimerosal (OR = 0.77, p = .0023) were associated with increasing age. Patients with allergic contact dermatitis on the scalp had a significantly higher risk of sensitization to 4-phenylenediamine (OR = 3.07, p = .0013). Patients with allergic contact dermatitis on the hands had significantly higher risks of sensitization to wool alcohol (OR = 3.44, p = .0083), formaldehyde (OR = 2.52, p = .0178), and colophony (OR = 2.05, p = .0499). CONCLUSIONS: These results demonstrate trends in patch test results in Korea and the basis for the presumption of the route of allergen exposure.

Understanding chemical allergen potency: role of NLRP12 and Blimp-1 in the induction of IL-18 in human keratinocytes.

Keratinocytes (KCs) play a key role in all phases of skin sensitization. We recently identified interleukin-18 (IL-18) production as useful end point for determination of contact sensitization potential of low molecular weight chemicals. The aim of this study was to identify genes involved in skin sensitizer-induced inflammasome activation and to establish their role in IL-18 production. For gene expression analysis, cells were treated for 6 h with p-phenylenediamine (PPD) as reference contact allergen; total RNA was extracted and examined with a commercially available Inflammasome Polymerase Chain Reaction (PCR) array. Among genes induced, NLRP12 (Nod-like receptor P12) was selected for further investigation. NLRP12 promoter region contains Blimp-1 (B-lymphocyte-induced maturation protein-1)/PRDM1 binding site, and from the literature, it is reported that Blimp-1 reduces NLRP12 activity and expression in monocytes/macrophages. Their expression and role in KCs are currently unknown. To confirm NLRP12 expression and to investigate its relationship with Blimp-1, cells were exposed for different times (3, 6 and 24 h) to the extreme sensitizer 2,4-dinitrochlorobenzene (DNCB) and the strong sensitizer PPD. Allergens were able to induce both genes, however, with different kinetic, with DNCB more rapidly upregulating Blimp-1 and inducing IL-18 production, compared to PPD. NLRP12 and Blimp-1 expression appeared to be inversely correlated: Blimp-1 silencing resulted in increased NLRP12 expression and reduced contact allergen-induced IL-18 production. Overall results indicate that contact allergens of different potency differently modulate Blimp-1/NLRP12 expression, with strong allergen more rapidly downregulating NLRP12, thus more rapidly inducing IL-18 production. Data confirm that also in KCs, NLRP12 has an inhibitory effect on inflammasome activation assessed by IL-18 maturation.

Tolerance to a Hair Dye Product Containing 2-Methoxymethyl-P-Phenylenediamine in an Ethnically Diverse Population of P-Phenylenediamine-Allergic Individuals.

BACKGROUND: Allergic contact dermatitis after exposure to p-phenylenediamine (PPD)-containing hair dye products is a common and important clinical problem. Because there is a high rate of cross-elicitation of allergic contact dermatitis to other important hair dye products (such as p-toluene diamine and other aminophenol hair dyes) in PPD-allergic patients, safer alternative dyes with excellent hair coloring options are needed. OBJECTIVE: This study aimed to study tolerance to Me-PPD in a PPD-allergic cohort. METHODS: Twenty ethnically diverse volunteers with a history of contact dermatitis to hair dyes or other PPD-containing chemicals and positive patch test results to 1% PPD in petrolatum were recruited to study their immediate and delayed skin reactivity to PPD, vehicle control, and 2-methoxy-methyl-PPD (Me-PPD) using the allergy alert test (simulating hair dyeing conditions) on volar forearm skin. This test is a short-contact open patch test. CONCLUSIONS: The Me-PPD may offer a safer alternative for PPD-allergic patients with an absent or reduced elicitation response in the allergy alert test simulating hair dye use conditions. The absent or reduced response to Me-PPD diagnosed using the allergy alert test has been shown to help reduce the possibility of moderate to severe cross-elicitation reactions among consumers during hair dyeing.

Prevalence of Contact Allergy to p-Phenylenediamine in the European General Population.

Population-based studies on contact allergy to p-phenylenediamine (PPD) are scarce. A cross-sectional study was performed to assess the prevalence of contact allergy to PPD and its risk factors in the general population of 5 European countries. A total of 10,425 subjects were interviewed, and a random sample (n = 2,739) was patch tested to PPD. Overall, 5,286 individuals (50.9%) reported having used hair colorants at least once in their lifetime (78% female, 20% male), and 35% had used hair colorants during the last 12 months. Hair colorant avoidance because of any skin problem during the lifetime was reported by 6%. Black henna tattoos had been used by 5.5% during their lifetime. The prevalence of PPD contact allergy was 0.8% (95% confidence interval 0.6-1.0%), with no statistically significant association with gender or hair dye use. The prevalence of PPD in black henna tattoo users was 3.2% versus 0.6% in nonusers (P < 0.001). A clinically relevant positive patch test reaction to PPD related to hair coloring products was found in 0.1% (95% confidence interval 0.0-0.2%). A significant association with PPD contact allergy was observed for subjects who had black henna tattoos in their lifetime, with an age- and gender-adjusted odds ratio of 9.33 (95% confidence interval 3.45-25.26, P < 0.001). Black henna tattoos are an important risk factor for PPD contact allergy.

Skin testing of gallic acid-based hair dye in paraphenylenediamine/paratoluenediamine-reactive patients.

Incidence of allergic contact dermatitis (ACD) to para-phenylenediamine (PPD)/paratoluenediamine (PTD) hair dyes is increasing. Hair dyes utilizing gallic acid (GA) may be a safe alternative. However, pretesting is recommended. We investigated the contact sensitivity to ingredients of a dye product; GA, monoethanolamine thioglycolate (MT), l-cystein and ferrous sulfate, and an appropriate pretest method in 31 patients reactive to PPD and/or PTD. An open test was performed with the test dye following the patch test. Subsequently, a use test was performed twice, with a 4-week interval. One subject showed a positive reaction to ferrous sulfate in the patch test. Another subject reacted to the first compound alone in the open test. Thirteen subjects manifesting cutaneous lesions from previous regular hair dyeing, showed reactions at the first use of the test dye; and six had reactions with reduced severity at the second test. GA and MT are safe for use in ACD patients reactive to PPD and/or PTD. For predicting contact allergy to hair dyes, the open test appeared to be a better pretest method than the patch test.

A laboratory test based on determination of cytokine profiles: a promising assay to identify exposition to contact allergens and predict the clinical outcome in occupational allergic contact dermatitis.

BACKGROUND: Para-phenylenediamine (PPD) is the main allergen causing adverse reactions to hair dyes and a frequent cause of occupational-related skin sensitization among hairdressers and beauticians. The immunologic mechanism of the disease relies on the production of inflammatory cytokines by allergen-specific T cells, while regulatory T cells are thought to down-modulate the allergic response. This study was aimed at investigating the expression of effector or regulatory cytokines in exposed subjects in order to verify whether different cytokine profiles might predict distinct clinical outcomes. Peripheral blood mononuclear cells (PBMC) from 21 subjects occupationally exposed or not (10) to PPD were kept in short term cultures in the presence of optimized concentrations of NiSO4 × 6H2O or PPD. The production of IFN-γ and IL-10 elicited by antigens were analyzed by the ELISpot assay. RESULTS: The presence of IFN-γ responses toward PPD was significantly correlated with a positive patch test (P = 0.002) and allergic symptoms, while IL10 responses were invariably found in PPD-exposed but clinically asymptomatic subjects with negative patch testing. We found concordance between the different cytokine profiles and patch test results. No false-positive results were found for the different cytokine profiles induced by PPD, resulting in 100% specificity. The sensitivity of the test was 87.5% (95% CI 65.9-100.0) with an overall test accuracy of 93.3%. Although larger prospective-retrospective studies are necessary to validate the predictive potential of the test, the negative and positive predicted values for PPD in this study were NPV = 87.5% and PPV = 100%, respectively. CONCLUSIONS: These data indicate that distinct cytokine profiles are associated with different clinical manifestations. The test, which is based on a simple and rapid profiling of cytokine responses by T lymphocytes against allergens, has proven to be a promising laboratory tool, useful for both the identification of previous contact with allergens and the etiologic diagnosis of contact allergies as well as capable of predicting the clinical outcome (development of an allergic or tolerant response).

Cross-elicitation responses to 2-methoxymethyl-p-phenylenediamine under hair dye use conditions in p-phenylenediamine-allergic individuals.

BACKGROUND: The factors influencing elicitation responses in individuals allergic to p-phenylenediamine (PPD) in hair dyes are not well understood. OBJECTIVES: Investigation of the elicitation response to the new, less-sensitizing PPD alternative 2-methoxymethyl-p-phenylenediamine (ME-PPD) under simulated hair dye use conditions. METHODS: The cross-elicitation response to ME-PPD (2% in a hair dye test product for 30 min on forearm then rinsing) was analysed at days 2 and 3 in 30 PPD-allergic individuals with diagnostic patch test grades +, ++ or +++ according to the classification of the International Contact Dermatitis Research Group. RESULTS: Cross-reactivity to the ME-PPD-containing hair dye test product was elicited in nine of 30 subjects (30%), while 70% were negative. Cross-reactivity was elicited in two of four cases with grade +++, three of 10 with grade ++ and four of 16 with grade +. Under identical conditions, PPD was previously found to elicit a response in 21 of 27 PPD-allergic individuals. In 18 of these 21 individuals, either the strength of the cross-elicitation response to ME-PPD was decreased or no response occurred. CONCLUSIONS: Under simulated hair dye use conditions, a significantly lower degree of cross-elicitation to ME-PPD (30%) was observed than previously reported for PPD (32 of 38, 84%). Additionally, a decreased cross-elicitation strength was observed across all three patch test grades, likely reflecting the reduced skin-sensitization properties of ME-PPD. Consequently, careful dermatological evaluation is required to assess cross-reactivity to ME-PPD in patients allergic to hair dyes.

The importance of hapten-protein complex formation in the development of drug allergy.

PURPOSE OF REVIEW: Drug allergy is an adverse drug reaction that is immune-mediated. Immune activation can occur when drugs or haptens bind covalently to proteins and then act as antigens. The purpose of this review is to summarize the recent data on the formation of hapten-protein complexes and to assess the importance of these complexes in the generation of drug allergy. RECENT FINDINGS: The formation of hapten-protein complexes by drugs and their reactive metabolites has largely been investigated using model proteins such as human serum albumin. Precise identification of the structure of the hapten and the resulting modified residue(s) in the protein has been undertaken for a small number of drugs, such as p-phenylenediamine, nevirapine, carbamazepine, ß-lactams and abacavir. Some progress has also been made in identifying hapten-protein complexes in the serum of patients with allergy. SUMMARY: Drug-specific T cells have been isolated from different patients with allergy. Formation of hapten-protein complexes, their processing and antigen presentation have been implicated in the development of drug allergy to p-phenylenediamine, sulfonamides and ß-lactams. However, evidence also supports the pi mechanism of immune activation wherein drugs interact directly with immune receptors. Thus, multiple mechanisms of immune activation may occur for the same drug.

Positive relationship-intensity of response to p-phenylenediamine on patch testing and cross-reactions with related allergens.

BACKGROUND: Hair dye exposure is the most common cause of sensitization to p-phenylenediamine (PPD). Cross-reactions with structurally related allergens occur. OBJECTIVES: It is suggested that a stronger patch test reaction (3+ rather than 1+) to PPD (usually tested as 1% petrolatum) is associated with an increased propensity for cross-reactions. In this article we will demonstrate this association. METHODS: Of 230 patients with allergic reactions to PPD on patch testing identified during 2007-2012 from clinical records, notes for 221 were available for review. Data were collected regarding age, sex, and grade of reaction [International Contact Dermatitis Research Group (ICDRG) criteria] to PPD. Cross-reactions with the following allergens, found in our baseline series, were recorded: Disperse Yellow 3, N-isopropyl-N'-phenyl-p-phenylenediamine (IPPD), and caine mix. Having excluded 23 doubtful reactions, the reactions from 198 patients were further considered. RESULTS: Of the patients, 75.3% (n = 149) were female, and the mean age was 48.6 years (12-82 years). Of the patients allergic to PPD, 16.6% (n = 33) showed cross-reactions with one or more related allergens. Cross-reactions were seen in 16% with a grade of 1+, 14.5% with a grade of 2+, 28.6% with a grade of 3+ when PPD was tested 1% pet., and 50.0% when PPD was tested at 0.1-0.001%, arbitrarily considered to be 4+ (p = 0.02; Cramér's V = 0.23). CONCLUSION: An increasing likelihood of reactions to Disperse Yellow 3, IPPD or caine mix was seen with increasing strength of patch test reaction to PPD. The clinical relevance of these cross-reactions is unclear.

TRIF signaling is essential for TLR4-driven IgE class switching.

The TLR4 ligand LPS causes mouse B cells to undergo IgE and IgG1 isotype switching in the presence of IL-4. TLR4 activates two signaling pathways mediated by the adaptor molecules MyD88 and Toll/IL-IR domain-containing adapter-inducing IFN-ß (TRIF)-related adaptor molecule (TRAM), which recruits TRIF. Following stimulation with LPS plus IL-4, Tram(-/-) and Trif(-/-) B cells completely failed to express Cε germline transcripts (GLT) and secrete IgE. In contrast, Myd88(-/-) B cells had normal expression of Cε GLT but reduced IgE secretion in response to LPS plus IL-4. Following LPS plus IL-4 stimulation, Cγ1 GLT expression was modestly reduced in Tram(-/-) and Trif(-/-) B cells, whereas Aicda expression and IgG1 secretion were reduced in Tram(-/-), Trif(-/-), and Myd88(-/-) B cells. B cells from all strains secreted normal amounts of IgE and IgG1 in response to anti-CD40 plus IL-4. Following stimulation with LPS plus IL-4, Trif(-/-) B cells failed to sustain NF-κB p65 nuclear translocation beyond 3 h and had reduced binding of p65 to the Iε promoter. Addition of the NF-κB inhibitor, JSH-23, to wild-type B cells 15 h after LPS plus IL-4 stimulation selectively blocked Cε GLT expression and IgE secretion but had little effect on Cγ1 GLT expression and IgG secretion. These results indicate that sustained activation of NF-κB driven by TRIF is essential for LPS plus IL-4-driven activation of the Cε locus and class switching to IgE.