Nickel Sensitivity Research Articles

Patch Testing in Atopic Dermatitis

Because atopic dermatitis (AD) patients differ from non-AD patients in immunologic responses (they lack β-defensins, are more likely to react to protein allergens, and are harder to experimentally sensitize to the nonprotein allergens), patch-test responses to commercially available patch test series may differ in AD patients. To compare responses to conventional patch tests in AD and non-AD patients and to assess the importance of specific allergens in AD. AD patients were strictly defined by history of childhood flexural dermatitis. Patients with active disease were routinely pretreated with systemic antistaphylococcal and antiyeast antibiotics before patch testing unless contraindicated. All final patch-test readings occurred at day 7. The overall number of positive patch-test results did not differ significantly in AD patients (n = 146) versus non-AD patients (n = 1,003). There was no significant increase in nickel sensitivity. There was a nonsignificant trend toward an increased number of positive patch-test reactions to tixocortol pivalate, Compositae mix, and propylene glycol in AD patients. In AD patients treated with antibiotics and systemic azoles before patch testing, the number of positive patch-test reactions is almost identical to that of non-AD patients. Patch-test reactions to components of topical medicaments may be more frequent in AD as compared to non-AD patients.

Does airborne nickel exposure induce nickel sensitization?

Nickel is one of the most prevalent causes of contact allergy in the general population. This study focuses on human exposure to airborne nickel and its potential to induce allergic sensitization. The study group consisted of 309 children at school-starter age living in the West of Germany in the vicinity of two industrial sources and in a rural town without nearby point sources of nickel. An exposure assessment of nickel in ambient air was available for children in the Ruhr district using routinely monitored ambient air quality data and dispersion modelling. Internal nickel exposure was assessed by nickel concentrations in morning urine samples of the children. The observed nickel sensitization prevalence rates varied between 12.6% and 30.7%. Statistically significant associations were showed between exposure to nickel in ambient air and urinary nickel concentration as well as between urinary nickel concentration and nickel sensitization. Furthermore, an elevated prevalence of nickel sensitization was associated with exposure to increased nickel concentrations in ambient air. The observed associations support the assumption that inhaled nickel in ambient air might be a risk factor for nickel sensitization; further studies in larger collectives are necessary.

Nickel, cobalt and chromate sensitization and occupation*

Exposure to nickel, cobalt and chromate are important causes of occupational contact dermatitis. To estimate the prevalence of nickel, cobalt and chromate allergy in a population of consecutive patients and to investigate the possible association with individual and occupational risk factors. A total of 14 464 patients (67.6% women and 32.4% men) with suspected allergic dermatitis underwent patch tests. The associations between patch test results and occupations were studied by multivariate logistic regression analysis. About 24.6% of the patients reacted positively to nickel sulphate, 10.2% to cobalt chloride and 8.7% to potassium dichromate. Nickel sensitization was higher in women aged 26-35 years in comparison with the youngest group (15-25 years) and the older group (> 45 years). In women, the prevalence of positive reactions to nickel was positively associated with metal and mechanical work (OR 1.54; 95%, CI 1.16-2.05). Chromate sensitization was more prevalent in building trade workers for both women (OR 1.58; 95% CI 1.00-2.49) and men (OR 2.24; 95% CI 1.55-3.22). Cobalt sensitization was associated with textile and leather work in women (OR 1.52; 95% CI 1.09-2.12) and with cleaning work in men (OR 1.86; 95% CI 1.18-2.93). Our study showed interesting associations between some occupations and nickel, chromate and cobalt allergy.

The association between null mutations in the filaggrin gene and contact sensitization to nickel and other chemicals in the general population

It was recently shown that filaggrin gene (FLG) null mutations are positively associated with nickel sensitization. We have hypothesized that histidine-rich filaggrin proteins in the epidermis chelate nickel ions and prevent their skin penetration and exposure to Langerhans cells. Furthermore, we have proposed that the low degree of genetic predisposition to nickel sensitization found by a Danish twin study was explained by a high prevalence of ear piercing among participants resulting in 'bypassing' of the filaggrin proteins. To investigate the association between FLG null mutations and (nickel) contact sensitization. A random sample of 3335 adults from the general population in Denmark was patch tested and genotyped for R501X and 2282del4 in the FLG gene. The combined carrier frequency of FLG null mutations was 8·1%. Nickel, fragrance and contact sensitization to at least one allergen were not associated with FLG null mutations. A crude analysis on women who did not have ear piercings revealed a positive association between FLG null mutations and nickel sensitization [8·3% vs. 2·4%; odds ratio (OR) 3·71, 95% confidence interval (CI) 0·73-18·96] as well as between FLG null mutations and allergic nickel dermatitis (8·3% vs. 1·3%; OR 6·75, 95% CI 1·17-38·91). FLG mutation status and atopic dermatitis were positively associated with neomycin or ethylenediamine sensitization. This study suggests that FLG null mutations may be a risk factor for the development of nickel sensitization. However, ear piercing was a much stronger risk factor in our general population and we could therefore identify a positive association only in women without ear piercings. Contact sensitization to specific chemicals is related to treatment exposure.

Nickel sensitisation in mice: A critical appraisal

The market release of new domestic and industrial chemical and metal products requires certain safety certification, including testing for skin sensitisation. Although various official guidelines have described how such testing is to be done, the validity of the available test models are in part dubious, for which reason regulatory agencies and research aim to further improve and generalise the models for testing of skin sensitisation. We applied a recently published murine model of nickel allergy as to test its applicability in a regulatory setting and to study and better understand the events leading to type-IV hypersensitivity. Nickel was chosen as model hapten since it induces allergic contact dermatitis with high incidence in the general population. Typically, C57BL/6 mice were sensitised and challenged by intradermal applications of nickel, and cutaneous inflammation was analysed by the mouse ear-swelling test, by histology, and by lymphocyte reactivity in vitro. Surprisingly, the study suggested that the skin reactions observed were results of irritant reactions rather than of adaptive immune responses. Non-sensitised mice responded with cutaneous inflammation and in vitro lymphocyte reactivity which were comparable with nickel-sensitised mice. Furthermore, histological examinations as well as experiments in T-cell deficient mice demonstrated that lymphocytes were not involved and that nickel caused an irritant contact dermatitis rather a true allergic type-IV contact dermatitis. The authors question the validity of the described murine model of nickel allergy.

Dermatology in public health - a model for surveillance of common skin diseases

The aim was to establish a baseline prevalence of skin conditions of public health importance in the general population and taking the validity of the questions into account. Our model is intended for future surveillance of skin conditions. The suggested questions have for the first time been used in Swedish population surveys. A random sample was taken from the general population aged 16 to 84 years of the participating areas. During the past 12 months, hand eczema was reported by 9.4%, childhood eczema by 15.7% and nickel allergy by 13.7% of the population. Hand and childhood eczema questions have previously been validated. Taking the validity into account, the actual population prevalence of hand eczema (11.7%) is underestimated, and the prevalence of atopic childhood eczema (10.0%) is overestimated based on the results of the questionnaire. In addition to presenting prevalence, population survey results can be used for risk analyses. A 10-fold risk of hand eczema in individuals with childhood eczema and self-reported nickel sensitivity is shown in our study. Questionnaires can be used for epidemiologic surveillance so long as the questions are validated and that the validity is taken into account when estimating the occurrence of the conditions. Public health surveys such as this one lay the basis for future epidemiological surveillance of skin conditions that can be subject to interventions. We propose that these, or similar, questions should be used regularly in population surveys and supplemented by questions on skin exposure.

Nickel hypersensitivity: a clinical review and call to action

Nickel sensitivity is common and increasing in prevalence. This review discusses nickel sensitivity and its association with body piercing and other environmental factors, occupational relevance, and potential implications for implantable metal medical devices. In addition, current European legislation that limits the release of nickel from jewelry is highlighted and an argument for similar legislation elsewhere is presented.

Effect of Tobacco Smoking and Alcohol Consumption on the Prevalence of Nickel Sensitization and Contact Sensitization

There is evidence that stimulants such as alcohol and tobacco have an effect on the immune system, but little is known about how these lifestyle factors affect the prevalence of contact sensitization. This study investigated whether smoking and alcohol consumption were associated with contact sensitization and nickel sensitization. A random sample of adults (n=3460) from the general population of Copenhagen was invited to participate in a general health examination including patch-testing. Alcohol consumption was not associated with nickel sensitization, whereas a significant trend (p<0.05) was identified between smoking status and nickel sensitization in an adjusted model; i.e. nickel sensitization was higher among both previous smokers (odds ratio (OR) = 1.19; confidence interval (CI) = 0.81-1.76), current light smokers (OR=1.50; CI=0.94-2.37) and current heavy smokers (OR=1.56; CI = 0.87-2.80) compared with never smokers. This study confirmed that smoking is associated with nickel sensitization, but rejected an association with alcohol consumption.

Association of CD69 Up-Regulation on CD4+ CLA+ T cells versus patch test, strip patch test and clinical history in nickel sensitization

ObjectiveThe patch test (PT) with its modification - the strip patch test (SPT) - is the standard in vivo procedure to diagnose an allergic contact dermatitis (ACD). To date, none of the in vitro tests for the diagnosis of ACD fulfils the requirements of an easy, valid and reliable test. To investigate the prediction ability of a flow cytometric assay of CD69 up-regulation on CD4+ CLA+ T cells in nickel-sensitive and non-nickel-sensitive patients.MethodsIn a prospective, investigator-blinded, clinical study a total of 85 nickel-sensitive (n = 44; 51.8%) and non-nickel-sensitive patients (n = 41; 48.2%) were enrolled. The association between CD69 up-regulation on CD4+ CLA+ T cells on the one hand and PT, SPT, and clinical history on the other hand was measured. Association is expressed with c statistic values (receiver operating characteristic analysis) and corresponding 95% CIs.ResultsThe associations were c = 0.57 (95% CI: 0.42-0.72) between CD69 up-regulation and PT, c = 0.49 (95% CI: 0.36-0.62) between CD69 up-regulation and SPT, and c = 0.51 (95% CI: 0.37-0.64) between CD69 up-regulation and clinical history.ConclusionsCD69 up-regulation on CD4+ CLA+ T cells in vitro could not predict neither a positive PT or SPT result nor a positive clinical history to nickel sulfate. The combination of clinical history and patch testing still remains the basis for diagnosing ACD.

Benefit of iron therapy in the management of chronic urticaria due to nickel sensitivity

Benefit of iron therapy in the management of chronic urticaria due to nickel sensitivity

Nickel allergy presenting as mobile phone contact dermatitis

A 39-year-old man presented with a 6-month history of a treatment-resistant facial dermatitis. The patient regularly used his mobile phone, predominantly on the left cheek. Patch testing confirmed the clinical suspicion of mobile phone contact dermatitis from nickel contained in the phone casing. Although infrequently reported, with the trend towards metallic mobile phone casings and the high incidence of nickel sensitization in the community, the incidence of mobile phone contact dermatitis is likely to increase.

Nickel-induced allergy and contact dermatitis: does it induce autoimmunity and cutaneous sclerosis? An experimental study in Brown Norway rats

Nickel sensitization is a growing problem and the most common cause of allergic contact dermatitis. The aim of this study was to investigate whether nickel chloride can induce autoimmunity and cutaneous sclerosis in immunosensitive rats. Nickel chloride, in a dose of 4.5 mg in 0.2 ml NS, was administered by the oral and subcutaneous routes to 20 Brown Norway rats. Autoantibodies (ANA, anti-RNP, anti-SCL70 and anti-centromere) were measured and compared in pre- and post-challenge serum samples. Histological studies were also performed in skin biopsies obtained from six positively responding rats and compared with an equal number of control rats at the 14th week post-challenge. Serum ANA was high in a significant number of rats in both the oral (P < 0.005) and subcutaneously nickel-treated groups (P = 0.02), while the anti-SCL70 was high in a significant number of rats in only the orally nickel-treated group (P = 0.04). Histologically, subcutaneous and oral nickel-treated groups showed sclerodermic features of the skin (P = 0.22, P = 0.5), respectively. It may be concluded that nickel chloride can induce scleroderma-related autoantibodies and cutaneous sclerosis. More prolonged duration of exposure is probably associated with greater risk. This is the first study showing the potential risk of nickel in triggering the development of cutaneous sclerosis in susceptible hosts.

Serum levels of protein oxidation products in patients with nickel allergy

Nickel sensitization can not only induce allergic contact dermatitis (ACD), but also can induce an overlapping disease referred to as "systemic nickel allergy syndrome" (SNAS), characterized by urticaria/angioedema and gastrointestinal symptoms correlated to the ingestion of nickel-containing foods. This study was designed to determine if oxidative stress occurs in patients with nickel allergy. Thirty-one female patients (mean age 31.26 + 13.04 years, range 16-64 years) with confirmed nickel CD underwent oral nickel challenge because of clinically suspected SNAS; serum concentrations of protein carbonyl groups (PCGs) and nitrosylated proteins (NPs; biomarkers of oxidative stress) were measured before and after oral nickel challenge as well as in healthy female controls. Twenty-three of these 31 patients were diagnosed with SNAS because they had a positive reaction to the oral nickel challenge, and 8 patients had no reaction and therefore were classified as patients with contact nickel allergy only. Although both nickel-allergic patients and controls presented similar serum levels of PCGs, NP values in nickel-allergic patients appeared higher than in controls and tended to decrease after the challenge; furthermore, serum levels of NPs in patients affected by SNAS were higher (although not significantly) than in patients with nickel ACD only. The involvement of specific biomarkers of oxidative stress such as NPs and the lack of involvement of other biomarkers such as PCGs may help to better understand the alteration of the redox homeostasis occurring in nickel ACD and particularly in SNAS.

A Comparative Biocompatibility Analysis of Ternary Nitinol Alloys

Nitinol alloys are rapidly being utilized as the material of choice in a variety of applications in the medical industry. It has been used for self-expanding stents, graft support systems, and various other devices for minimally invasive interventional and endoscopic procedures. However, the biocompatibility of this alloy remains a concern to many practitioners in the industry due to nickel sensitivity experienced by many patients. In recent times, several new Nitinol alloys have been introduced with the addition of a ternary element. Nevertheless, there is still a dearth of information concerning the biocompatibility and corrosion resistance of these alloys. This study compared the biocompatibility of two ternary Nitinol alloys prepared by powder metallurgy (PM) and arc melting (AM) and critically assessed the influence of the ternary element. ASTM F 2129-08 cyclic polarization in vitro corrosion tests were conducted to evaluate the corrosion resistance in phosphate buffered saline (PBS). The growth of endothelial cells on NiTi was examined using optical microscopy.

The Th1-promoting effects of dehydroepiandrosterone can provide an explanation for the stronger Th1-immune response of women.

Estrogens foster immunological processes driven by CD4+ Th2 cells and B cells and androgens foster Th1 CD4+ and CD8+ cell activity. Higher levels of IFN-gamma and IL-2 and lower levels of IL-4 and IL-10 are detected in the phytohemagglutinin-stimulated lymphocyte culture supernatants of men compared with women. It is documented that the physiologic levels of estrogens produced during the luteal phase of the menstrual cycle shift the female immune system toward a Th2-type response and that the Th1 cytokines are increased in postmenopausal women. However, the Th1 immune response is also surprisingly stronger in women, hence affording them a better protection against infections. Nickel sensitivity, a Th1 immune reaction, seems to be more common in women even if men wear earrings. Further, not only the Th2 but also the Th1 autoimmune diseases are generally more common in women than men. How do women advance a stronger Th1 response than men? It is suggested that in contrast to the paradigm that estrogens lead to a Th2 bias, estrogens can enhance Th1 cytokine production also. However, the discrepant effects of estrogens are difficult to be reconciled from a molecular viewpoint and hence are not advocated by all authors. This paper provides an explanation: The effects of dehydroepiandrosterone on Th1/Th2 balance seem to be model-specific; in humans dehydroepiandrosterone, represents a pivotal up-regulator of Th1 immune response. Steroid sulphatase is a microsomal enzyme that cleaves the sulphate group of dehydroepiandrosterone sulphate. This enzyme is controlled by an X-linked gene that escapes the Lyon effect of X-inactivation; as a result, women usually have about twice steroid sulphatase in their cells, including macrophages, as have men. Putting all these facts together, it could be concluded that women's macrophages, which contain higher steroid sulphatase levels and enter peripheral lymphoid organs through afferent lymphatic drainage, produce higher levels of dehydroepiandrosterone in these organs; and higher levels of this hormone produce stronger Th1 immune responses.

Response to cytosolic nickel of Slow Vacuolar channels in the hyperaccumulator plant Alyssum bertolonii

We applied the patch-clamp technique to investigate the transport properties of the Slow Vacuolar (SV) channel identified in leaf vacuoles of Alyssum bertolonii Desv., a nickel hyperaccumulator plant growing in serpentine soil of the northern Apennines (Italy). SV currents recorded in vacuoles from adult plants collected in their natural habitat showed high sensitivity towards cytosolic nickel. Dose-response analyses indicated half-maximal current inhibition at submicromolar concentrations, i.e. up to three orders of magnitude lower than previously reported values from other plant species. The voltage-dependent increase of residual currents at saturating nickel concentrations could be interpreted as relief of channel block by nickel permeation at high positive membrane potentials. Including young plants of A. bertolonii into the study, we found that SV channels from these plants did not display elevated nickel sensitivity. This difference may be related to age-dependent changes in nickel hyperaccumulation of A. bertolonii leaf cells.

Prurigo pigmentosa in a patient with nickel sensitivity

Prurigo pigmentosa in a patient with nickel sensitivity

A case of severe metal hypersensitivity post tibial plating

Metal hypersensitivity is a well-recognised phenomenon post implantation of orthopaedic devices, though rarely tested for or considered prior to implantation ofsaid devices. Our report outlines a case of severe metal hypersensitivity to stainless steel, and raises the issue of a need for preoperative screening of patients for metal sensitivity prior to implantation. Studies would suggest a baseline incidence of nickel sensitivity in the general population to be in the order of 10-15%12, with the rates doubling in those with chronic nickel exposure. The role such hypersensitivity plays in hardware failure, pain, and cutaneous reactions remains unproven in clinical studies, though many cases, such as this one, suggest a direct causal relationship.

Nickel Sensitization, Hand Eczema, and Loss-of-Function Mutations in the Filaggrin Gene

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease. Recently, it was demonstrated that a large proportion of individuals with AD have an epidermal expression deficiency of filaggrin (FLG). This unique finding may have great implications for our understanding of nickel sensitization because nickel is chelated in the epidermis and perhaps to FLG. This review aims to briefly present the current knowledge about nickel sensitization in relation to FLG deficiency and speculate on its possible implications. The new knowledge concerning loss-of-function mutations in the FLG gene (the lack of specific nickel-chelating power in the stratum corneum and a generally defective skin barrier) suggests that an additive effect from irritants and nickel may aggravate hand eczema in individuals with loss-of-function mutations in the FLG gene. This hypothesis calls for a reevaluation of the potential risk of nickel sensitization through the establishment of cohorts with and without such mutations.

The outcome of dimethylglyoxime testing in a sample of cell phones in Denmark

Nickel dermatitis may be caused by frequent and prolonged use of cell phones. Because little is known about the frequency of nickel release from cell phones, it is difficult to estimate the risk of nickel sensitization and dermatitis among their users. Inspired by a recent case of nickel dermatitis from prolonged cell phone use, the frequency of dimethylglyoxime (DMG)-positive cell phones on the Danish market was investigated. Five major cell phone companies were contacted. Two were visited, and the DMG test was performed on a sample of their products. 5 of 15 (33.3%) phones from company A and 3 of 26 (11.5%) phones from company B showed at least 1 positive reaction. 3 phones had more than 1 positive DMG spots. This study documents that excessive nickel release (i.e. a positive DMG test) is relatively frequent in a sample of cell phones from the Danish market. Prolonged use of cell phones may in some cases fulfil the criteria for items included in the European Union Nickel Directive. We believe that this new cause of nickel dermatitis should be carefully followed and that regulatory steps may be necessary.