Nickel allergy and allergic contact dermatitis: A clinical review of immunology,epidemiology, exposure,and treatment

Nickel is the most frequent cause of contact allergy worldwide and has been studied extensively. This clinical review provides an updated overview of the epidemiology, exposure sources, methods for exposure quantification, skin deposition and penetration, immunology, diagnosis, thresholds for sensitization and elicitation, clinical pictures, prevention, and treatment. The implementation of a nickel regulation in Europe led to a decrease in the prevalence of nickel allergy, and changes in the clinical picture and disease severity. Nevertheless, the prevalences of nickel allergy in the European general population are approximately 8% to 19% in adults and 8% to 10% in children and adolescents, with a strong female predominance. Well‐known consumer items such as jewellery and metal in clothing are still the main causes of nickel allergy and dermatitis, although a wide range of items for both private and occupational use may cause dermatitis. Allergic nickel dermatitis may be localized to the nickel exposure site, be more widespread, or present as hand eczema. Today, efficient methods for exposure quantification exist, and new insights regarding associated risk factors and immunological mechanisms underlying the disease have been obtained. Nevertheless, questions remain in relation to the pathogenesis, the persistent high prevalence, and the treatment of severe cases.     

Nickel earlobe dermatitis and clinical non‐relevance of the oral exposure

Objective Nickel is the most common cause of allergic contact dermatitis (ACD). Because nickel restriction is commonly imposed on many patients with the only earlobe ACD to nickel hypersensitivity, the aim of this study was to identify the role of occasional and extended oral nickel exposure in these patients. Design This is a case–control study Subjects Thirty‐four outpatients, previously diagnosed as monosensitized to nickel, suffering from earlobe dermatitis were enrolled; 11 of them showed active dermatitis. The control group consisted of six healthy (non‐nickel‐sensitive) subjects. Interventions High oral nickel challenge (20 mg) and protracted oral challenge (1 mg once a day). Observation period: 6 weeks. Results Clinical earlobe lesions were not affected by a high oral nickel intake nor by a protracted oral challenge. Conclusions Dietary nickel restriction seems to be useless in patients with earlobe ACD due to nickel hypersensitivity.     

The balance between pro‐ and anti‐inflammatory cytokines is crucial in human allergic contact dermatitis pathogenesis: the role of IL‐1 family members

The interleukin (IL)‐1 family includes 11 members that are important in inflammatory processes. It includes various agonists and two antagonists, IL‐1Ra and IL‐36Ra. Our aim was to investigate whether the IL‐1 family is involved in allergic contact dermatitis (ACD). The expression of IL‐1 family members was evaluated by PCR and immunohistochemistry in the positive patch test reaction site (involved skin) and in the uninvolved skin of ACD patients. We also examined these cytokines in an ex vivo model of ACD. The antagonistic activity of IL‐36Ra was evaluated by injecting recombinant IL‐36Ra in uninvolved skin biopsies of ACD patients. IL‐1Ra and IL‐36Ra expression was quantified in mononuclear cells of nickel‐sensitized patients challenged in vitro with nickel. IL‐33 involvement in ACD was investigated by intra‐dermal injection of anti‐IL‐33 in the uninvolved skin of patients ex vivo. Results showed that IL‐1β, IL‐1Ra, IL‐36α, IL‐36β, IL‐36γ and IL‐33 expression, but not IL‐36Ra expression, was enhanced in ACD‐involved skin. Immunohistochemical analysis and ex vivo skin cultures confirmed these results. Injection of anti‐IL‐33 in ACD‐uninvolved skin inhibited IL‐8 expression, whereas IL‐36Ra inhibited IL‐36α, IL‐36β, IL‐36γ and IL‐8 expression. Nickel induced IL‐1Ra expression in lymphocytes of nickel‐sensitized patients. Hence, various IL‐1 agonists and antagonists may be involved in ACD pathogenesis.     

Occupational hand eczema caused by nickel and evaluated by quantitative exposure assessment

Background. EU legislation has reduced the epidemic of nickel contact allergy affecting the consumer, and shifted the focus towards occupational exposure. The acid wipe sampling technique was developed to quantitatively determine skin exposure to metals. Objectives. To assess the clinical usefulness of the acid wipe sampling technique as part of the diagnostic investigation for occupational nickel allergy‐associated hand dermatitis. Patients and methods. Six patients with vesicular dermatitis on the hands were included. Acid wipe sampling of skin and patch testing with a nickel sulfate dilution series were performed. Results. Nickel was detected in all samples from the hands. In all patients, the nickel content on the hands was higher than on the non‐exposed control area. Conclusions. Occupational exposure to nickel‐releasing items raised the nickel content on exposed skin as compared with a non‐exposed control site. Nickel‐reducing measures led to complete symptom relief in all cases. In cases of a positive nickel patch test reaction and hand eczema, patients should perform the dimethylglyoxime (DMG) test on metallic items at home and at work. The acid wipe sampling technique is useful for the diagnosis of occupational hand eczema following screening with the inexpensive DMG test.     

An arm immersion model of compromised skin

The transition metal nickel is a very common cause of allergic contact dermatitis (ACD), In the general population, adults with hand eczema have a high incidence of allergy to nickel, and nickel allergy is high in occupational dermatoses and is often linked to wet work. Nickel may be found as a trece contaminant in some consumer products, e.g., household cleaning agents. It has therefore been debated whether these levels, whilst not a primary cause, might be sufficient to maintain ACD. The minimal concentration of nickel in patch tests on normal skin that will elicit an allergic reaction in highly sensitised subjects is 1–10 ppm. This trial assessed whether reactivity to nickel was altered on compromised dorsal forearm skin and compared this to normal skin on the contralateral dorsal forearm and on the back. Skin damage consequent upon arm immersion in sodium dodecyl sulphate (SDS) greatly enhanced reactivity to nickel on the forearm, with the dorsal aspect reacting most both in number of reactions at each concentration and in the minimal eliciting concentration, which was 0.5 ppm in 2/20 under the conditions of a 48 h occluded patch.     

Prevalence,incidence rates and persistence of contact allergy and allergic contact dermatitis in The Odense Adolescence Cohort Study: a 15‐year follow‐up

Background A cohort of 1501 unselected 8th grade schoolchildren was established 15 years ago with the aim to follow the course of contact allergy and allergic contact dermatitis (ACD) from school age into adult life. To date no studies have evaluated incidence rates and persistence of contact allergy and ACD in an unselected population from adolescence to adulthood. Objectives To estimate the incidence rates and persistence of contact allergy and ACD from adolescence to adulthood, and the point prevalence in adulthood. Methods In total, 1206 young adults from the cohort were contacted and asked to complete a questionnaire and participate in a clinical examination including patch testing with TRUE Test^®. The questionnaire was answered by 899 (74.6%), however, only 442 (36·7%) of those invited participated in patch testing. Results Over the 15‐year period the incidence rates of contact allergy and ACD were 13·4% and 7·8%, respectively. The point prevalence of contact allergy was 20·1%, and present or past ACD was found in 12·9% of those followed. Nickel was the most common contact allergen (11·8%), followed by cobalt (2·3%), colophony (2·0%), thiomersal (1·4%) and p‐phenylenediamine (1·1%). Most nickel reactions were persistent, and a significant number of new nickel sensitizations were found. Fragrance mix I reactions from adolescence could not be reproduced. Conclusions From adolescence to adulthood the incidence rates of contact allergy and ACD were high. Nickel was still the most common contact allergen, and new sensitizations occurred despite the European Union nickel regulation. Fragrance mix I was a poor marker for history of eczematous skin reaction to perfumed products.     

Relationship between nickel allergy and diet

Nickel is a ubiquitous trace element and it occurs in soil, water, air and of the biosphere. It is mostly used to manufacture stainless steel. Nickel is the commonest cause of metal allergy. Nickel allergy is a chronic and recurring skin problem; females are affected more commonly than males. Nickel allergy may develop at any age. Once developed, it tends to persist life-long. Nickel is present in most of the dietary items and food is considered to be a major source of nickel exposure for the general population. Nickel content in food may vary considerably from place to place due to the difference in nickel content of the soil. However, certain foods are routinely high in nickel content. Nickel in the diet of a nickel-sensitive person can provoke dermatitis. Careful selection of food with relatively low nickel concentration can bring a reduction in the total dietary intake of nickel per day. This can influence the outcome of the disease and can benefit the nickel sensitive patient.     

Nickel skin levels in different occupations and an estimate of the threshold for reacting to a single open application of nickel in nickel-allergic subjects

Background Nickel is a frequent allergen throughout the world. However, the extent to which nickel is relevant as an occupational contact allergen as opposed to being simply a reflection of jewellery exposure has been unclear. Some thresholds for cutaneous nickel exposure to induce a dermatitis reaction in nickel‐allergic individuals have been defined. Over recent years it has become possible to measure accurately the quantity of nickel on the skin of individuals in a number of occupations. Objectives To measure the quantities of nickel on the skin of the fingers in workers employed in occupations for which nickel has been suspected as a contact allergen. To define the threshold for a dermatitis reaction after the single application of a quantity of nickel to the skin of nickel‐allergic individuals when read at 2 days. Methods We employed the ‘finger immersion’ technique for sample collection and induction coupled plasma mass spectrometry for the nickel measurement. Nickel platers, cashiers, sales assistants, caterers, healthcare assistants, office workers, dental nurses and hairdressers were studied (five in each group except for seven cashiers). A correction was made for the fact that the finger immersion method underestimates the amount of nickel on the fingertip. The threshold for reactivity to a single application of nickel was studied by the application of various concentrations of nickel (μg cm^?2) [0·05 (two subjects), 0·5 (two subjects), 2·5 (three subjects), 5·0 (21 subjects), 15 (19 subjects), 30 (19 subjects) and 45 (18 subjects)] in 21 subjects overall using Finn chambers on forearm skin. The reading was made at 2 days and reactions were graded using the International Contact Dermatitis Research Group classification. Results Nickel levels on the fingers of platers, cashiers, sales assistants, caterers, and even office staff, were at or above the 0·035 μg cm^?2 level at which 22% of nickel‐allergic subjects will react (after applying a correction). The single open application of nickel study demonstrated a dose–response relationship, with no subjects reacting to ≤ 2·5 μg cm^?2, but increasing numbers reacting at the higher concentrations as follows: six of 21 (28%) at 5·0 μg cm^?2, six of 19 (31%) at 15 μg cm^?2, seven of 19 (37%) at 30 μg cm^?2 and 11 of 18 (61%) at 45 μg cm^?2. Conclusions This study confirms that nickel levels on the skin in coin handling occupations and some others are sufficient to induce an allergic contact dermatitis in some nickel‐allergic subjects. A single application of 5 μg cm^?2 when read at 2 days induced a dermatitis reaction in six of 21 nickel‐allergic subjects.     

Sun protection education in the United States: what we know and what needs to be taught

The incidence of skin cancers in the United States is rising. This has correlated with a life-time of sun exposure and cumulative damage of repetitive sun-related injuries such as tanning and sunburning. It is estimated that 80% of sun damage occurs before the age of 18 years. This relates to excessive tanning, blistering sunburns, and ineffective sun protection. It has been demonstrated that children can be taught to protect themselves from the sun. However, teaching of sun protection needs to begin at an early age. Such education requires that parents enforce protection in the household and through their actions in sunny situations. It has become apparent from the literature in the United States that we have made strides in sun education, but we have not yet instituted an effective nationwide education plan. This article reviews the data we have in the United States on sun protection, with a focus toward helping to design better education programs for the future. Based on the literature, it would seem that sun education should combine teaching mothers about sun protection in the nursery and teaching schools how to educate youngsters on the need for sun protection, beginning in nursery school. Improvements in education will have a latency of many years for reducing skin cancer incidence but will be an excellent investment in the future cutaneous health of today's children.     

The EU Nickel Directive revisited--future steps towards better protection against nickel allergy

In July 2001, the EU Nickel Directive came into full force to protect European citizens against nickel allergy and dermatitis. Prior to this intervention, Northern European governments had already begun to regulate consumer nickel exposure. According to part 2 of the EU Nickel Directive and the Danish nickel regulation, consumer items intended to be in direct and prolonged contact with the skin were not allowed to release more than 0.5 μg nickel/cm2/week. It was considered unlikely that nickel allergy would disappear altogether as a proportion of individuals reacted below the level defined by the EU Nickel Directive. Despite this, the EU Nickel Directive part 2 was expected to work as an operational limit that would sufficiently protect European consumers against nickel allergy and dermatitis. This review presents the accumulation of epidemiological studies that evaluated the possible effect of this major public health intervention. Also, it evaluates recent exposure assessment studies that have been performed using the dimethyl glyoxime test. It is concluded that the EU Nickel Directive has started to change the epidemiology of nickel allergy in Europe but it should be revisited to better protect consumers and workers since nickel allergy and dermatitis remain very frequent.     

Release of nickel from coins and deposition onto skin from coin handling--comparing euro coins and SEK

Background:  Nickel exposure is the most common cause of contact allergy. The role of contact with nickel-containing coins has been controversial.
Objectives:  To compare the release of nickel from 1 and 2 EUR coins (both composed of two alloys: Cu 75%, Zn 20%, Ni 5% and Cu 75%, Ni 25%) and Swedish 1 SEK coin (alloy: Cu 75%, Ni 25%) and to assess the deposition of nickel onto skin by coin handling.
Methods:  Nickel release was determined by immersion in artificial sweat (2 min, 1 hr, 24 hr, and 1 week). Deposition of nickel onto the skin was assessed in three subjects after 1-hr handling of 2 EUR and 1 SEK coins. Samples ( n  = 48) were taken from fingers and palms by acid wipe sampling and analysed by inductively coupled plasma mass spectrometry.
Results:  Amounts of nickel released by 1 week from 1 SEK, 1 EUR, and 2 EUR coins were 121, 86, and 99 μg/cm², respectively. Corresponding 2 min values were 0.11, 0.25, and 0.22 μg/cm². Nickel was deposited onto the skin by 1 hr coin handling (range 0.09–4.1 μg/cm²), the largest amounts were on fingers; similar amounts of nickel were deposited from 1 SEK and 2 EUR coins.
Conclusions:  Nickel is released from 1 and 2 EUR and 1 SEK coins at similar amounts. Nickel is deposited onto skin at substantial and similar amounts by coin handling. Acid wipe sampling is suitable for studies of skin exposure to nickel and in risk assessment.     

Coin exposure may cause allergic nickel dermatitis: a review

Nickel is used in coins because the metal has beneficial properties, including price, colour, weight, and corrosion resistance, and also because it is easy to stamp. It has often been claimed that the duration of skin contact with coins is too short to cause nickel release and dermatitis. However, it is well known by dermatologists specialized in occupational skin diseases, and by their nickel‐allergic patients, that hand eczema in cashiers and other professionals who handle coins may be caused or aggravated by nickel release from coins. In this review, we present evidence from past studies showing that nickel‐containing coins can indeed pose a risk for those who handle them. For protection of the health of consumers, cashiers, and other workers who handle coins, it is suggested that coins without nickel release should be used as a substitute for the high nickel‐releasing coins currently in widespread use. The key risk factor in this situation is the ability of metal alloys in coins to release nickel and contaminate the skin after repeated contact from coin handling.     

Contact sensitization to common haptens is associated with atopic dermatitis: new insight

Background It has been much debated whether atopic dermatitis (AD) is associated with contact sensitization as past findings have been conflicting. A positive association might change our clinical practice. Objectives To investigate the association between AD and contact sensitization taking the likely route of allergen exposure into account. Methods Questionnaire and clinical data from a cross‐sectional study performed in a general population in Copenhagen. In total, 3202 adults aged 18–69 years were patch tested, filaggrin genotyped for 2282del4 and R501X and questioned about AD. Results The variable ‘contact sensitization to at least one allergen, but not nickel and thimerosal’ was significantly associated with AD (odds ratio 2·53, 95% confidence interval 1·59–4·04). The higher prevalence of contact sensitization was driven mainly by fragrance chemicals. In a subanalysis in nonpierced women, a positive association was also found for nickel sensitization. Nickel and thimerosal sensitization may introduce bias in data analysis as these allergies often develop following skin piercing where the skin compartments are bypassed. Conclusions We suspect that individuals with self‐reported AD from this study mainly had mild disease. However, clinicians should be aware of increased levels of contact sensitization in individuals with AD. Patch testing should therefore be considered at an early point in individuals with a history of AD and active disease. The fundamental relationship between atopic disease and environmental chemical exposure may be of a more complex and intimate nature than previously supposed.     

Prevalence of nickel allergy among Finnish university students in 1995

Nickel allergy was studied in a sample of 1st-year university students starting their studies in 1995. A total of 296 subjects (72%) of 413 invited participated in the clinical examination, and 284, 96 male and 188 female, were patch tested (69%). A history of nickel sensitization was enquired for. Prick tests and serum specific IgE levels were determined. Occurrence of atopic dermatitis, hand eczema, and current exposure to metals were recorded. Nickel allergy was encountered in 39% of all female students, in 42% of females with pierced skin, and in 14% of females without pierced skin. The corresponding figures for males were 3%, 7% and 3%. In the multiple regression analysis, the risk factors for nickel allergy were female sex (OR 8.1, p<0.01), current metal exposure at examination (OR 4.1, p<0.01) and skin piercing (OR 3.6, p<0.05). Positive prick tests or elevated IgE levels to common allergens were not significantly associated with nickel allergy. In female students, the prevalence of nickel allergy has increased from 13% in 1986 to 39%. The prevalence among males has remained low at 3%. The results indicate that, in addition to skin piercing, current metal contacts are important risk factors for nickel allergy. This finding gives support to the EU Nickel Directive.     

“Mint” Condition: Contact Dermatitis in an Adolescent Numismatist

Allergic contact dermatitis (ACD) is common in children and adolescents. A history of persistent rash despite appropriate treatment should raise suspicion of ACD. We present the case of a 16‐year‐old boy with chronic dermatitis suspected of being a possible nickel allergy. He and his mother denied known common exposures. Patch testing confirmed allergies to multiple metals and several preservatives. A detailed social history revealed that the patient was an avid coin collector. Information about hobbies and activities should be elicited in any patient in whom ACD is suspected to determine exposures they may not initially have considered relevant. This case highlights the importance of pre‐ and posttest counseling and exposure history.     

Nickel on the Swedish market before the Nickel Directive

Nickel allergy is by far the most frequent contact allergy, affecting 10-15% of women in the general population, and causing dermatitis and hand eczema. The EU Nickel Directive, aimed at the prevention of nickel allergy, comes fully into force by July 2001. The Directive covers piercing materials, items in contact with the skin, and requirements on resistance to wear. We carried out a study of the prevalence on the market, before the Nickel Directive, of items that release nickel and of nickel in piercing posts. Nickel release, as shown by a positive dimethylglyoxime (DMG) test, was detected in 25% of 725 items intended for direct and prolonged contact with the skin. Of 15 posts intended for use during epithelialization after piercing, 60% contained more than 0.05% nickel. These products do not comply with the requirements of the EU Nickel Directive. It is suggested that experts in contact dermatitis participate in the prevention of nickel allergy by explaining its effects: the r le of skin exposure and which parts of an item are in contact with the skin, and the crucial question of nickel release versus nickel content.     

Nickel deposited on the skin-visualization by DMG test

Background. Nickel is the most common cause of contact allergy and an important risk factor for hand eczema. Visualization techniques may be powerful in showing exposures. The dimethylglyoxime (DMG) test might be used to establish skin exposure to nickel. Objectives. To develop and evaluate methods for visualization of nickel on the skin by the DMG test and hand imprints. Methods. Nickel solutions at different concentrations were applied in duplicate on the hands in healthy subjects (n = 5). The DMG test and acid wipe sampling for quantification were then performed. Hand imprints were taken after manipulation of nickel‐releasing tools (n = 1), and in workers performing their normal tasks (n = 7). The imprints were developed by the DMG test. Results. The DMG test on hands gave positive results in all subjects. The lowest concentration giving rise to a colour change was set to 0.13 µg/cm² for DMG testing on skin. DMG test‐developed imprints worked well except when hands were heavily contaminated by other particles/dust. Conclusions. The DMG test may be used as a simple and powerful tool for visualization of nickel on skin. DMG test‐developed hand imprints may, in the future, be used for semi‐quantitative or quantitative exposure assessment.     

Pathogenesis and diagnosis of contact dermatitis:Applications of reflectance confocal microscopy

Contact dermatitis(CD) is the most common professional skin disease, with frequencies ranging from 24 to 170 every 100000 individuals. Approximately 20% of the United States population suffers from CD. CD can be classified according to its origin and severity. ICD stands for irritant CD, whereas ACD means allergic CD. Their clinical presentation includes acute, sub-acute and chronic eczema. Despite their different origin, ICD and ACD often present similar clinical and histologic findings. The current gold standard for diagnosis is patchtesting. However, patch-testing is being questioned in terms of validity and reproducibility, as it relies heavily on the skill of the observer. Real-time reflectance confocal microscopy is a non-invasive imaging technique that bears strong promise for the study of CD, and it enables the evaluation of cellular and subcellular changes over time with similar resolution compared to that of conventional histology.     

The cost of nickel allergy: a global investigation of coin composition and nickel and cobalt release

Background. Nickel is widely used in coins; nickel may cause contact allergy and allergic contact dermatitis in those who handle them. Objectives. To investigate alloy use, coin composition and nickel and cobalt release for a worldwide selection of currently circulating coins. Materials and methods. Eight hundred and fifty coins of 361 different denominations or issues from 52 countries were collected and analysed with X‐ray fluorescence spectrometry and nickel and cobalt spot tests. Results. Copper–nickel was the most frequently identified coin alloy, being observed in 100 denominations (28%), followed by aluminium–bronze (62, 17%). In total, 239 denominations released nickel (28%). Coins from Bolivia, Brazil and Costa Rica did not release nickel. Fewer than one‐third of the denominations or issues from China, India, the euro area and Indonesia released nickel. In the United States, the Russian Federation, Japan, and Mexico, one‐third or more of the denominations released nickel. Conclusions. This worldwide selection of circulating coins covered countries with 75% of the world population, and shows that the majority of the world population lives in countries where coins release nickel. Pertinently, ～ 40% of circulating coin denominations do not release nickel.