SO FREQUENTLY POSITIVE in patch-test populations, so commonly suspected from clinical history, this long-standing top allergen seems old news. Because of its common frequency and many highly characteristic patterns of clinical skin disease, some of us have been guilty of often dismissing nickel allergy with a pedestrian “ho hum.” But with the rising incidence of nickel allergy in the United States and elsewhere, high nickel sensitization rates documented in children, and a resurgent issue of biomedical device complications (specifically, nickel allergy) due to metal, to dismiss nickel's importance and relevance to public health and skin disease would be a mistake. Nickel is an allergen whose time has come—yet again! Let us tell you more about nickel and why we should refocus our attention on it and highlight nickel as Allergen of the Year.
A Short History of Nickel
Nickel is a ubiquitous metal used in a wide range of products in the transportation and aerospace industries and for military, health, household, and architectural applications. It has been found in metallic artifacts dating back some 2,000 years but was first identified in 1751 by Swedish chemist Baron Axel Fredrik.1,2 Upon the discovery of a feasible extraction method in the nineteenth century, nickel was soon being used in large amounts because of its attractive qualities, chief among them corrosion resistance and durability. In addition, nickel alloys readily with many other metals, lending them these properties.2,3
As the production of nickel alloys and nickelcontaining goods increased, so did reports of allergy. The first case of “galvanization eczema” was described by Blascho in the late 1880s.4 At that time, nickel dermatitis was observed in workers of the electroplating and mining industries. Though initially a cause of occupational dermatitis, nickel allergy shifted to affect the general population as nickel was incorporated into products such as suspenders, zippers and snaps, and jewelry that had prolonged contact with the skin.4,5 The prevalence and etiology of nickel sensitization tend to reflect societal trends; nickel allergy was noted to decrease during World War II when imports were diminished and then rose owing to the availability and popularity of nickel suspenders in the 1950s.6,7 Blue-jean buttons were the primary culprits in the 1970s.4,8 Jewelry and especially ear piercing at an early age (and the recent trend of an increasing number of other body piercings) are consistently linked to the rise in nickel sensitization in the recent decade.4,7
Currently, nickel allergy is the most common cause of contact dermatitis in the industrial world, particularly affecting females.5,7,9-13 Several studies have examined the striking discrepancy of sensitization incidence to nickel in females versus males and have associated this with the increased popularity of ear piercing.14-16 Moreover, nickel allergy is on the rise in the United States, an increase largely attributed to the increasing rate of allergy in females.13 The most recent patch-test data from the North American Contact Dermatitis Group from 2003 to 2004 reveals that 18.8% of patients from this primarily referral population are sensitized to nickel,13 a significant increase from the 10.5% reported from 1985 to 1990.17 Europe had similarly high rates of nickel allergy18,19; however, because of laws regulating nickel products, this fortunately appears to be decreasing in the younger population.
In 1992, in an effort to quell the rising rates of nickel dermatitis, the Danish Ministry of Environment implemented legislation to regulate nickel exposure to products in prolonged contact with the skin.20,21 The European Union followed shortly afterward with the Nickel Directive (1994). This directive limited the nickel release threshold from alloys and nickel-plated objects in prolonged contact with the skin to 0.05 μg/cm2 per week and the nickel content of post assemblies (material inserted into pierced parts of the body) to less than 0.05%.22 The legislation was recently revised for post assemblies, amending the content limit of 0.05% to a migration limit of 0.2 μg/cm2 per week23 because it is the ability of a substance to release nickel ions, rather than the actual nickel content, that determines the risk of sensitization.24,25 The allowed rate of nickel release for post assemblies differs from that for items intended to be next to the surface of skin, such as jewelry, to reflect the increased nickel release in blood plasma compared to the artificial sweat used in sensitization studies. Despite this lower threshold, it is inevitable that a small proportion of sensitized individuals capable of reacting to a very low nickel concentration will continue to react.24 Nevertheless, evidence thus far suggests that the initiative has been successful in reducing nickel sensitization in a younger population.18-20 A study by Jensen and colleagues reported in 2002 investigated the prevalence of nickel allergy in Danish schoolgirls to determine if the prevalence was decreased in girls who had their ears pierced subsequent to nickel exposure regulations (1992) as compared to those who had their ears pierced prior to the regulations. The younger girls had significantly less nickel sensitization as detected by patch testing (5.7% vs 19%); this considerable decrease in nickel allergy is most likely explained by these regulations.20
Reports of dermatitis near or at sites of endoprostheses26,27 and from dental and orthodontic28-30 treatments have peppered the medical literature for years although systemic or localized reactions to medical-grade stainless steel is quite uncommon.11,31,32 During the production of stainless steel, a crystal lattice structure forms, locking in the metals and decreasing the likelihood of sensitization.11
Consultation requests from orthopedic surgeons and (less frequently) orthodontists in regard to the safety of permanent or semipermanent metal medical devices in the suspected nickel-sensitized individual continue rather frequently despite the fact that reactions to joint arthroplasty prostheses and orthodontic braces rarely cause a problem in the nickel-sensitized individual. A high variability of care no doubt results for these patients in terms of testing and recommendations, contributing to concern on the part of the patient and their referring physician and to increased health care costs. Medicolegal concerns likely contribute to testing consultations and, in some instances of joint replacement, the selection of a more expensive and less durable option. As nickel allergy incidence increases, this problem also presumably will increase. An expert consensus panel guideline or evidencebased position paper on specific biomedical devices (joint arthroplasty prostheses, fixed implants, orthopedic braces, and stents) and nickel and other metal allergy is sorely needed.
The potential for complications due to nickel allergy and nickel in biomedical devices has understandably risen anew and come under more critical scrutiny owing to a report questioning the role of metal allergy in endovascular stenting procedures and in-stent restenosis. Can nickel allergy contribute to stent stenosis? Köster and colleagues stimulated this debate with an article in The Lancet in 2000 revealing the results of a retrospective study of 131 patients suspected of coronary in-stent restenosis 6 months following 316L stainless steel stent placement. Patch testing was performed 2 months after angioplasty, and not prior to the procedure. Of 131 patients (109 men and 22 women) who were patch-tested, there were 11 positive patch-test reactions in 10 (8%) of the patients. Important, and as noted in other studies of nickel allergy, the clinical history was not predictive of a positive or negative patchtest result. Other risk factors for restenosis were similar among patients with positive and negative patch-test results. All 10 patients with a positive patch-test reaction to metal (7 to nickel and 4 to molybdenum) had in-stent restenosis associated with clinical symptoms, a higher frequency of restenosis than in patients without metal allergy, thus suggesting that allergy to metals, nickel in particular, plays a relevant role in inflammatory fibroproliferatory restenosis.33 However, Köster and colleagues did not investigate possible metal allergy in patients without suspected re-stenosis, and their study thus lacked a critical control group.34 Since this provocative study, other investigations of this important issue have been reported.35-37 Iijima and colleagues, in their prospective study of 174 stented patients (109 restudied for initial placement and 65 restudied for in-stent restenosis), did note that patients with a recurrence of in-stent restenosis had a significantly higher positive patch-test reaction to metals, most commonly nickel and manganese. However, they found no correlation of metal allergy with restenosis after initial stent placement.36 So far, the evidence confirming that nickel allergy contributes to stent restenosis remains in question. Large prospective clinical studies are needed.
Although much attention has been directed towards coronary stents, other stenting procedures have infre-quently raised the question of complications due to nickel allergy. The evidence for complications is weak and remains on the case report level. For instance, a case report of early biliary stent occlusion thought to be directly related to nickel allergy was noted in the literature38 in addition to a case of generalized dermatitis after endovascular stenting of an abdominal aortic aneurysm.39 The stents used in the above-mentioned examples were composed of a nickel-titanium (NiTi) alloy. NiTi alloy contains nearly equal mixtures of nickel and titanium and is coveted for its “shape memory” properties.40 NiTi alloy is used in many biomedical applications where consistency of shape and stress are essential, including dental devices, stents, blood filters, and bone staples.40 One risk assessment study using guinea pig sensitization testing of the alloy did not reveal any tissue reaction, and the nickel release was deemed to be within acceptable limits.40 Yet this study does point out that the findings cannot be extrapolated to all clinical conditions.
Nickel is commonly used in orthodontics without difficulty, and preorthodontic testing for metal allergy is not routine. However, for patients with contact allergy to orthodontics, nickel is the most common allergen.32 Certain flexible titanium-nickel arch wires used in orthodontics are thought to release increased amounts of nickel as compared to stainless steel, and one article recommends avoiding them in patients known to be nickel sensitive.32
Dietary Nickel and Oral Hyposensitization
Systemic contact dermatitis from oral ingestion of nickel in the nickel-sensitive individual is a known clinical entity and has been demonstrated by dose-response studies of nickel administration in sensitized subjects.41,42 Evidence to support the contribution of dietary nickel to dermatitis exists from studies that have treated nickel dermatitis, particularly vesicular hand eczema, with low-nickel diets43,44 and/or the chelating agent disulfiram.45 Nickel is found in natural foods such as legumes, nuts, grains, potatoes, chocolate, and fish.46,47 Daily nickel intake can vary substantially, depending on the cooking utensils used, whether food is grown in nickel-rich soil, whether the food is fresh or canned, and the nickel level of water ingested.11,47 Nickel may also be found in medications, vitamins, and herbal remedies. An example of this is a prescription homeopathic medication for the treatment of acne. Each tablet of Acunol (Plymouth Pharmaceuticals, Inc., Tulsa, OK), an oral acne medication, contains 0.5 mg of ionized nickel.48 The daily dose more than doubles the amount of nickel people normally consume in the average diet (0.22 to 0.35 mg per day42 but as high as 0.9 mg per day49). Jensen and colleagues, in a meta-analysis of systemic contact dermatitis following oral exposure to nickel, estimated that 1% of patients with allergy to nickel in the studies reviewed would react with a systemic reaction to the nickel content of a normal diet. Their calculations predicted that 10% would react to exposures to 0.55 to 0.89 mg of nickel.42
Whereas decreasing oral nickel ingestion can control flares of dermatitis, perhaps oral nickel intake can actually aid in actually preventing sensitization from cutaneous nickel exposure through immune tolerance induction.50-52 Oral tolerance to nickel has been demonstrated in animal models53,54 as well as in some retrospective human studies investigating the rate of nickel allergy in young populations with dental braces.15,50 In vitro studies of stainless steel braces in artificial saliva demonstrate that metal ions are leached into saliva over time.55 Case reports of systemic dermatitis from dental appliances support the conclusion that there is likely absorption of nickel from this nickel leaching.30,32,56 This absorption may plague few previously sensitized individuals but may more commonly induce immunologic tolerance to nickel in the previously unsensitized individual. Kerosuo and colleagues studied Finnish adolescents and the effect of age, gender, onset, duration and specific orthodontic treatment, and age of ear piercing on the incidence of nickel sensitization. One striking finding of this study was that 35% of the girls who had ear piercing prior to orthodontic treatment were nickel allergic versus none of the girls who had fixed orthodontic treatment prior to ear piercing.15 The immune mediators of oral tolerance are beginning to be elucidated, but clearly more research into this area is needed.52
Nickel Allergy in Children
Numerous recent single and multicenter international studies of children have confirmed that nickel is far and away the number-one contact allergen in patch-tested patient populations, ranging in incidence from 20 to 33%.57-61 In these studies, the reported relevance of a positive patch-test result varies from little relevance to high relevance, and conclusions regarding relevance are regrettably limited. Of 391 children aged 18 years or less who were patch-tested between 2001 and 2004 by the North American Contact Dermatitis Group, 28% had a positive patch-test to nickel, and 26% were deemed to have a nickel allergy of either current or past relevance.62 Not only is nickel allergy prevalent in the young population, NACDG data show that as in adult females, nickel sensitization in girls is on the rise.13
Bruckner and colleagues asked the question, “Does sensitization begin in infancy?” In their study of asymptomatic children and contact allergy, nickel was the most common positive allergen; 12.9% of children aged 6.0 to 67.5 months reacted positively to nickel.63 Remarkable and concerning, children younger than 16 months accounted for 7 of 11 of those positive results to nickel.63 Because nickel may be an irritant, the question of interpreting an irritant versus an allergic result arises commonly although jewelry and fasteners are potential and likely sources of exposure for this age group. Where does this well-documented epidemiology of nickel sensitization lead us? Kütting and colleagues make a case for prevention, recommending that ear piercing be delayed until after 10 years of age64 (presumably to allow for the development of immune tolerance).
Contact allergy to nickel can range from a nuisance to a frustrating, itch-ridden, and vexatious chronic problem that interferes with sleep, activities of daily living, work, and play. Persistent hand dermatitis, systemic contact dermatitis, and nickel allergy with auto-eczematization are some fairly common and pervasive troublesome examples.
Nickel is ubiquitous and practically unavoidable in everyday life; from coins and tools65,66 to pant snaps8 and cosmetics,11,67 nickel can be found in a variety of both obvious and unlikely products. Prolonged and often unrecognized exposure to sensitizing amounts of nickel nowadays occurs often at a young age in North America and is practically inevitable. Preventing sensitization or implementing strategies to reduce sensitization are likely the most effective methods of reducing the considerable effects of nickel allergy. The development of expert consensus guidelines or an evidence-based position paper on the issue of biomedical devices is another practical relevant proposition whose time has come. Regulation of nickel release from consumer goods that involve contact with skin would be a challenging but potentially successful solution to our current nickel allergy predicament.
- Expensive white or yellow gold can contain enough nickel to cause sensitization when used in ear piercing. Beware of earrings labeled “hypoallergenic.” The Food and Drug Administration says, “There are no Federal standards or definitions that govern the use of the term hypoallergenic. The term hypoallergenic means whatever a particular company wants it to mean.”68
- Some high-nickel-content foods (in micrograms [μg] of nickel per gram of food) are cocoa (10 μg); licorice (4.4 μg); margarine (4, μg); peanuts (2.9 μg); brown lentils (1.9 μg); walnuts, almonds, or hazelnuts (1.5 μg); and French beans or beans (1.4 μg).46
- In 2003 to 2004, 25% of women patch-tested by the North American Contact Dermatitis Group (NACDG) were allergic to nickel, compared to only 8% of men.13 Ear piercing was deemed the most likely reason.
- Adolescents constitute a significant portion of the patch-test population allergic to nickel; 36% of girls (aged < 18 years) and 15% of boys patch-tested by the NACDG from 2001 to 2004 had clinically relevant allergy.13
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