Nickel allergy results in a skin response after the skin comes in contact with an item that releases a large amount of nickel from its surface, and is commonly associated with nickel-containing belt buckles coming into prolonged contact with the skin. The skin reaction can occur at the site of contact, or sometimes spread beyond to the rest of the body. Free (released) nickel that is able to penetrate the skin is taken up by scavenger (dendritic cells) and then presented to the immune system T-Cells. With each subsequent exposure to nickel these T cells become stimulated and duplicate (clone) themselves. With enough exposures to nickel, the amassing clones of T-cells reach “threshold” and the skin develops a rash. The rash can present as acute, subacute, or chronic eczema-like skin patches, primarily at the site of contact with the nickel (e.g. earlobe from nickel earrings). From time of exposure the rash usually presents within 12–120 hours and can last for 3–4 weeks or for the continued duration of nickel contact/exposure.
Three simultaneous conditions must occur to trigger Ni-ACD:
1. Direct skin contact with nickel-releasing item.
2. Prolonged skin contact with nickel-releasing item.
3. A sufficient amount of nickel is released and absorbed into the skin to cause a reaction.
The pathophysiology is divided into induction elicitation phases. Induction is the critical phase (immunological event) when skin contact to nickel results in antigen presentation to the T cells, and T cell duplication (cloning) occurs. The metal cation Ni++ is a low molecular weight hapten that easily penetrates the stratum corneum (top layer of skin). Nickel then binds to skin protein carriers creating an antigenic epitope. The determining factor in sensitization is exposure of significant amounts of “free nickel”. This is important because different metal alloys release different amounts of free nickel. The antigenic epitope is collected by dermal dendritic cells and Langerhans cells, the antigen-presenting cells (APC) of the skin, and undergo maturation and migration to regional lymph nodes. The complex is predominantly expressed on major histocompatibility complex (MHC) II, which activates and clonally expands naive CD4+ T cells. Upon re-exposure these now primed T cells will be activated and massively recruited to the skin, resulting in the elicitation phase and the clinical presentation of Ni-ACD.
Although ACD has been considered a Th1 predominate process, recent studies highlight a more complex picture. In Ni-ACD other cells are involved including: Th17, Th22, Th1/IFN and the innate immune responses consistent with toll-like receptor 4.  
Josef Jadassohn described the first case of metal contact dermatitis in 1895, to a mercurial-based therapeutic cream, and confirmed the cause by epi-cutaneous patch testing. Systemic contact dermatitis (SCD) is defined as a dermatitis occurring in an epi-cutaneously contact-sensitized person when exposed to haptens systemically such as orally, per rectum, intravesically, transcutaneously, intrauterinely, intravenously, or by inhalation.
Systemic nickel allergy syndrome (SNAS) pathophysiology is extremely complex and not well understood. The clinical course is determined by an immunological interplay between two diverse types of T cells (Th1 and Th2 responses). SCD is often considered a subset of SNAS, but with only skin manifestations. SNAS presents with an array of symptoms ranging from respiratory to generalized skin rash to gastrointestinal symptoms Interestingly, a meta review evaluating SNAS found that 1% of patients sensitized to nickel reacted to the nickel content of a 'normal' diet, and with increasing doses of nickel more individuals reacted SNAS is a multilayered immunologic response demonstrating variance between individuals and doses of nickel exposure.
1600's copper miners in Saxony, Germany began to get irritated by a distinctly unknown "dark red ore" The miners thought the substance was copper, and since it led to many ailments they believed it to be protected by "goblins"—subsequently, naming what would eventually be discovered nickel as "Goblin's Copper" In the next century nickel began to be mass-produced for jewelry worldwide due to its cheap cost, resistance to corrosion and high supply.
In 1979 a large comprehensive study of healthy US volunteers found that 9% had been unknowingly sensitized to nickel As of 2008[update], that number has tripled. Most importantly, nickel allergy among children is increasing, with an estimated 250,000 children sensitized to nickel.
Published literature shows an exponential increase in reported nickel allergy cases. The North American Contact Dermatitis Group (NACDG) patch tested 5085 adults, presenting with eczema-like symptoms, showing 19.5% had a positive reaction to nickel Nickel allergy is also more prevalent in women (17.1%) than men (3%), possibly due to cultural norms related to jewelry and ear piercings and therefore increased exposure to nickel. In order to investigate the current prevalence of nickel, Loma Linda University, Nickel Allergy Alliance, and Dermatitis Academy, are conducting a self-reporting nickel allergy-dermatitis survey.
Sources of Ni-ACDEdit
Nickel is a cheap and widely available core metal. Today, it can be found in a wide variety of items including jewelry, zippers, buttons, belt buckles, coins, cell phones, tablets, surgical implants, and certain foods.
Nickel is present in a wide range of foods, in varying concentrations. Exposure to nickel through one's diet may result in acute (systemic) flareups of Ni-ACD. Adults should consume less than 150μg of nickel per day, and avoid foods such as chocolate, granola, oatmeal, and beans. Whilst systemic elicitation of ACD in individuals sensitized by direct skin contact is well documented for a small proportion of nickel-sensitized individuals, there exists some controversy about the ability to sensitize individuals when nickel exposure is oral, intravenous, or inhaled. Only about 1-10% of dietary nickel is absorbed by the body. Average daily-ingested intake of nickel is about 200 micrograms. A few studies have shown that nickel-sensitive individuals orally given greater than 5,000 micrograms nickel (as NiSO4) as a single dose had a nickel ACD response. While such exposures are in excess of those encountered in normal diets, some researchers suggest that dietary control of nickel intake may help in the ongoing treatment of nickel ACD caused by other sources. These researchers have correctly identified foods high in nickel content (e.g., nuts, chocolate, beans), but they have sometimes incorrectly advocated the avoidance of cutlery, bowls, etc. made from stainless steel, which do not release significant amounts of nickel.
Within the workplace, individuals may be exposed to significant amounts of nickel, airborne from the combustion of fossil fuels, or from contact with tools that are nickel-plated. Historically, workplaces where prolonged contact with soluble nickel has been high, have shown high risks for allergic contact nickel dermatitis. For example, nickel dermatitis was common in the past among nickel platers. Due to improved industrial and personal hygiene practices, however, over the past several decades, reports of nickel sensitivity in workplaces, such as the electroplating industry, have been sparse. In the workplace, exposure reduction includes personal protection equipment and other risk management measures.
Nickel allergy results in a skin response (rash) after the skin comes in direct and sustained contact with any item which releases a large amount of free nickel from its surface. The skin reaction can occur at the site of contact, or sometimes spread beyond to the rest of the body. Cutaneous exposure can cause localized erythematous, pruritic, vesicular, and scaly patches. Ingestion of nickel may cause a systemic reaction, that will affect a larger skin surface. Examples of systemic reactions can include hand dermatitis, baboon syndrome, or generalized eczematous reactions.
Nickel has wide utility of application in manufactured metals, because it is both strong and malleable, leading to ubiquitous presence and the potential for consumers to be in contact with it daily. However, for those that have the rash of allergic contact dermatitis (ACD) due to a nickel allergy, it can be a challenge to avoid. Foods, common kitchen utensils, cell phones, jewelry and many other items may contain nickel and be a source of irritation due to the allergic reaction caused by the absorption of free released nickel through direct and prolonged contact. The most appropriate measure for nickel allergic persons is to prevent contact with the allergen.
In 2011, researchers showed that applying a thin layer of glycerine emollient containing nanoparticles of either calcium carbonate or calcium phosphate on an isolated piece of pig skin (in vitro) and on the skin of mice (in vivo) prevents the penetration of nickel ions into the skin. The nanoparticles capture nickel ions by cation exchange, and remain on the surface of the skin, allowing them to be removed by simple washing with water. Approximately 11-fold fewer nanoparticles by mass are required to achieve the same efficacy as the chelating agent ethylenediamine tetraacetic acid. Using nanoparticles with diameters smaller than 500 nm in topical creams may be an effective way to limit the exposure to metal ions that can cause skin irritation'.
Pre-emptive avoidance strategies (PEAS) might ultimately lower the sensitization rates of children who would suffer from ACD It is theorized that prevention of exposure to nickel early on could reduce the number of those that are sensitive to nickel by one-quarter to one-third. Identification of the many sources of nickel is vital to understanding the nickel sensitization story, food like chocolate and fish, zippers, buttons, cells phones and even orthodontic braces and eyeglass frames might contain nickel. Items that contain sentimental value (heirlooms, wedding rings) could be treated with an enamel or rhodium plating.
Sensitized individuals may check product labels or contact the manufacturer or retailer regarding possible nickel content. The Dermatitis Academy has created an educational website to provide more information about nickel, including information about prevention, exposure, sources, and general information about nickel allergy. These resources provide guidance in a prevention initiative for children worldwide.
Nickel allergy can be confirmed by a properly trained health care provider based on the medical history, physical exam and a painless specialized patch test— when necessary. A significant number of people may self-diagnose, and not contact medical professionals, which could result in massive underreporting of the problem by scientific researchers.
Confirming the diagnosis of Ni-ACD specifically involves inducing the skin to demonstrate a rash where the chemicals are applied (a delayed type hypersensitivity reaction), evidence that the patient is exposed to nickel, and establishing that the reaction and the exposure explain the current rash/symptoms under question. The patch test plays a significant role in diagnosing ACD.
The patch test evokes a delayed, Type IV hypersensitivity reaction, which is a cell-mediated, antibody independent, immune response. Patch testing is the "gold standard" diagnostic tool for Ni-ACD. In this sense, a positive patch test to nickel establishes that the subject has been previously exposed and is therefore sensitized to nickel. It does not necessarily indicate that the patch reaction is the cause of the current clinical disease. A negative test demonstrates that the patient is sub-threshold, either minimally or not sensitized. Cumulatively, clinical reasoning and a patch test help determine if nickel could be the cause of a current dermatitis reaction.
Once a nickel allergy is detected, the best treatment is avoidance of nickel-releasing items. It is important to know the main items that can cause nickel allergy, which may be remembered using the mnemonic "BE NICKEL AWARE". The top 13 categories that contain nickel include beauty accessories, eyeglasses, money, cigarettes, clothes, kitchen and household, electronics and office equipment, metal utensils, aliment, jewelry, batteries, orthodontic and dental appliances, and medical equipment. Other than strict avoidance of items that release free nickel, there are other treatment options for reduction of exposure. The first step is to limit friction between skin and metallic items. Susceptible people may try to limit sweating while wearing nickel items, to reduce nickel release and thus decrease chances for developing sensitization and/or allergy. Another option is to shield electronics, metal devices, and tools with fabric, plastic, or acrylic coverings.
There are test kits that can be very helpful to check for nickel release from items prior to purchasing. The ACDS providers can give a guidance list of safe items. In addition to avoidance, healthcare providers may prescribe additional creams or medications to help relieve the skin reaction.
As nickel can be harmful to skin, its use in daily products must be regulated. A safety directive has been in place in Europe since 2004. In 1980, Denmark and then shortly after the European Union (EU) enacted legislation that limited the amount of free nickel in consumer products that come in contact with the skin. This resulted in significantly decreased rates of sensitization among Danish children 0 to 18 years of age from 24.8% to 9.2% between 1985 and 1998, with similar reductions in sensitization throughout the EU.
No such directive exists in the United States, but efforts are under way to mandate safe use guidelines for nickel. In August 2015, the American Academy of Dermatology (AAD) adopted a nickel safety position paper. The exact prevalence of Ni-ACD in the general population in the US is largely unknown. However, current estimates gauge that roughly 2.5 million US adults and 250,000 children suffer from nickel allergy, which costs an estimated $5.7 billion per year for treatment of symptoms. Loma Linda University, Nickel Allergy Alliance, and Dermatitis Academy created the first open access self-reported patient registry to record nickel allergy prevalence data in the US.
- Usatine R (May 2001). "A belt buckle allergy?". The Western Journal of Medicine. 174 (5): 307–8. doi:10.1136/ewjm.174.5.307. PMC . PMID 11342499.
- "Nickel allergy - Symptoms and causes".
- "Nickel Contact Dermatitis Picture Image on MedicineNet.com".
- "What Do You Need To Know About Nickel Allergy?". nickelinstitute.org.
- Lu L, Vollmer J, Moulon C, Weltzien HU, Marrack P, Kappler J (March 2003). "Components of the ligand for a Ni++ reactive human T cell clone". The Journal of Experimental Medicine. 197 (5): 567–74. doi:10.1084/jem.20021762. PMID 12615898.
- Silverberg NB, Licht J, Friedler S, Sethi S, Laude TA (2002). "Nickel contact hypersensitivity in children". Pediatric Dermatology. 19 (2): 110–3. doi:10.1046/j.1525-1470.2002.00057.x. PMID 11994170.
- Girolomoni G, Gisondi P, Ottaviani C, Cavani A (April 2004). "Immunoregulation of allergic contact dermatitis". The Journal of Dermatology. 31 (4): 264–70. doi:10.1111/j.1346-8138.2004.tb00671.x. PMID 15187320.
- Peana M, Zdyb K, Medici S, Pelucelli A, Simula G, Gumienna-Kontecka E, Zoroddu MA (December 2017). "Ni(II) interaction with a peptide model of the human TLR4 ectodomain". Journal of Trace Elements in Medicine and Biology. 44: 151–160. doi:10.1016/j.jtemb.2017.07.006. PMID 28965571.
- Dhingra N, Shemer A, Correa da Rosa J, Rozenblit M, Fuentes-Duculan J, Gittler JK, Finney R, Czarnowicki T, Zheng X, Xu H, Estrada YD, Cardinale I, Suárez-Fariñas M, Krueger JG, Guttman-Yassky E (August 2014). "Molecular profiling of contact dermatitis skin identifies allergen-dependent differences in immune response". The Journal of Allergy and Clinical Immunology. 134 (2): 362–72. doi:10.1016/j.jaci.2014.03.009. PMID 24768652.
- Jadassohn J (1895). "Zur kenntnis der medikamentössen dermatosen". Verhandlungen der Deutschen Dermatologischen Gesellschaft. Fünfter Kongress, Raz (in German). Berlin: Julius Springer. pp. 103–129.
- Veien NK (December 2011). "Systemic contact dermatitis". International Journal of Dermatology. 50 (12): 1445–56. doi:10.1111/j.1365-4632.2011.05104.x. PMID 22097987.
- Di Gioacchino M, Ricciardi L, De Pità O, Minelli M, Patella V, Voltolini S, Di Rienzo V, Braga M, Ballone E, Mangifesta R, Schiavino D (February 2014). "Nickel oral hyposensitization in patients with systemic nickel allergy syndrome". Annals of Medicine. 46 (1): 31–7. doi:10.3109/07853890.2013.861158. PMID 24256166.
- Matiz C, Jacob SE (2011). "Systemic contact dermatitis in children: how an avoidance diet can make a difference". Pediatric Dermatology. 28 (4): 368–74. doi:10.1111/j.1525-1470.2010.01130.x. PMID 20807367.
- Jensen CS, Menné T, Johansen JD (February 2006). "Systemic contact dermatitis after oral exposure to nickel: a review with a modified meta-analysis". Contact Dermatitis. 54 (2): 79–86. doi:10.1111/j.0105-1873.2006.00773.x. PMID 16487279.
- Baldwin WH (1931). "The story of nickel. How "old nick's" gnomes were outwitted". Journal of Chemical Education. 8 (9): 1749. doi:10.1021/ed008p1749.
- Prystowsky SD, Allen AM, Smith RW, Nonomura JH, Odom RB, Akers WA (August 1979). "Allergic contact hypersensitivity to nickel, neomycin, ethylenediamine, and benzocaine. Relationships between age, sex, history of exposure, and reactivity to standard patch tests and use tests in a general population". Archives of Dermatology. 115 (8): 959–62. doi:10.1001/archderm.1979.04010080023015. PMID 157103.
- Rietschel RL, Fowler JF, Warshaw EM, Belsito D, DeLeo VA, Maibach HI, Marks JG, Mathias CG, Pratt M, Sasseville D, Storrs FJ, Taylor JS, Zug KA (2008). "Detection of nickel sensitivity has increased in North American patch-test patients". Dermatitis. 19 (1): 16–9. PMID 18346391.
- Jacob SE, Goldenberg A, Pelletier JL, Fonacier LS, Usatine R, Silverberg N (2015). "Nickel Allergy and Our Children's Health: A Review of Indexed Cases and a View of Future Prevention". Pediatric Dermatology. 32 (6): 779–85. doi:10.1111/pde.12639. PMID 26212605.
- Goldenberg A, Vassantachart J, Lin EJ, Lampel HP, Jacob SE (2015). "Nickel Allergy in Adults in the U.S.: 1962 to 2015". Dermatitis. 26 (5): 216–23. doi:10.1097/der.0000000000000130. PMID 26177034.
- Fransway AF, Zug KA, Belsito DV, Deleo VA, Fowler JF, Maibach HI, Marks JG, Mathias CG, Pratt MD, Rietschel RL, Sasseville D, Storrs FJ, Taylor JS, Warshaw EM, Dekoven J, Zirwas M (2013). "North American Contact Dermatitis Group patch test results for 2007-2008". Dermatitis. 24 (1): 10–21. doi:10.1097/der.0b013e318277ca50. PMID 23340394.
- Thyssen JP, Menné T (February 2010). "Metal allergy--a review on exposures, penetration, genetics, prevalence, and clinical implications". Chemical Research in Toxicology. 23 (2): 309–18. doi:10.1021/tx9002726. PMID 19831422.
- "Nickel Contact Dermatitis". Dermatitis Academy.
- "Fact Sheet: Nickel and Human Health". nickelinstitute.org.
- Grandjean P. "Human exposure to nickel". IARC Scientific Publications (53): 469–85. PMID 6241927.
- "Safe Use of Nickel in the Workplace". nickelinstitute.org.
- Zirwas MJ, Molenda MA (June 2009). "Dietary nickel as a cause of systemic contact dermatitis". The Journal of Clinical and Aesthetic Dermatology. 2 (6): 39–43. PMC . PMID 20729949.
- Vemula PK, Anderson RR, Karp JM (2011). "Nanoparticles reduce nickel allergy by capturing metal ions". Nature Nanotechnology. 6 (5): 291–5. doi:10.1038/nnano.2011.37. PMID 21460828.
- Hill H, Goldenberg A, Golkar L, Beck K, Williams J, Jacob SE. "Pre-Emptive Avoidance Strategy (P.E.A.S.) - addressing allergic contact dermatitis in pediatric populations". Expert Review of Clinical Immunology. 12 (5): 551–61. doi:10.1586/1744666X.2016.1142373. PMID 26764601.
- Hill H, Goldenberg A, Sheehan MP, Patel A, Jacob SE (2015). "Nickel-Free Alternatives Raise Awareness". Dermatitis : Contact, Atopic, Occupational, Drug. 26 (6): 245–53. doi:10.1097/DER.0000000000000135. PMID 26551602.
- Kerr M, Cafasso J (11 January 2016). Weatherspoon D, ed. "Nickel Allergies Symptoms, Tests, and Treatment". Healthline.
- Ale IS, Maibacht HA (March 2010). "Diagnostic approach in allergic and irritant contact dermatitis". Expert Review of Clinical Immunology. 6 (2): 291–310. doi:10.1586/eci.10.4. PMID 20402391.
- Schalock PC, Menné T, Johansen JD, Taylor JS, Maibach HI, Lidén C, Bruze M, Thyssen JP (January 2012). "Hypersensitivity reactions to metallic implants - diagnostic algorithm and suggested patch test series for clinical use". Contact Dermatitis. 66 (1): 4–19. doi:10.1111/j.1600-0536.2011.01971.x. PMID 21957996.
- "Be Nickel Aware" (PDF). Dermatitis Academy. Retrieved 2016-04-16.[permanent dead link]
- Johansen JD, Menné T, Christophersen J, Kaaber K, Veien N (March 2000). "Changes in the pattern of sensitization to common contact allergens in denmark between 1985-86 and 1997-98, with a special view to the effect of preventive strategies". The British Journal of Dermatology. 142 (3): 4905. doi:10.1046/j.1365-2133.2000.03362.x. PMID 10735956.
- Thyssen JP, Uter W, McFadden J, Menné T, Spiewak R, Vigan M, Gimenez-Arnau A, Lidén C (March 2011). "The EU Nickel Directive revisited--future steps towards better protection against nickel allergy". Contact Dermatitis. 64 (3): 121–5. doi:10.1111/j.1600-0536.2010.01852.x. PMID 21226718.
- "Position Statement on Nickel Sensitivity" (PDF). American Academy of Dermatology.
- Jacob SE, Goldenberg A, Pelletier JL, Fonacier LS, Usatine R, Silverberg N (2015). "Nickel Allergy and Our Children's Health: A Review of Indexed Cases and a View of Future Prevention". Pediatric Dermatology. 32 (6): 77985. doi:10.1111/pde.12639. PMID 26212605.