Nickel Allergic Contact Dermatitis: Identification, Treatment, and Prevention

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Review and Synopsis by Jalal Maghfour, MD and Alina Goldenberg, MD of Original Peer-Reviewed Article:

Silverberg NB, Pelletier JL, Jacob SE, Schneider LC; SECTION ON DERMATOLOGY, SECTION ON ALLERGY AND IMMUNOLOGY. Nickel Allergic Contact Dermatitis: Identification, Treatment, and Prevention. Pediatrics. 2020;145(5):e20200628. doi:10.1542/peds.2020-0628

Nickel (Ni) remains one of the most common causes of allergic contact dermatitis (ACD), a type IV hypersensitivity reaction, since the publication of its first case in 1888 by Dr. George Henry Fox. This metal continues to be highly prevalent in every day goods within the US. Ni ACD is considered a public health issue and has been gaining international attention.

The impact of nickel on both adults and children has been increasingly reported in the literature. However, Ni ACD is primarily a disease of the young as it rarely affects elderly (> 60 years). In this synopsis, we provide a brief overview on an article written by Silverberg et al. in which the authors discussed epidemiology, clinical presentation, pathogenesis and management of Ni ACD among pediatric population.

With the discovery of Ni in the 18th century and advancement in the steel industry in early 19th century, Ni has become commonly utilized among manufacturers and is now considered the 5th most common metal in the world. Ni ACD may manifest as mild pruritus with ill-defined erythema to diffuse and pronounced redness with oozing and bullae. Classically, Ni ACD presents as an erythematous lichenified papule/plaque and matches the object touching the specific skin area. Any parts of the body can be affected by nickel.

Ni ACD has a multifactorial etiology with a combination of genetic and environmental factors. Contact with nickel is simply not enough for a reaction to occur. The following conditions must be met for both induction and elicitation phase to occur: 1) Contact with a metal containing corroded Ni, 2) degree of solubility of Ni (higher the solubility the higher ion leakage); 3) Ni ions being absorbed by the skin.

In case of a Ni ACD, the majority of diagnoses are clinical. However, when the cutaneous patterns are atypical, the diagnosis may be difficult in which cases patch testing can be performed. Patch testing is the criterion standard method to diagnose Ni ACD. While it is usually a localized reaction, the appearance of 3 large papules following Ni patch testing strongly suggests a systemic nickel hypersensitization.  

Ni ACD can be a diagnostic challenge in AD patients as the morphologic eruption may not match the triggering object. In addition, patients may also experience an exacerbation of their AD. In parallel, adults with psoriasis often experience flare of their disease during a Ni ACD episode. Although Ni ACD is primarily a type IV reaction, immediate hypersensitivity through IgE has been reported as a cause of Ni ACD.

For Ni ACD treatment, this review recommends the avoidance of the offending agent as the next best step in management, followed by the treatment of inflammation with the use of glucocorticoids (potency is based on the affected area). Finally, restoration of the skin barrier is essential. This can be performed with a generous application of emollients. 

As exemplified by Denmark and Finland, enacting a national policy to regulate the amount of Ni that a population is exposed to was proven efficacious in reducing the rate of Ni ACD and has increased awareness on the topic among adolescents. There is no such regulation within the US. Because Ni is primarily found in jewelry and ear piercings, it may be beneficial to regulate Ni found in other forms of jewelry, as well as children’s toys, metal protectors for phone which are now increasingly recognized to as a cause of Ni ACD.

Increased production and manufacturing regulations, specific diagnoses and focused avoidance strategies can make Ni ACD a preventable pediatric health issue.  As it was shown with European countries, the United States can benefit from limiting Ni exposure to its population.  Until then, individual awareness and knowledge of daily objects containing nickel should be encouraged as part of avoidance.

SNAS and thyroid autoimmunity risk

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SNAS (Systemic nickel allergic syndrome may predispose susceptible individuals to developing chronic autoimmune thyroiditis (CAT)

 

Systemic nickel allergic syndrome as an immune-mediated disease with an increased risk for thyroid autoimmunity

Original Article:

Andrioli M, Trimboli P, Maio D, Persani L, Minelli M. Systemic nickel allergic syndrome as an immune-mediated disease with an increased risk for thyroid autoimmunity. Endocrine. 2015;50(3):807-810.

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Reviewed by Erin Wesner, BS, MSII & Jack Guccione, BS, MSIII. Loma Linda University School of Medicine

 

Keywords: Systemic nickel allergic syndrome, Nickel, Chronic autoimmune thyroiditis, Hashimoto

 

Key points:

  • Systemic nickel allergic syndrome (SNAS) may predispose susceptible individuals to developing chronic autoimmune thyroiditis (CAT)
  • Thyroid dysregulation is identified by elevated blood levels of thyroglobulin antibody and symptoms including fatigue, constipation, and weight gain.
  • Prior nickel sensitization with gastrointestinal and diffuse cutaneous symptoms and elevated thyroglobulin antibody may indicate SNAS-related thyroid disorder.
  • In over 200 patients studied, SNAS positive individuals showed a two-fold greater prevalence of CAT.

 

Introduction:

  • Chronic autoimmune thyroiditis (CAT) is the most common cause of hypothyroidism in areas with adequate iodine intake.1
    • CAT results from high circulating levels of anti-thyroid antigens and inflammatory mediators that cause gradual thyroid destruction.
    • Genetic, autoimmune and environmental factors (viruses, stress, hormones, pollution) have been identified as potential causes of CAT.2
  • Systemic nickel allergic syndrome (SNAS) is a chronic inflammatory disorder. It is characterized by a constellation of symptoms which can involve cutaneous, respiratory, gastrointestinal, and/or neurologic following systemic exposure to nickel (eg:  ingestion, implantation, inhalation) in individuals with prior nickel sensitization. (Table 1).1,3
    • This is in contrast to allergic contact dermatitis (ACD) wherein localized skin lesions erupt in response to direct contact with nickel (jewelry).
    • Approximately 20% of patients with a delayed allergy to nickel sulfate experience SNAS.1
    • SNAS is mediated through the release of cytokines by Th2 cells and Th1 cells, particularly IL-5 and IL-4.1,3
    • Intestinal biopsies taken from SNAS patients following nickel ingestion have shown increased amounts of CD4+ lymphocytes in the duodenal lamina propria and a decrease in the number of epithelial CD8+ lymphocytes due to apoptosis.3

Andrioli et al Article Review:

  • Andrioli et. al evaluated 239 patients over a 12-month period who had presented with immune-mediated inflammatory disease at the Department of Immune-Mediated Inflammatory Diseases of the Padre Pio Hospital in Campi Salentina, Lecce, Italy.1
    • All subjects underwent thyroid function testing as well as thyroid gland ultrasonography to identify thyroid disease.1
    • Thyroglobulin antibody (TGAb) (a blood test for thyroid dysfunction) was used to identify CAT in the study participants.
    • The authors defined SNAS by cutaneous and systemic manifestations, positive Ni patch testing in conjunction with an oral Ni challenge test, and clinical improvement following 4 weeks of a low Ni diet.1
      • 136 subjects met the diagnostic criteria for SNAS.1
      • Out of the remaining 103 subjects (non-SNAS), 40 tested positive for non-SNAS hypersensitivities (gluten, idiopathic dermatitis, lactose intolerance, allergic sensitivity to aeroantigens).1
      • The authors reported positive CAT in 26.5% of the SNAS group versus 12.7% in the non-SNAS group.
        • Notably, the global prevalence of CAT is estimated to be 1-2% in Caucasian women, but elevated in individuals with immune-mediated inflammatory disease, although the precise mechanisms remain unknown.1,4,5
        • For example, individuals with type 1 diabetes, celiac disease, Sjogren’s syndrome, rheumatoid arthritis and systemic lupus erythematosus all carry increased risk of developing CAT. None of these diseases were specifically identified in the non-SNAS group studied in Andrioli et al.1,6-9
      • Of note, TGAb levels were two fold higher in the SNAS group when compared to the non-SNAS group (19.9% vs. 7.8%).1

 

Key Points:

  • Andrioli et al. recognized a statically significant association between CAT and SNAS.1
  • The authors reported a two-fold greater prevalence of CAT in patients with SNAS (26.5%) compared to patients with other non-SNAS immune-mediated inflammatory disorders (12.7%).1
  • Based on Andrioli et al’s findings and literature review, the authors suggest that metal induced allergic reactions from nickel may promote increased production of TGAb through an autoimmune-inflammatory mechanism resulting in the development of CAT.
    • SNAS is associated with elevated levels of IL-4, a stimulator of B lymphocyte activity and differentiation.This cytokine may play a role in the production of TGAb in susceptible individuals when systemically exposed to nickel.
  • Concordant with these findings, elevated T-cell mediated pro-inflammatory cytokines are present in nickel-sensitized individuals, placing those with SNAS at a higher risk of developing autoimmune disorders (CAT).10
    • Further studies are warranted to define the pathogenic mechanism and protocol for screening for CAT in patients with SNAS.1

 

Table 1: Common SNAS and CAT individual and shared symptoms in descending order of frequency*10,11

Symptoms of SNAS10 Symptoms of CAT11 Shared symptoms10,11
Urticaria/angioedema Cold intolerance Fatigue
Dermatitis Impaired memory Edema
Recurrent abdominal pain Hair loss Constipation
Diarrhea Slowed movements Headache
Dyspepsia Brady cardia <60/min Bloating
Gastro-esophageal reflux Dry, coarse skin  
Itching Weight gain  
     
*SNAS – systemic nickel allergy syndrome; CAT – chronic autoimmune thyroiditis

 

References:

  1. Andrioli M, Trimboli P, Maio D, Persani L, Minelli M. Systemic nickel allergic syndrome as an immune-mediated disease with an increased risk for thyroid autoimmunity. Endocrine. 2015;50(3):807-810.
  2. Duntas LH. Environmental factors and thyroid autoimmunity. Ann Endocrinol (Paris). 2011;72(2):108-113.
  3. Braga M, Quecchia C, Perotta C, et al. Systemic nickel allergy syndrome: nosologic framework and usefulness of diet regimen for diagnosis. Int J Immunopathol Pharmacol. 2013;26(3):707-716.
  4. Weetman AP. Non-thyroid autoantibodies in autoimmune thyroid disease. Best Pract Res Clin Endocrinol Metab. 2005;19(1):17-32.
  5. Fallahi P, Ferrari SM, Ruffilli I, Elia G, Biricotti M, Vita R, Benvenga S, Antonelli A. The association of other autoimmune diseases in patients with autoimmune thyroiditis: Review of the literature and report of a large series of patients. Autoimmun Rev. 2016; 15(12):1125-1128.
  6. Appenzeller S, Pallone AT, Natalin RA, Costallat LT. Prevalence of thyroid dysfunction in systemic lupus erythematosus. J Clin Rheumatol. 2009;15(3):117-119.
  7. Biro E, Szekanecz Z, Czirjak L, et al. Association of systemic and thyroid autoimmune diseases. Clin Rheumatol. 2006;25(2):240-245.
  8. Counsell CE, Taha A, Ruddell WS. Coeliac disease and autoimmune thyroid disease. Gut. 1994;35(6):844-846.
  9. Piatkowska E, Szalecki M. Autoimmune thyroiditis in children and adolescents with type 1 diabetes. Pediatr Endocrinol Diabetes Metab. 2011;17(4):173-177.
  10. Ricciardi L, Carni A, Loschiavo G, et al. Systemic nickel allergy: oral desensitization and possible role of cytokines interleukins 2 and 10. Int J Immunopathol Pharmacol. 2013;26(1):251-257.
  11. Kostoglou-Athanassiou I, Ntalles K. Hypothyroidism – new aspects of an old disease. Hippokratia. 2010;14(2):82-87.

 

Nickel in Cocoa – speciation

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Food Chem. 2017 Sep 1;230:327-335. doi: 10.1016/j.foodchem.2017.03.050. Epub 2017 Mar 10.

Nickel speciation in cocoa infusions using monolithic chromatography – Post-column ID-ICP-MS and Q-TOF-MS.

Peeters K1, Zuliani T2, Žigon D3, Milačič R4, Ščančar J5.

Author information

Abstract

Nickel (Ni) is considered to be a potentially harmful element for humans. Its levels in foodstuffs are normally low (below 0.2mgkg-1), but sensitive individuals may develop allergy to Ni as a result of dietary consumption. Cocoa contains relatively high Ni concentrations (around 3mgkg-1). Ni bioavailability, its role in the flavour of food and its potential impact on human health depends primarily on its chemical species. However, there is a lack of information about Ni speciation in cocoa. In this work Ni species were separated on a weak convective interaction media diethylamine (CIM DEAE) monolithic chromatographic column and quantified by the post-column isotope dilution inductively coupled plasma mass spectrometry (ID-ICP-MS). The Ni binding ligands in the separated fractions were identified “off line” by quadrupole time-of-flight mass spectrometry (Q-TOF MS). Ni was found to be present in the cocoa infusions as Ni2+ and Ni-gluconate and Ni-citrate complexes.

Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

nickel allergy cartoon

Detection of Nickel Sensitization – Article Review

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Original article: HERE

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. Detection of Nickel Sensitivity has Increased in North American Patch-test Patients. Dermatitis. 2008 Jan-Feb;19(1):16-9.

Review by Daniel No, BA. MSIII Loma Linda University School of Medicine

The prevalence of nickel contact allergy has steadily increased in men and women since the 1990s. The authors, Rietschel et al., enrolled 25,626 patients during the years 1992 to 2004 to undergo patch testing to detect nickel sensitivity. The data from this study demonstrated:

  • The nickel sensitization rate has steady increased from 14.5% in 1992 to 18.8% in 2004. The upward trend further emphasizes the importance of public awareness and education of nickel contact dermatitis. significant impact this allergen has on the North American population.
  • Females from 2001 to 2004 were 1.1 to 1.2 times more likely to be sensitive to nickel in comparison to females tested from 1992 to 2000. Similar results were found in the male population, however, the findings were not statistically significant.
  • Younger males (< 19 years old) were 2.33 times more likely to be sensitive to nickel than their older counterparts. Similarly, younger females were found to be 1.51 times more likely to be nickel sensitive.
  • The patch test is essential in identifying specific allergens in allergic contact dermatitis. Patches containing 2.5% nickel sulfate were applied and left in place for 2 days and subsequently interpreted when removed. A follow-up interpretation was conducted one to five days later.
dermatitis stories

Nickel-Allergic Patient Considering Hysteroscopic Sterilization

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Original article:

Bergman D., B.S., Goldenberg A. MAS, MD, Jacob S.E., MD Update on Providing Re-Essure-ance to the Nickel-Allergic Patient Considering Hysteroscopic Sterilization.

Review by Daniel Bergman, BS. MSIII, Loma Linda University

Nickel allergic contact dermatitis (Ni-ACD) has become a widely recognized disease process with an exponential increase in the last three decades within the United States. A subpopulation of ACD patients will manifest with systemic contact dermatitis (SCD) when exposed to nickel systemically such as orally, per rectum, intravenously, intravesically, transcutaneously, intrauterinely, or by inhalation. The Bergman et al[i] article highlights:

 

  • The FDA reports 212 incidences of EssureTM removal due in part to nickel allergy with 55% confirmed improvement of symptoms after removal.
  • Nickel allergy is not a contraindication for EssureTM, however, assessing for a history of moderate to severe reactions to nickel is crucial in reducing patient morbidity. This history should prompt further evaluation including possible referral to a specialist and patch testing.
  • The patch test is the gold standard for diagnosing ACD. In the hands of a trained professional the patch test is a proven predictor of ACD.
  • The pathophysiology is different between ACD and SCD. Therefore, not every woman with a history of ACD and a positive patch test will develop SCD to EssureTM.

 

[i] Bergman D., B.S., Goldenberg A. MAS, MD, Jacob S.E., MD Update on Providing Re-Essure-ance to the Nickel-Allergic Patient Considering Hysteroscopic Sterilization.