Delayed-type hypersensitivity to metals in connective tissue diseases

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Delayed-type hypersensitivity to metals in connective tissue diseases and Fibromyalgia

 

Original article:

Bjørklund G, Dadar M, Aaseth J. Delayed-type hypersensitivity to metals in connective tissue diseases and fibromyalgia. Environmental Research. 2018;161:573-579. doi:10.1016/j.envres.2017.12.004

Reviewed by Jack Guccione, MS3 Loma Linda University School of Medicine.

Keywords: Fibromyalgia, Mixed connective tissue disease, Rheumatoid arthritis, Nickel, Mercury, Gold, Palladium, Metals, Allergy.

Abstract excerpt from: Delayed-type hypersensitivity to metals in connective tissue diseases

“Rheumatoid arthritis (RA) often involves the small joints of the hands in a symmetrical fashion that can lead to loss of joint function, and RA, as well as Sjögren’s syndrome (SS) and other rheumatic diseases, are often accompanied by sensitivity to metals… Metal-related DTH [delayed-type hypersensitivity] in these patients will induce an inflammatory response. Such inflammations are important factors in CTD [connective tissue disease] progress. It is hypothesized that metal-specific T cell reactivity can act as an etiological agent in the propagation and chronification of rheumatic inflammation. The key responses of metal delayed-type hypersensitivity in autoimmunity are precipitating as an appealing challenge for further investigations.”

Review:

  • Connective Tissue Disease (CTD) refers to a group of autoimmune diseases including rheumatoid arthritis (joint pain, malformation), Sjogren’s syndrome (excess tears and saliva), dermatomyositis, and systemic lupus erythematosus (joint pain, swelling).3
  • Fibromyalgia (FM) is a chronic rheumatic disease with an unknown cause that presents with tenderness and pain at 11-18 “trigger points” on the body and a constellation of symptoms that include cognitive and sleep impairment and widespread musculoskeletal pain and stiffness.
    • It is found in up to 6.6% in the general population, affecting women 2x more than men.1,2
    • There is significant overlap in non-musculoskeletal symptoms with chronic fatigue syndrome.
    • Persistent symptoms can lead to social inability, depression, and poor overall quality of life.1
  • Bjorklund et al. reviewed more than 100 studies and two case reports which had found positive associations between metal allergies (see table 1) and CTD or FM1
    • One study in the review reported THAT over 50% of women who tested positive for FM also self-reported having prior positive skin testing to nickel (bracelets, earrings).5
    • This is a significantly higher sensitization rate than is estimated in the US general population to nickel of 17-20%.6Similarly, two reviewed case reports anecdotally showed removal of nickel-containing dental appliances (bridges, wires) resulted in resolution of fatigue and FM pain in the patients.8
    • Bjorklund reviewed Hart et al.’s paper which found exposures to silica, mineral oils, and traffic pollution containing detectable levels of nickel, mercury, and palladium to be a significant risk factor for the development of RA.7
    • Bjorklund et al.’s review of a larger study (N=111), showed up to 76% of patients reported improvement of their chronic fatigue when dental metals containing nickel were removed.9
      • This study documented removal of mercury tooth-fillings resulted in substantial “health improvements” in individuals with FM including reduced migraine, less joint pain in wrists, hands, and fingers, and reduced fatigue symptoms.9
    • Another review was of an environmental study from 2007 on a community subdivision located near a petroleum tank battery.
      • The primary researchers found a significantly higher incidence of confirmed diagnosed SLE in the exposed community, compared to an unexposed near-by community.4
      • In this same study, ambient air testing found higher levels of petroleum hydrocarbons as well as increased levels of mercury in the air, which are known to suppress the immune system and lead to SLE.4
      • One of Bjorklund’s reviewed studies described the use of the ‘Memory Lymphocyte Immunostimulation Assay (MELISA) that detected delayed T-cell reactivity to dental-metals in patients suffering from FM.9
        • In this study, all patient with a history for FM also tested positive for at least one of the metals in their dental materials with MELISA
        • A 5-year follow up from removing these metals showed that half the patients no longer fulfilled the American college of rheumatology 1990 criteria for FM.9
        • An explanation for this finding is that sensitization to nickel or mercury in dental amalgams can cause higher levels of pro-inflammatory cytokines such as interferon-gamma when compared to healthy individuals.
        • Though not reviewed by Bjorklund, studies have found changes in free radical/antioxidant balance, as well as low levels of glutathione, correlate with metal induced inflammation, thus putting certain individuals at higher risk for developing FM.10
          • This remarkable finding suggests metal-induced inflammation may be reversible and is an important risk factor in patients with FM.
        • Bjorklund also reviewed literature regarding the potential protective effects of micronutrients in apparently alleviating autoimmune diseases..
          • For example, selenium was reported to potentially inhibits the toxic effects of exposure to other metals.11
          • These authors proposed low selenium in our diet can result in higher levels of other metals (mercury) thereby aggravating muscle pains seen in FM.12

Conclusion:

  • The authors review compelling findings from a variety of published studies that show patients suffering from CTD or FM may benefit from reduced exposure to certain metals.
    • These benefits include reduced inflammation and potential partial reversal of symptoms, which can ultimately help restore the efficacy of conventional therapies.

 

Table 1: Summary of metals and their relation to CTD and FM compiled from various papers reviewed in Bjorklund et al.

Metals and their relation to CTD and FM 1 What is it used for? What conditions or connective tissue disease is associated with it? What are the symptoms?
Gold 13 -Injectable Treatment for Rheumatoid arthritis14

 

-Jewelry, dental alloys, and orthopedic appliances 15

 

-chinaware16

 -Gold allergy seen in 50% of RA patients studied (n=399) after treatment with gold salts14 Eczematous skin reaction 15
Palladium 15 -Dental Crowns, toothbrushing may increase palladium release, 17 Jewelry -Cross-reaction with nickel resulting in dermatitis 18 -Oral diseases such as lichen planus or stomatitis 19
Titanium 20 -Dental implants20 -Chronic Fatigue Syndrome, Multiple chemical sensitivity20 -Joint pain, nerve pain, chronic fatigue syndrome, depression, acne-like inflammation 20
Chromium 21 -Dye, detergent, cosmetics, leather, wood preservative 21

-Cement production 15

 -Shoe contact dermatitis 22-Insulin dysregulation 23

 

 -Bronchial asthma, hepatotoxicity 24

 

References:

  1. Bjorklund G, Dadar M, Aaseth J. Delayed-type hypersensitivity to metals in connective tissue diseases and fibromyalgia. Environ Res. 2018;161:573-579.
  2. Salaffi F, Sarzi-Puttini P, Girolimetti R, Atzeni F, Gasparini S, Grassi W. Health-related quality of life in fibromyalgia patients: a comparison with rheumatoid arthritis patients and the general population using the SF-36 health survey. Clin Exp Rheumatol. 2009;27(5 Suppl 56):S67-74.
  3. Iaccarino L, Gatto M, Bettio S, et al. Overlap connective tissue disease syndromes. Autoimmun Rev. 2013;12(3):363-373.
  4. Dahlgren J, Takhar H, Anderson-Mahoney P, Kotlerman J, Tarr J, Warshaw R. Cluster of systemic lupus erythematosus (SLE) associated with an oil field waste site: a cross sectional study. Environ Health. 2007;6:8.
  5. Regland B, Zachrisson O, Stejskal V, Gottfries CG. Nickel Allergy is Found in a Majority of Women with Chronic Fatigue Syndrome and Muscle Pain—and may be Triggered by Cigarette Smoke and Dietary Nickel Intake. Journal of Chronic Fatigue Syndrome. 2001;8(1):57-65.
  6. Thyssen JP, Menne T. Metal allergy–a review on exposures, penetration, genetics, prevalence, and clinical implications. Chem Res Toxicol. 2010;23(2):309-318.
  7. Hart JE, Laden F, Puett RC, Costenbader KH, Karlson EW. Exposure to traffic pollution and increased risk of rheumatoid arthritis. Environ Health Perspect. 2009;117(7):1065-1069.
  8. Muris J, Feilzer AJ. Micro analysis of metals in dental restorations as part of a diagnostic approach in metal allergies. Neuro Endocrinol Lett. 2006;27 Suppl 1:49-52.
  9. Stejskal V, Ockert K, Bjorklund G. Metal-induced inflammation triggers fibromyalgia in metal-allergic patients. Neuro Endocrinol Lett. 2013;34(6):559-565.
  10. De Luca C, Scordo MG, Cesareo E, et al. Biological definition of multiple chemical sensitivity from redox state and cytokine profiling and not from polymorphisms of xenobiotic-metabolizing enzymes. Toxicol Appl Pharmacol. 2010;248(3):285-292.
  11. Turner RJ, Finch JM. Selenium and the immune response. Proc Nutr Soc. 1991;50(2):275-285.
  12. Stoffaneller R, Morse NL. A review of dietary selenium intake and selenium status in Europe and the Middle East. Nutrients. 2015;7(3):1494-1537.
  13. Moller H. Dental gold alloys and contact allergy. Contact Dermatitis. 2002;47(2):63-66.
  14. Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013;381(9865):451-460.
  15. Forte G, Petrucci F, Bocca B. Metal allergens of growing significance: epidemiology, immunotoxicology, strategies for testing and prevention. Inflamm Allergy Drug Targets. 2008;7(3):145-162.
  16. Eisler R. Mammalian sensitivity to elemental gold (Au degrees). Biol Trace Elem Res. 2004;100(1):1-18.
  17. Wataha JC, Lockwood PE, Frazier KB, Khajotia SS. Effect of toothbrushing on elemental release from dental casting alloys. J Prosthodont. 1999;8(4):245-251.
  18. Faurschou A, Menne T, Johansen JD, Thyssen JP. Metal allergen of the 21st century–a review on exposure, epidemiology and clinical manifestations of palladium allergy. Contact Dermatitis. 2011;64(4):185-195.
  19. Durosaro O, el-Azhary RA. A 10-year retrospective study on palladium sensitivity. Dermatitis. 2009;20(4):208-213.
  20. Muller K, Valentine-Thon E. Hypersensitivity to titanium: clinical and laboratory evidence. Neuro Endocrinol Lett. 2006;27 Suppl 1:31-35.
  21. Thyssen JP, Strandesen M, Poulsen PB, Menne T, Johansen JD. Chromium in leather footwear – risk assessment of chromium allergy and dermatitis. Contact Dermatitis. 2012;66(5):279-285.
  22. Mortz CG, Andersen KE. Allergic contact dermatitis in children and adolescents. Contact Dermatitis. 1999;41(3):121-130.
  23. Ryan GJ, Wanko NS, Redman AR, Cook CB. Chromium as adjunctive treatment for type 2 diabetes. Ann Pharmacother. 2003;37(6):876-885.
  24. Shrivastava R, Upreti RK, Seth PK, Chaturvedi UC. Effects of chromium on the immune system. FEMS Immunol Med Microbiol. 2002;34(1):1-7.

 

FREE Access – Medical Necessity of Comprehensive Patch Testing

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Free Access for 90 days, granted by publisher!!!

A Review of the Medical Necessity of Comprehensive Patch Testing

Zhu, Tian, Hao*; Suresh, Raagini†; Warshaw, Erin‡§; Scheinman, Pamela∥; Mowad, Christen; Botto, Nina**; Brod, Bruce††; Taylor, James, S.‡‡; Atwater, Amber, Reck§§; Watsky, Kalman∥∥; Schalock, Peter, C.¶¶; Machler, Brian, C.***; Helms, Stephen†††; Jacob, Sharon, E.‡‡‡; Murase, Jenny, E.**§§§

Abstract:
Allergic contact dermatitis is associated with significant disease and economic burden in the United States. To properly manage allergic contact dermatitis, it is important to accurately identify the substance(s) implicated in the dermatitis to prevent disease recurrence. The commercially available T.R.U.E Test (36 allergens) screening panel has been reported to have a conservative hypothetical allergen detection rate of 66.0%, at most. Importantly, these calculations are based on the 78% of patients who had clinically relevant reactions to allergens present on the North American Contact Dermatitis Group screening series (70 allergens), without the use of supplemental allergens. Testing with supplemental allergens beyond a screening series can more fully evaluate an individual’s environmental and occupational exposure, which may significantly increase diagnostic accuracy. Comprehensive patch testing with additional allergens in sunscreens, cosmetics, and fragrances, for example, may increase the diagnostic yield as well as the likelihood of achieving a cure if the dermatitis is chronic and recalcitrant.
Free access provided by LWW for 90days.

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Palladium allergic contact granuloma

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Discussion on Palladium granuloma

Title:Palladium-induced allergic contact granuloma in a child wearing an earring

Original article:

Gonzalez-Perez, R, Carrillo-Ruiz, G, & Soloeta, R. Sarcoid-type Allergic Contact Granuloma Caused by Earrings in a Boy. Actas Dermo-Sifiliográficas (English Edition). 2012;103(1):73-74. doi: 10.1016/j.adengl.2010.12.008

Reviewed by Jack Guccione, BS. MSIII & Brittanya Limone, MA, BS, MSIV. Loma Linda University School of Medicine

Case Description

  • A case of granulomatous allergic contact dermatitis (ACD) in an 11-year-old boy due to an earring containing palladium reported in Spain.
    • He complained of a firm, asymptomatic papule on his left earlobe that had been present since he began wearing an earring 3-years prior.
    • Surgical removal and pathology evaluation of the papule revealed a reactive “sarcoidal granulomatous infiltration with no evidence of refringent material”, suggesting that the papule did not form due to retention of a foreign body (metal fragment) present in the skin.
    • Skin patch testing determined that the boy was sensitized to palladium.
  • Palladium chloride skin patch testing resulted in a primary eczematous response.
  • Mass spectrometry of the patient’s earring identified palladium as the primary metal composing the earring.
  • Given the temporal association between the skin patch testing and confirmation of palladium in the earring, the diagnosis of granulomatous allergic contact dermatitis reaction (gACDr) due to palladium was made [aka palladium granuloma].
  • The boy stopped wearing his earring and there was complete resolution of the reaction, confirming the diagnosis of palladium granuloma.

 

Discussion:

  • Sarcoidal-type (non-caseating/non-necrotizing) granulomas are abnormal nodules composed of inflammatory immune cells and macrophages.
    • They develop in response to a perceived need of the skin to encase a ‘foreign’ substance it is unable to eliminate.
    • This type of granuloma suggests the lesion is not caused by an infection from Mycobacteria tuberculosis, Treponema pallidum (syphilis) or some fungi, all of which can cause the necrotizing (internally breaking down) type of granuloma.
  • Several metals have been reportedly to cause gACDr (See Table 1).

 

Allergic contact granulomas are a less common presentation (variant) of allergic contact dermatitis.  The article was reviewed to acknowledge the spectrum of allergic dermatitis.

 

Table 1. Metals and Respective Sources Implicated in Granulomatous ACD

Metal Sources of Exposure
Palladium Earrings
Beryllium Mining

Fluorescent lighting tubes

Beryllium alloy production
Aluminum Vaccine & hypo-sensitization extract adjuvants

Deodorants

Tattoos
Zirconium Deodorants
Titanium Pacemakers
Mercury Tattoos
Chromium
Cobalt

 

References:

Gonzalez-Perez, R, Carrillo-Ruiz, G, & Soloeta, R. Sarcoid-type Allergic Contact Granuloma Caused by Earrings in a Boy. Actas Dermo-Sifiliográficas (English Edition). 2012;103(1):73-74. doi: 10.1016/j.adengl.2010.12.008

Lubeck, G., & Epstein, E. (1952). COMPLICATIONS OF TATTOOING. California Medicine, 76(2), 83–85.