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:

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  11. Turner RJ, Finch JM. Selenium and the immune response. Proc Nutr Soc. 1991;50(2):275-285.
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  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.
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  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.
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