Metal Hypersensitivity to Implant Materials

By: Marco Caicedo, Ph.D

Hypersensitivity to TMJ implant materials is an issue that we are frequently hearing from TMJ patients. Given this concern we contacted Marco Caicedo, Ph.D., Senior Scientists and COO at Orthopedic Analysis in Chicago, IL. Orthopedic Analysis is an independent diagnostics company dedicated to the quantitative analysis of immune responses to biomaterials (i.e. metal allergy to implant materials). The TMJ Association thanks Dr. Caicedo for writing this state-of-the-art article.

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What is a Metal Hypersensitivity?

Metal hypersensitivity (or metal sensitivity) can be defined as an immune reaction that is triggered by specific cells of the body’s immune system in response to certain metals including, but not limited to nickel, cobalt, and chromium.[14] While metal hypersensitivity can be considered a type of allergy, it does not induce the immediate allergy symptoms that can occur when exposed to seasonal or household allergens like pollen, animal dander, mold, etc. Metal hypersensitivities have a delayed onset from the time of exposure to the implant metal and are not caused by specific antibodies or histamine release that lead to the classical symptoms of common allergies like itching, watery eyes, or sneezing.

Metal hypersensitivity requires a first-step sensitization stage where specific cells of the immune system (T lymphocytes) recognize, activate, proliferate and form immunological memory upon contact with sensitizing metal components.[2,4,14,17] Immunological memory occurs once specific cells of the immune system are exposed to enough quantities of a metal sensitizer and recognize it as foreign (i.e. metals released from implant materials). Once immunological memory has been formed, a secondary exposure to the metal sensitizer can lead to all the classical inflammatory symptoms of a delayed type hypersensitivity, which are described below.

What are the Symptoms of a Metal Hypersensitivity?

The symptoms of a metal hypersensitivity can be best described
in cases of skin allergic contact dermatitis due to metal exposure from jewelry, belt buckles and other metal-containing accessories.[13] The most common symptoms reported are a rash around the contact area, but may also include blisters, vesicles (small, fluid-filled elevations of the skin), redness, itching and general inflammation around the area exposed to the contact metal.[12] Generally, symptoms of a metal hypersensitivity do not
appear until the second day after exposure and they may continue for several days before returning to a normal state.

Metal hypersensitivity symptoms caused by metal implant
devices (i.e. Total Temporomandibular Joint, Total Hip and knee replacements) are more challenging to describe because the implant is inside the body, restricting access to visual examination. However, several studies of tissues surrounding the  implant in subjects with aseptically (not infected) failed prostheses indicate the presence of immune cells typically found in a delayed type hypersensitivity response, such as lymphocytes and macrophages interacting with implant debris products in the
affected area.[3,7,8,16,19] Implant debris products are metal particles resulting from friction and metal ions leached from implant components due to inevitable corrosion mechanisms [19]. General symptoms that have been reported by patients with non-infected failing metal prostheses are pain, swelling, loss of range of motion in the affected joint, effusions from the joint, inflammation and premature osteolysis (bone loss) around the metal device.[6,7,9,19] Effusions from an inflamed joint are the result of excess fluids caused by an excessive inflammatory response. Patients may have one or more symptoms that can occur at any time during the lifetime of the implant depending on the degree of sensitization and exposure to metal degradation products. Because all these symptoms can also be caused by other problems not associated with metal hypersensitivity, it is important to consult with your physician and conduct a thorough clinical history to confirm a diagnosis.

What Happens to My TMJ if I Have a Metal Hypersensitivity?

All implant materials undergo wear and corrosion when in the body. Microscopic metal particles and soluble concentrations of metal ions leached from the implant surface are released over time in the surrounding implant tissue.[11,17,19] While exposure to minute concentrations of metals may not trigger an adverse response in the majority of cases, people with a known hypersensitivity to any of the components of their implant may respond differently. Immune cells in contact with a metal (i.e. nickel, cobalt, chromium) may activate, divide and recruit more immune cells, initiating an inflammatory response [2,3,19]. The response can range from mild to severe depending on the degree of sensitization and on the amount of wear debris that is being generated.[2,14,17,19] This vicious cycle of inflammation can lead to detrimental effects around the bone-implant interface causing symptoms that can include myofascial pain, muscle spasms, headaches, earaches, tinnitus, vertigo, and facial swelling in TMJ patients.[16,17]

Continuous exposure to metal sensitizing agents can create a chronic painful inflammatory state around the implant, which can also lead to a loss of bone maintenance mechanisms, potentially resulting in osteolysis (bone loss) and implant loosening.[8,16,17,19]

How Can I Find Out if I Have a Metal Hypersensitivity?

There are two kinds of testing that have been historically used to diagnose hypersensitivity to metals: 1. The patch skin test and 2. The lymphocyte transformation test (LTT) in whole blood. While the techniques for these two tests are vastly different, they both diagnose hypersensitivity type responses in the skin and in blood, respectively.
  1. Patch testing in which a sample of the suspected allergy-causing material (i.e. metal) is applied to the skin is considered the gold standard to detect SKIN contact hypersensitivities to metals. Patch testing is widely available through allergy and immunology practices. However, there are definite concerns regarding the applicability of this testing for people with metal implants [18,19]. The central concern is that patch testing has the potential to sensitize the patient to the very same metals they are testing for, so the patch test itself can cause the recipient to become more sensitive to implant metals. Furthermore, the on-the-skin approach is a much different environment compared to the deep tissue around an implant. Patch testing can be costly as it may require two visits to the physician (one for application and one to read a subjective result) and it does not provide a wide range of clinically relevant orthopedic challenge agents (metals mixed with petroleum jelly) applicable for the purpose of diagnosing a metal hypersensitivity to a specific orthopedic device (i.e. TMJ).[15,17,18,19]
  2. The lymphocyte transformation test (LTT) is a blood test that can detect if the patient has a metal hypersensitivity (immunological memory to metal-haptens). The lymphocyte transformation test has been available for over 25 years and was first used as a test to detect drug hypersensitivity reactions. The LTT is now used for multiple applications that include, but are not limited to immune function testing, drug hypersensitivity and metal hypersensitivity.[5,17,19] The LTT requires drawing a blood sample at a physician’s office or local laboratory with special tubes. Once the sample is submitted and processed at a laboratory with the expertise to perform the test, it provides results within 7 to 10 days. Advantages of the LTT include a non-subjective evaluation (it doesn’t depend on a physician’s visual judgment) and can be used to test numerous clinically relevant implant metals and other materials tested at different concentrations with a simple blood draw.

What are the Facts About Metal Hypersensitivity and Implant Performance?

The United States Food and Drug Administration has acknowledged and released a comprehensive review of the literature regarding “Biological Responses to Metal Implants” including metal hypersensitivity. [19] Several studies of metal hypersensitivity and its correlation to orthopedic implants have been performed over the past two decades. It is a fact that 10-15 % of the general population have a hypersensitivity to one of the most common sensitizers (nickel, cobalt, chromium).[4,16,17,19] Studies also reveal that 20-25% of people with well-performing total joint replacements have a metal hypersensitivity and 60% of individuals with poorly performing implants have a metal hypersensitivity.[4,16,19] Recently, it has been well documented that devices with metal-on-metal articulations (compared to traditional metal on polyethylene) release more metal debris and consequently have induced a greater rate of failures that have been attributed to metal toxicity, hypersensitivity and other adverse tissue reactions.[10,19]

Clearly, metal hypersensitivity is correlated with poor implant performance and the utility of testing could be lifesaving by avoiding certain metals and risky revision surgeries for people with painful aseptic and well-fixed implants. However, implant outcome or the status of a prosthesis cannot be based solely on a metal hypersensitivity test. The patient’s clinical history, results from other clinical tests performed and more importantly, the patient’s current health status and quality of life must be considered by a qualified healthcare provider before making a conclusive diagnosis.

Where Can I get Tested for Metal Hypersensitivity and What Will the Results Tell Me?

Patch testing: Patch testing may be performed at most allergy and/or immunology practices by appointment.

Lymphocyte Transformation tests: While some clinical laboratories around the country offer lymphocyte transformation tests on their testing menu, they may not offer specific metal concentrations or panels of metals that are relevant to a metal prosthesis.

Orthopedic Analysis, LLC is a CLIA certified laboratory based in Chicago that concentrates specifically in the diagnosis of immune responses to implant materials (i.e. metal hypersensitivity). Samples may be submitted from any state in the U.S through the mail in a kit provided by the company. www.orthopedicanalaysis.com

References

  1. Atanaskova MN, Tellez A, Molina L, et The effect of patch testing on surgical practices and outcomes in orthopedic patients with metal implants. Arch Dermatol 2012; 148 687-93
  2. Caicedo MS, Pennekamp PH, McAllister K, et al. Soluble ions more than particulate cobalt-alloy implant debris induce monocyte costimulatory molecule expression and release of proinflammatory cytokines critical to metal-induced lymphocyte reactivity. J Biomed Mater Res A 2010; 93 1312-21
  3. Hallab N. Metal sensitivity in patients with orthopedic implants. J Clin Rheumatol 2001; 7 215-8
  4. Hallab N, Merritt K, Jacobs Metal sensitivity in patients with orthopaedic implants. J Bone Joint Surg Am 2001; 83-A 428-36
  5. Hallab NJ. Lymphocyte transformation testing for quantifying metal-implant-related hypersensitivity responses. Dermatitis 2004; 15 82-90
  6. Hallab NJ, Anderson S, Stafford T, et Lymphocyte responses in patients with total hip arthroplasty. J Orthop Res 2005; 23 384-91
  7. Hallab NJ, Jacobs JJ. Biologic effects of implant debris. Bull NYU Hosp Jt Dis 2009; 67 182-8
  8. Jacobs JJ, Hallab NJ. Loosening and osteolysis associated with metal-on-metal bearings: A local effect of metal hypersensitivity? J Bone Joint Surg Am 2006; 88 1171-2
  9. Jacobs JJ, Roebuck KA, Archibeck M, et Osteolysis: basic science. Clin Orthop Relat Res 2001; 71-7
  10. Langton DJ, Jameson SS, Joyce TJ, et al. Early failure of metal-on-metal bearings in hip resurfacing and large-diameter total hip replacement: A consequence of excess wear. J Bone Joint Surg Br 2010; 92 38-46
  11. Mathew MT, Abbey S, Hallab NJ, et al. Influence of pH on the tribocorrosion behavior of CpTi in the oral environment: synergistic interactions of wear and corrosion. J Biomed Mater Res B Appl Biomater 2012; 100 1662-71
  12. Seyfarth F, Schliemann S, Antonov D, Elsner P. Teaching interventions in contact Dermatitis 2011; 22 8-15
  13. Thyssen JP, Hald M, Avnstorp C, et Characteristics of nickel-allergic dermatitis patients seen in private dermatology clinics in Denmark: a questionnaire study. Acta Derm Venereol 2009; 89 384-8
  14. Wang Y, Dai S. Structural basis of metal hypersensitivity. Immunol Res 2013; 55 83-90
  15. Mihalko W, et al.. Skin Patch Testing and Associated Total Joint Outcomes. AAOS, Chicago, IL 2013
  16. Wolford Factors to consider in joint prosthesis systems. Proc (Bayl Univ Med Cent ) 2006; 19 232-8
  17. Mercuri L, Caicedo, M. Material Hypersensitivity and Alloplastic TMJ Replacement. J Oral Maxillofac Surg; 2019 Jul;77(7):1371-1376
  18. Thomas P, Geier J, Dickel H, et.al. DKG statement on the use of metal alloy discs for patch testing in suspected intolerance to metal implants; J Dtsch Dermatol Ges. 2015 Oct;13(10):1001-4
  19. U.S Food and Drug Administration (FDA). Biological Responses to Metal Implants. https://www.fda.gov/media/131150/download

Material Composition for the TMJ Devices