Cutaneous reactions to metals used in orthopaedic implants have been well documented since the 1970s. Recently, a rise in the incidence of cutaneous reactions has been ascribed to certain metals and types of implants. Whether cutaneous reactions are the dominant symptom associated with hypersensitivity responses to implanted orthopaedic devices is controversial.

Some reports have shown a poor correlation between skin testing and implanted materials. A recent study in the Archives of Dermatology, however, reported a correlation between patients who had a poor outcome after total knee arthroplasty (TKA) and positive skin patch testing that indicated metal sensitivity. Although this study may have implications for future screening of patients before scheduling elective surgery that involves an implanted metallic medical device, based on the totality of the available evidence, we, the authors, believe that it is not prudent to recommend routine screening for metal hypersensitivity prior to TKA using either patch or in vitro testing modalities.

Hypersensitivity to an implanted medical device is typically a delayed, Type IV cell-mediated reaction and not an immediate humoral immune response. In hypersensitivity reactions, antigens activate T lymphocytes. Through this cascade, CD4 and CD8 cells are activated, releasing a multitude of cytokines including interferon gamma, interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF) alpha. These reactions are in addition to those typical of any surgical procedure that uses an implant, in which the surgical insult initiates a local inflammatory tissue reaction. Endogenous proteins, including serum proteins, adhere to the surface of the material, which also activates the complement cascade.

Recent evidence has confirmed that repeated exposure to metallic materials can sensitize patients to the constituent materials. This theory of multiple exposures holds that repeated exposure to different forms of metals will increase an individual’s sensitivity to those metals. An increase in latex and peanut allergies over the past few decades has also been ascribed to the theory of multiple exposures.

In 2009, the North American Skin Patch testing group reported the results of testing almost 5,000 patients (a representative cross section of the population) to a wide variety of materials. Nickel (Ni) was the most common reactant (21 percent); reactions to other substances found in orthopaedic implants such as cobalt (Co) (8 percent) and chrome (Cr) (8 percent) were on the rise.

Both chromates and forms of Co are used in many cosmetics and preservatives. In the past, Co has been used as a food additive and implicated in multiple cases of cobalt poisoning. As more patients are repeatedly exposed to metal variants commonly used in orthopaedic implants, the possibility of increased sensitivity reactions to these metals may arise.

In a small subset of patients, patch test results will shift from negative to positive after joint replacement surgery, suggesting that in vivo metal exposure can cause sensitization. This presents a problem for surgeons because predicting who will or will not become metal sensitive during the first 18 months after surgery is not currently possible. Thus, unless a patient has a documented history of metal allergy to deeply seated (as opposed to cutaneous) implants, general preoperative metal sensitivity testing is probably not beneficial and should not be recommended.

Diagnosing metal hypersensitivity
Symptoms ascribed to metal hypersensitivity include the following: pain, swelling, cutaneous rash, patient dissatisfaction, and loss of function. As with any painful TKA, the clinician should perform a careful history and physical examination, including blood tests (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], complete blood count [CBC] and differential). An arthrocentesis to rule out the presence of an infection may also be ordered. Other causes of chronic pain after TKA—including midflexion instability, synovitis from wear debris, referred pain from a spinal or hip disorder, complex regional pain syndrome, or somatization disorder—should also be ruled out.

Only if laboratory tests and radiologic findings indicate no loosening, infection, or other tissue abnormalities should the surgeon consider metal hypersensitivity and order a patch test or an in vitro lymphocyte transformation test (LTT). A metal-related LTT is reimbursed by and typically costs between $250 and $500 (generally less than half the total cost of a patch test). Although the number of laboratories that perform metal-related LTT is limited, several laboratories follow similar standards (two or three different dose concentrations, 0.001–0.1 mM, for each implant metal tested).

Unfortunately, the clinical cause for pain and the results of the patch testing or LTT can’t be easily correlated. Some evidence indicates that LTT is useful in specific situations (eg, in symptomatic total hip arthroplasty patients with metal-on-metal bearings). However, no large-scale prospective evidence exists that implicates preexisting metal allergy as a cause of implant failure in people who received components containing metal(s) to which they are reactive. Conducting these studies is problematic, given the number of retrospective studies showing elevated levels of metal sensitivity in patient cohorts whose implants have failed or are failing.

Treatment considerations
So how can the orthopaedic surgeon respond to a primary TKA patient who claims sensitivity to a specific metal and wants to know what his or her options are? If patch testing or LTT find high reactivity, the surgeon should discuss options for avoiding the reaction-producing metal(s). For example, if the patient has high reactivity to a prominent implant metal such as Co or Cr, then using an implant with an alternative bearing surface of less environmentally prevalent metals may be an option.

Some alternative bearing surfaces, such as oxidized zirconium, may also release fewer reactive metals and less metal in general. With oxidized zirconium, the metal surface is transformed into a ceramic layer. The element is in the same family as titanium, but harder. It forms a thick enough ceramic layer to be more wear resistant than typical cobalt-chrome-molybdenum (Co-Cr-Mo) alloy TKA femoral components.

Other options include titanium or zirconium nitride coatings and alumina (currently in premarket approval trials in the United States). Titanium nitride is coated onto the surface of a titanium-alloy femoral component facilitating improved wear performance while eliminating exposure to cobalt and chromium metals. Zirconium nitride is a ceramic surface coating applied to a cobalt chrome alloy that encases the implant and reduces the metal ion exposure.

Using an oxidized zirconium or nitrided femoral component and an all-polyethylene– or titanium alloy/zirconium nitride–coated tibial component will minimize the risk of Co, Cr, and/or Ni reaction. However, this does not preclude the risks associated with nickel and other metallic byproducts that could emanate from the stainless steel instrumentation during implantation.

Testing problems
The following problems associated with skin patch testing of patients undergoing implantation of a metal device should also be considered:

• Subjectivity: Interpreting the +1 to +3 dermal reaction results is subjective and far from optimal, given observer biases.
• Cell locations: Antigen-presenting cells (Langerhans cells) within the skin layers do not react in the same way as macrophages and dendritic cells located in the deep tissues around the implant. This calls into question the results and correlations to orthopaedic implant performance.
• Sensitization: Perhaps of most concern for orthopaedic surgeons is that patch testing involves mixing metal chlorides in petroleum jelly and applying them to the patient’s skin for at least 48 hours. The same phenomenon (T-cell response) that provokes a response can theoretically induce sensitivity in people (as it has been shown to do in animal models). Although a minimal risk, it is consistently mentioned in the literature on the topic. The interpretation of skin patch testing results should be considered only in the context of the history, physical examination, and results of other diagnostic testing modalities.

Although a discussion of hypersensitivity reactions to metallic implants for joint replacement should be considered for concerned patients, excessive concern is unwarranted, given the rarity of documented metal hypersensitivity reactions following TKA. Understanding the relevant issues and options can aid the surgeon in dealing with preoperative patient concerns and any possibility of hypersensitivity becoming an issue after surgery.

Surgeons must be attentive to patient concerns and realize that the plethora of information available via the Internet is not always beneficial or accurate. Patients who have preconceived notions on how to best treat their “allergy” situation need careful counseling and open discourse to ensure that they fully understand the current risks and gaps in knowledge about metal hypersensitivity following TKA. Patients who have a highly metal-reactive patch or LTT may need implants fabricated from other metals, if possible.

William M. Mihalko, MD, chairs the AAOS Biomedical Engineering Committee; Stuart B. Goodman, MD, chairs the AAOS Biological Implants Committee; Nadim J. Hallab, PhD, is the director of the biomaterials laboratory and associate professor in the department of orthopaedic surgery at Rush University Medical Center; Joshua J. Jacobs, MD, is the AAOS first vice-president and William A. Hark, MD/Susanne G. Swift professor and chairman, department of orthopaedic surgery, Rush University Medical Center.

Disclosure information: Dr. Mihalko—Aesculap/B.Braun; Surgical Solutions; Saunders/Mosby-Elsevier; Journal of Arthroplasty; ASTM International; Dr. Goodman— Accelalox; StemCor; Tibion; Clinical Orthopaedics and Related Research; Biomaterials; Journal of Arthroplasty; Journal of Biomedical Material Research; Journal of Orthopaedic Research; Open Biomaterials Journal; Open Orthopaedics Journal; Orthopaedic Research Society; Dr. Hallab— Medtronic Sofamor Danek; Smith & Nephew; Biomet; InVibio; Zimmer; Dr. Jacobs—Implant Protection; Medtronic Sofamor Danek; Nuvasive; Zimmer

Bottom Line

• Metals used in orthopaedic implants are frequently found in other compounds, such as cosmetics and preservatives; repeated exposure to these metals may result in hypersensitivity to them.
• The hypersensitivity response to an implanted metal device is typically a cell-mediated delayed-type hypersensitivity response.
• Symptoms ascribed to metal hypersensitivity may include the following: pain, swelling, cutaneous rash, patient dissatisfaction, and loss of function.
• Current modalities for metal allergy assessment (patch testing and lymphocyte transformation testing [LTT]) lack robust clinical validation for either their diagnostic accuracy in symptomatic patients or their predictive value in patients prior to surgery.
• Although routine skin patch or in vitro LTT is not recommended, orthopaedic surgeons should discuss these issues with concerned patients and should consider alternative materials if test results indicate high reactivity.

References

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