Healio
Healio
August 01, 2007
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Orthopedic Metal Immune Hypersensitivity

Abstract

For many patients, the metals used in contemporary joint replacement surgery produce little or no reaction from the immune system. In a small but significant percentage of patients, however, a very rapid, T cell-mediated, allergic response may occur. If untreated, this reaction may ultimately lead to implant failure. Diagnosis may be complicated, and no effective treatments are available. Fortunately, alternative materials show great promise.

At a recent international knee surgery symposium, the attendees were polled to identify how many had observed an allergic reaction in their arthroplasty patients. The result was an unimpressive 11% positive response.1 At the same time, one prosthesis manufacturer that specialized in ceramic knee implants suggested that more than half of all total knee arthroplasty (TKA) revisions are because of hypersensitivity to the cobalt-chromium alloy used in the failed knee implants. The difference is substantial and initiated a controversy about biomaterial allergy.

Biomaterial hypersensitivity reactions involve a complex series of steps that elicit a T-lymphocyte cellular response to the antigen.2 This response is significantly different than the antibody response commonly seen in allergic reactions such as allergic rhinitis or hay fever. As implanted metals degrade (and all implanted metals degrade to some degree), the reaction products (ie, particulates, oxides, insoluble salts, and free metal ions) rapidly interact with host proteins in a process known as haptenization. The combination of protein and degradation product may become immunogenic, eliciting the hypersensitivity reaction. As expected, these reactions differ substantially from one material to another, but they also vary significantly among patients.

Metal Allergies

Nickel has long been identified as a cause of allergic dermatitis, with approximately 11% to 14% of patients in the United States and Canada demonstrating sensitivity.3 Anecdotally, nickel sensitivity seems to be more common in women and also in industrial areas, possibly indicating some form of sensitization. Cobalt sensitivity has been observed in approximately 1% to 2% of the same population, with a significant degree of cross-reactivity between the two metals.4

The first report of an allergic reaction to an orthopedic implant described an eczematous rash over a stainless steel fracture plate.5 Since then, numerous reports documented similar observations, with symptoms of discomfort, erythema, swelling, and skin changes in the general area of the implant.6 In addition, some patients report general malaise, fatigue, or weakness. The majority of reports involve implants manufactured from alloys containing nickel and cobalt.7

On the other hand, three orthopedic metals in particular appear to be nearly inert, both with regard to dermal and implant reactivity. Titanium has a low incidence of immune hypersensitivity, and the reported cases almost always described either alloys containing vanadium, a relatively high concentration of nickel contaminates, or both.8 Tantalum has been reported once as a cause of an allergic response,9 and zirconium has never been shown to induce immune reactions.

When the existence of immune hypersensitivity to implanted orthopedic materials is accepted, the surgeon must consider whether the problem is clinically significant. Certainly, the incidence of reactions to implanted metals approaching just 1% of the population does not match the 11% rate of dermal sensitivity, but several other factors must be considered.2 First, most patients who report metal allergies relate the manifestations to inexpensive jewelry. Second, implants such as fracture-fixation devices can be removed when no longer needed. For patients with fracture-fixation devices, the small risk of sensitivity is outweighed by the benefits of surgery. The risk must be considered seriously, however, in patients with a history of dermal sensitivity who are undergoing permanent placement of orthopedic implants such as arthroplasty components. The risk to these patients cannot yet be identified preoperatively in a reliable manner.

Detecting Metal Allergies

Skin testing is the conventional method of identifying material allergic hypersensitivities. Usually, the patient wears a small billet of metal against the skin for several days to 1 week, and the test result is positive if the area becomes erythematous (Figure 1). Skin testing as it is usually performed is unreliable for several reasons. One key issue is that skin is an excellent barrier, sealing the immune system from direct environmental contact. A better surface for allergy testing would be a mucous membrane such as the oral cavity,10 but placement and maintenance of test samples would be difficult, and they still would not have the same environment of proteins, cellular elements, and pH of a synovial cavity. The inability to implant test material on the joint surface has lead to the development of in vitro testing methods (Figure 1).11-13

Figure 1: Patient showing positive reaction for metal hypersensitivity to “skin test”

Figure 2: Reinforcement buttresses on the alumina ceramic femoral component

Figure 3: A zirconia ceramic femoral component (left) compared to an Oxinium implant

Figure 1: Patient showing positive reaction for metal hypersensitivity to “skin test”. Figure 2: Reinforcement buttresses on the alumina ceramic femoral component (Kyocera Inc.; Japan) compared to the conventional geometry of the Oxinium oxidized zirconium alloy femoral component on the left (Smith & Nephew, Memphis, Tenn). The Oxinium implant also has a textured finish that allows for better cement adhesion. Figure 3: A zirconia ceramic femoral component (left) compared to an Oxinium implant. Both show hypoallergenic properties.

Currently, there are several in vitro tests for metal sensitivity, based on leukocyte migration or proliferation.3 However, all have limited clinical application, and none are totally reliable. As a result, the issue of material hypersensitivity is most often addressed retrospectively, after the patient has developed symptoms of an immune response. These symptoms often resemble infection, with periincisional erythema, urticaria, effusion, and pain. However, if the infection work-up is negative, with the joint fluid showing few white cells, then the diagnosis is usually made by exclusion. This process is often a frustrating experience for both the surgeon and the patient.

Other than revision surgery and removal of the insulting materials, few treatment options exist. Allergy medications are ineffective because they prevent histamine release, not T cell responses. Low-dose corticosteroids may be used as an immune suppressive in making the diagnosis, but their numerous adverse effects make them inappropriate for long-term use. Other biomaterial options may make it possible for most patients with metal hypersensitivity to benefit from TKA.

Figure 4: A 56-year-old woman following TKA with a conventional cobalt-chrome femoral component

Figure 5A: The patient has subsequently undergone a primary replacement on the right knee

Figure 5B: Good results using an Oxinium femoral component

Figure 4: A 56-year-old woman following TKA with a conventional cobalt-chrome femoral component. Metal allergy testing was positive for cobalt-chrome alloy and negative for titanium. Sepsis work-up, including aspiration of the joint, was negative. Range of motion was limited to 80° flexion with a 10° flexion contracture. Figures 5A and 5B: Results for same patient following revision with all-poly tibial insert and ceramic femoral component. The patient has subsequently undergone a primary replacement on the right knee with equally good results using an Oxinium femoral component. (Figures 5A and 5B reprinted from Nasser S. Biology of Foreign Bodies: Tolerence, Osteolysis, and Allergy. In: Bellemans J, Ries MD, Victor JMK, eds. Total Knee Arthroplasty. Heidelberg, Germany; 2005: 343-352; Figures 55-8, 55-10B. Copyright © Springer Medizin Verlag Heidelberg 2005. Reprinted with kind permission of Springer Science and Business Media.)

Other Options

Ceramics, both alumina and zirconia, are among the least reactive biomaterials.14 Ceramic knee femoral components manufactured from both types of ceramic have been available for some time in Europe and Japan. Some designs are currently under evaluation by the US Food and Drug Administration and may soon be available in the United States. When combined with all polyethylene tibial and patellar components, metal can be totally eliminated from the knee replacement.

Some characteristics of ceramic implants limit their usefulness. Bioinert ceramics are brittle, and ceramic fractures can occur. As a result, the design and manufacture of ceramic implants often require compromises such as buttresses to support posterior condyles and gentle curves rather than sharp angles that can act as stress risers (Figure 2). In addition, ceramic femoral heads are substantially more expensive than those made of cobalt-chromium alloys.

Oxinium oxidized zirconium implants (Smith & Nephew; Memphis, Tenn) are an option for unicompartmental, patellofemoral, and TKA (Figure 3). Oxinium has a base of 97.5% zirconium/2.5% niobium that is surface oxidized to zirconia, forming a metal/ceramic composite. Oxidized zirconium has the hypoallergenic properties of ceramics15 without the adverse material properties and can cost less than ceramics. Preliminary studies show Oxinium particulate is as inert as zirconia and alumina ceramics. A recent clinical comparison of Oxinium femoral implants with alumina and zirconia ceramics implants showed no difference in immune response, including response in revision cases in which the Oxinium implants replaced ceramic components placed for reasons of metal allergy (Figures 4 and 5).15

Conclusion

Several studies show that immune hypersensitivity to implanted biomaterials is more common in patients with failed joint prostheses than in patients with stable implants.16-18 The obvious question is “do failing or loose implants stimulate the immune system to generate this response, or do some patients have a preexisting sensitivity that leads to implant failure?” If the first is the case, then it may soon be possible to modify the immune response by using medications or gene therapy, for example, to limit osteolysis and material hypersensitivity. It may also be possible in the near future to determine which materials are appropriate for the individual patient to avoid provoking the immune response. Such an integration of material science with immunology can only serve to improve total joint replacement surgery in the future.

References

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  14. Macchi F. Alumina ceramics in joint prostheses. J Bone Joint Surg Br. 2005; 87(supp 2):187-188.
  15. Nasser S, Mott MP, Wooley PH. A comparison of ceramic and oxinium total knee femoral components in patients with cobalt chrome hypersensitivity. Presented at: 74th Annual American Academy of Orthopaedic Surgeons Meeting; February 14-16, 2007; San Diego, Calif.
  16. Deutman R, Mulder TJ, Brian R, Nater JP. Metal sensitivity before and after total hip arthroplasty. J Bone Joint Surg Am. 1977; 59:862-865.
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  18. Merritt K, Rodrigo JJ. Immune response to synthetic materials sensitization of patients receiving orthopaedic implants. Clin Orthop Relat Res. 1996; 326:71-79.

Author

Dr Nasser is from the Departments of Orthopedic Surgery and Biomedical Engineering, Wayne State University School of Medicine, Detroit, Mich.

Dr Nasser is a consultant for Smith & Nephew.