Common Misconceptions Continue to Plague Implant-related Hypersensitivity Responses and Testing

The terms metal hypersensitivity and metal allergy have been used interchangeably to refer to metal delayed-type hypersensitivity (DTH) responses. DTH, or adaptive, immune responses differ dramatically from normal physiologic responses to metal debris.

A normal physiologic response to metal implant debris may be adverse (toxic and/or immunogenic) and increase in proportion to exposure. Everyone will have this normal innate immune response to varying degrees, but this is not true of metal hypersensitivity, which is a specific immune response that is relatively rare and will affect only some people. Despite a long history of hypersensitivity to metal debris in orthopaedics, common misconceptions exist.

Misconception: Metal hypersensitivity to implant devices is speculative science with no immunological mechanism known.

Reality: Although relatively rare, metal hypersensitivity to orthopaedic implant debris has been documented in more than 50 case studies and many group studies from multiple institutions for more than 25 years. Also, metal hypersensitivity has been established by many groups using animal models where lymphocyte cell proliferation/reactivity to a specific metal challenge has been well reported in hundreds of publications.

Total joint arthroplasty cohort studies indicate a strong correlation among metal exposure, performance of a metal-containing implant, and metal hypersensitivity. Not surprisingly, the highest reported rates of metal hypersensitivity are in symptomatic patients with high exposure to metal from metal-on-metal (MOM) implants, where the reported incidence has been as high as 76 percent to 100 percent. This tends to implicate metal exposure levels more than time in situ as a stimulus for hypersensitivity. Collectively, the reported high incidence rates of metal hypersensitivity in aseptic implant failures and hundreds of published articles in well-respected (PubMed-listed) journals regarding basic science and animal studies that demonstrated inducible metal hypersensitivity at clinically relevant levels of exposure strongly support a mechanistic link between metal exposure and metal hypersensitivity rates.

Misconception: As an orthopaedic surgeon, I don’t need to know about metal hypersensitivity because I can do little about it.

Reality: Cumulative evidence indicates that metal hypersensitivity is an important and fiduciary issue for orthopaedic surgeons. It can play a central role in preoperatively determining the type of implant material to use and how to assess implant performance to determine whether revision of a painful but well-fixed implant with little to no osteolysis is warranted.

Insufficient evidence exists to warrant comprehensive/detailed metal hypersensitivity assessment of all patients preoperatively. However, a history of metal allergy can be a critical determinant, and improved surgical results after diagnostic evaluation have been reported. Complete dismissal of this condition by orthopaedic surgeons is not recommended. Hypersensitivity testing is beneficial in some circumstances, such as a reported history of metal allergy, patient concern, patient-driven requests for MOM articulating surfaces, or aseptic pain/inflammation of an existing implant.

Misconception: Metal hypersensitivity responses are mediated by specific metals that act as typical antigens eliciting DTH, just like other antigens such as poison ivy.

Reality: Metal hypersensitivity responses are not reactions to metals themselves but reactions to altered serum proteins that bind to metal ions (haptens). Consequently, the altered serum proteins bound to metal ions “look” like foreign proteins to the immune system and, in addition to cell damage, can elicit a powerful DTH response that results in severe inflammatory responses.

Released metal ions from implants during wear and/or corrosion immediately complex with plasma proteins and interact both locally and systemically. Metal-altered self-protein complexes are processed by antigen-presenting cells that activate associated T cells, which initiates hypersensitivity responses (also commonly referred to as metal allergy). This is different than a food allergy/hypersensitivity response that is dominated by antibodies and can result in anaphylaxis reactions.

Misconception: There are no clinical data to support metal hypersensitivity as a cause of implant failure.

Reality: Well-established multicenter data over the past 30 years clearly demonstrate a cause-and-effect relationship between metal hypersensitivity reactions and implant failures.

Some implant failures have been linked directly to metal hypersensitivity responses in case studies and multicenter group studies. However, multiple reports of this phenomenon also have been tested with Koch’s postulate for causality, in which the stimulus is removed and the symptoms abate but return once the metal implant is reintroduced. This phenomenon of metal hypersensitivity as causative in poor implant performance in select patients has been well established over the past half-century.

Misconception: The importance of immune responses to implant debris is overblown and is not a concern for orthopaedic surgeons.

Reality: The most prominent reason for long-term arthroplasty failure is immune reactivity to implant debris (innate and adaptive). Because we are only beginning to understand the complexity of how and why immune reactivity occurs with implant debris at all, the importance of this issue will likely grow.

Normal untoward responses to metal debris are basically the same as those for polymeric implant debris. They induce normal innate immune responses (macrophage-mediated granulomas) to implant debris that are the most prominent cause/pathomechanism for long-term aseptic implant failure. The degree to which an individual’s specific adaptive immune response contributes to this innate immune reactivity is unclear. This is because implant failures attributed to hypersensitivity (lymphocyte) responses have been identified only in extreme cases, where peri-implant lymphocyte accumulation and activation have been identified histologically as aseptic, lymphocyte-dominated vasculitis-associated lesion, and where metal lymphocyte transformation testing (LTT) or patch testing has been conducted (e.g., in some early MOM failures). Currently, it is hypothesized that only 1 percent to 5 percent of aseptic failures are due to adaptive DTH immune responses.

Summary

Metal hypersensitivity to implant metals has been well established in the literature over the past 30 years. Advances in knowledge about innate and adaptive immune responses to implant debris point toward past underassessment of adaptive immune responses (DTH-type responses) to the long-term performance of orthopaedic implants. As our understanding grows, this area of diagnosis will likely become more incumbent upon orthopaedic surgeons, particularly as methods to counter these responses in a nonsurgical manner become more viable. Diagnostic testing such as the metal-LTT remains a diagnosis of exclusion. However, there are currently important limitations to the predictive utility of metal hypersensitivity testing without inclusion of patient history, symptomology, and physician assessment.

Nadim James Hallab, PhD, is a researcher in the Department of Orthopedic Surgery at Rush University Medical Center in Chicago.

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