Metal Hypersensitivity in Total Joint Arthroplasty
In this review article, the authors describe the current understanding of metal hypersensitivity, discuss diagnostic methodologies used to identify hypersensitivity reactions, and review current treatment approaches and alternatives.
Nima Eftekhary, MD; Nicholas Shepard, MD; Daniel Wiznia, MD; Richard Iorio, MD; William J. Long, MD, FRCSC; and Jonathan Vigdorchik, MD
The authors have no disclosures relevant to this article.
Metal hypersensitivity due to orthopaedic implants is highly debated and poorly understood. With a greater number of orthopaedic procedures being performed, there is increasing interest in exploring a possible link between metal hypersensitivity and implant functionality and survivorship.
This is especially true in total joint arthroplasties (TJA), which are among the most commonly performed orthopaedic procedures in the United States, with an expected 4 million surgeries annually by 2030.  As such, the number of complications – including aseptic loosening, pain of unknown etiology, and possible metal hypersensitivity – are also expected to increase. [2,3]
First described in the mid 1970s, implant-related hypersensitivity reactions have been reported in numerous case reports and cohort studies. [4-7] The prevalence of symptomatic metal hypersensitivity from metallic orthopaedic implants has been estimated at <0.1%, although the exact extent of the problem is difficult to define given its complicated presentation and diagnosis. 
Early attempts at investigating possible associations between hypersensitivity and implant failure found a prevalence of metal hypersensitivity of 10% in the general population, 25% in patients with well-functioning implants, and 60% in patients with poorly functioning implants.  However, a direct cause-and-effect relationship has not been well elucidated.
The discrepancy among patients who have metal hypersensitivity following implantation, those who become symptomatic, and those who are never sensitized is poorly understood and likely dependent on multiple factors, including type and corrosion potential of the metal implanted, pre-existing sensitivities or genetic dimorphisms, and duration of implantation.
The goals of this review are to:
- Describe the current understanding of metal hypersensitivity in orthopedics, with an emphasis on TJAs
- Discuss diagnostic methodologies used to identify hypersensitivity reactions
- Review current treatment approaches and alternatives
Basic Science and Metal Allergies
The overall prevalence of cutaneous metal allergy is high compared with hypersensitivity secondary to metallic orthopedic implants. In their most recent series,  the North American Contact Dermatitis Group (NACDG) noted that nickel is the most common allergen of those tested, with a prevalence of 20.1%. Other common allergens used in orthopaedic procedures include cobalt (7.4%) and methyl methacrylate (1.3%). 
There appears to be a slight gender-specific predilection for metal allergies in women. [3,11,12] A recent retrospective analysis by Caicedo et al  noted that 29% of women undergoing TJA had a self-reported history of metal allergy versus 4% of men. In vivo testing also confirmed a higher rate (49% vs 38%) and greater degree of metal hypersensitivity among females.  This is consistent with larger population-based studies that have noted a higher incidence of nickel allergy in females (20.4%) than in males (5.8%). 
Nickel, one the most common allergic sensitizers, is a significant component in stainless steel and cobalt chromium, accounting for 8.3% to 35% and less than 0.5% to 1% of each alloy, respectively. [14-16] These are high percentages compared with other metal alloys frequently used in orthopaedic implants. Titanium and oxinium, for example, contain no nickel or only trace amounts.  Cobalt chromium also contains significant amounts of cobalt (62% to 67%) and chromium (27% to 30%), both of which can illicit an immunologic response. [10,17,19]
Less frequently, non-metallic polymeric components in bone cement – such as methyl methacrylate, N,N-dimethyl-p-toluidine, and benzoyl peroxide – can produce similar hypersensitivity reactions. The exact composite responsible for the reaction is difficult to identify, however. [20-23]
Additional properties, such as corrosion potential, are also related to the production of reactive metal ions.  When introduced into a biologic system, all metals undergo varying degrees of corrosion. The resultant metal ions do not act as a sensitizer themselves, but may form complexes with native serum proteins that yield a reactive antigen. 
These implant degradation complexes are the primary stimulators in component-related metal hypersensitivity reactions. Unlike the classically described allergic reaction (type I hypersensitivity), which occurs immediately via an immunoglobulin E-mediated response to an innocuous antigen, the hallmark of metal hypersensitivity is a delayed type IV hypersensitivity reaction involving a cell-mediated response. 
A type IV cell-mediated mechanism triggers activation of T-lymphocytes that release inflammatory cytokines, including interferon- (IFN-, tumor necrosis factor- (TNF-, interleukin-1 (IL-1), and interleukin-2 (IL-2).  This pathway leads to a self-propagating series of macrophage and T-cell activation, with resultant tissue inflammation and degradation.
Compared with other cutaneous type IV hypersensitivity reactions, the exact mechanism of intra-articular antigen presentation remains unknown. Langerhans cells are the characteristic antigen presenters in the dermal layer, and they may be responsible for the cutaneous reactions involved with the metal ion complexes.
However, it is unclear which types of cells are the primary culprits that produce a systemic response leading to intra- and extra-articular manifestations in TJA patients. 
Symptoms and Initial Evaluation
Patients with metal hypersensitivity may present with a variety of signs and symptoms. The surgeon should be aware of the symptoms of a cutaneous metal allergy that a patient may mention prior to TJA, such as itching and eczematous dermatitis after contact with a metal pants button, wrist watch, or other jewelry. 
When evaluating metal hypersensitivity in a patient with a previous TJA, the surgeon should consider 2 main distinctions of signs and symptoms: cutaneous manifestations and those related to the implant and joint itself.
Nearly 40 years of case reports in the orthopaedic literature detail cutaneous reactions to stainless steel and cobalt chromium alloy implants;  reports of skin manifestations following arthroplasty can also be found in the dermatologic literature. The rash may be eczematous with erythematous papular lesions either on the knees, particularly laterally near the incision, or on the entire body. [27,28]
Most of these lesions respond to management with topical corticosteroids. However, a few case reports discuss patients with cutaneous lesions that are unremitting to topical steroid treatment and that required revision surgery with hypoallergenic implants. 
The more challenging symptoms to address are those attributed to the surgical site itself. For example, pain, swelling, and stiffness have been suggested as symptoms of metal hypersensitivity in total knee arthroplasty (TKA) patients. The presentation is often vague, and non-specific complaints are often encountered. [27,29] Panful synovitis and effusion can be observed on examination. It bears noting that this clinical picture is indistinguishable from a low-grade or indolent infection. 
Diagnosis of metal hypersensitivity is one of exclusion. Outside of dermatologic signs, the presenting features listed above are non-specific and can be present in a variety of pathologies. Initially, management is conservative while other possible causes of the patient’s symptoms are explored.  In TKA patients, common causes of pain include: [29,30]
- Mid-flexion instability
- Aseptic loosening
- Malrotation and patellar maltracking
Less-common causes include: [29,30]
- Complex regional pain syndrome
- Psychological disorders
- Crystalline arthropathy
- Patellar clunk
- Progression of disease in an unresurfaced patella
- Osteonecrosis of the patella
- Overstuffing of the patellofemoral compartment
Initial evaluation begins with a thorough history and physical exam. The workup should also include standard radiographs to assess for loosening, alignment, and component position and laboratory evaluation with inflammatory markers. Elevated inflammatory markers should be further investigated with arthrocentesis to include synovial white blood cell count with a differential, crystalline analysis, and cultures. [27,29,30]
Lachiewicz et al  suggest a second aspiration prior to any revision surgery, as the likelihood of indolent infection is much higher than that of metal hypersensitivity. This sample is incubated for 3 weeks to identify slow-growing or fastidious organisms.
If infection is ruled out, component position can next be assessed with CT scan to evaluate for malrotation, along with a bone scan to evaluate for aseptic loosening. If these studies are inconclusive, a workup for metal allergy can be considered.  However, residual pain TKA may have no identifiable cause in 10% to 15% of patients.  This bears noting when proceeding to special testing for metal hypersensitivity, as detailed below.
The 2 most commonly utilized tests for suspected metal hypersensitivity are cutaneous patch testing and lymphocyte transformation testing. 
Patch testing, which can be performed by a dermatologist routinely in the office, allows for the evaluation of a number of potentially offending agents. However, patch testing is wrought with disadvantages, including the subjective nature of the response to an antigen.
In addition, it is unclear if the cutaneous response to an allergen reflects the process occurring within the joint – the antigen presenting cell in a cutaneous reaction is the Langerhan’s cell, which is not present in the joint.
In patients with no documented or reported metal allergies (ie, no history of allergy to implant components), there is no indication for prophetic patch testing. The German Orthopaedic Society released an interdisciplinary statement in 2008 arguing against the use of prophetic patch test before performing arthroplasty.  One systematic review concluded that pre- or postoperative screening for metal hypersensitivity is not recommended due to a lack of predictive value of a positive or negative result. There may be evidence of a cutaneous reaction to the testing, but there is insufficient data to determine whether a positive test represents a true metal allergy. 
Although there are a variety of opinions on the matter, there is no convincing evidence for performing preoperative patch testing in patients with a reported metal allergy. One study found that a sensitivity to nickel or metal lacks the specificity to correlate hypersensitivity with implant materials. 
Although only 14% of the population is sensitive to patch testing for nickel, the percentage rises to 25% in patients with well-functioning implants and to 60% in patients with poorly functioning implants. No causal effect has been demonstrated, however. 
Another systematic review elaborated on this phenomenon, demonstrating that hypersensitivity testing was unable to discriminate between stable and failed arthroplasty and that the predictive value of hypersensitivity testing was not statistically proven.  Another study was unable to use hypersensitivity to predict implant status. 
One recent study of 127 patients (161 knees) who underwent TKA after cutaneous patch testing demonstrated that patients with a positive preoperative patch test did not have a higher rate of complications, reoperation, or revision compared with negative patch test controls. 
Lymphocyte Transformation Testing
In lymphocyte transformation testing, a patient’s peripheral blood lymphocytes and monocytes are challenged with a variety of metal salts including aluminum, cobalt, chromium, molybdenum, nickel, vanadium and zirconium.  A radioactive nucleotide (3H thymidine) is introduced, and its uptake is quantified after 6 days. [27,29] A proliferation of lymphocytes in response to presentation of an antigen indicates previous sensitization of the cells to that antigen. 
The lymphocyte transformation test is an alternative to cutaneous patch testing. It allows for testing of circulating lymphocytes and monocytes, which eliminates the confounder of Langerhan’s cells. This test is quantitative, and sensitivity may be high.
However, there are disadvantages to the lymphocyte transformation test: 
- It has not been convincingly validated.
- It is expensive to obtain.
- It may not be readily available at many institutions.
In addition, an enhanced lymphocytic proliferative response to an antigen does not necessarily imply disease. 
Certain groups have recommended against the lymphocyte transformation test, while others acknowledge the cost and limitation to mostly academic centers as barriers to its use. Perhaps more importantly, sensitivity and specificity of the test with regard to disease have not been established. These factors suggest that follow-up studies are needed to elucidate the value of this test. [35,36]
Despite the inability to predict implant status based on results on cutaneous patch testing or lymphocyte transformation test, researchers have found that the percentage of patients with a positive cutaneous patch test or lymphocyte transformation test is higher in patients who have undergone previous arthroplasty than in controls. The percentage seems to increase in patients with poorly functioning versus well-functioning arthroplasties.
One study  evaluated cutaneous patch testing and lymphocyte transformation testing in 100 patients with well-performing, symptom-free, cobalt chrome arthroplasties and 200 patients with symptoms (including pain, effusion, and loosening without evidence of malposition or infection). Among the patients with a well-functioning arthroplasty, 17% had increased reactivity to nickel; 36% of patients with poorly functioning arthroplasty had increased sensitivity.
The authors acknowledged, however, that it is not yet possible to establish causality with the positive test, and that the positive test may simply be a result of a poorly functioning implant. 
Another systematic review of 168 patients who had undergone a lymphocyte transformation test noted that the probability of a positive test was more than double in patients with a failed arthroplasty compared with a stable arthroplasty, but that between a stable and failed arthroplasty, the predictive value of a positive test was not proven. 
It bears repeating that a positive test in a patient with a poorly functioning arthroplasty does not imply causality.
Other Testing and Future Directions
Other tests can help reach the diagnosis of metal hypersensitivity:
- Cytokine assessment
- Histologic specimens
- Leukocyte migration inhibition test, which quantifies migration of cells in the presence of a sensitizing antigen by 1 of 4 tests 
One study suggests that a helper T-cell, type 2 (Th2) cytokine pattern can be used to identify a predisposition to development of an allergic reaction, while the presence of osteoclastogenic cytokines may be used to predict a negative outcome in patients with a painful arthroplasty.  However, the researchers conclude that use of cytokines as a prognostic indicator would require extensive testing for confirmation.
Some authors suggest the use of peri-implant histology, which evaluates tissue for diffuse or localized perivascular lymphocytic infiltrates (T-lymphocytic inflammation) as an indication of hypersensitivity. [35-37] Lymphocytes on a background of fibrous tissue are consistent with the type IV hypersensitivity reaction suspected to be responsible for metal hypersensitivity. 
Another review notes that in addition to a positive patch test, a typical T-lymphocyte rich immunohistopathology and healing of the inflammatory response after changing to an immunologically inert implant are required to establish a diagnosis of implant allergy.  However, the researchers conclude that due to the number of confounders present in these situations, even a healing response is not adequate evidence to prove the hypothesis that metal hypersensitivity was the cause for implant failure. 
Diagnostic accuracy in metal implant allergy still requires significant improvement, with the fundamental goal of distinguishing hypersensitivity from infection.  Because of the lack of clinical validation of cutaneous and in vitro testing, there is no protocol for metal sensitivity testing. Large-scale prospective studies are lacking, with many current recommendations in the literature being derived either from case reports or expert opinion.
In the next few years, biomarkers may be identified that link risk of implant failure to patients with metal allergy and allow for selection of an appropriate and safe implant for each patient. [35-37]
With regard to total hip arthroplasty, multiple hypoallergenic options exist, including systems with ceramic-on-ceramic and ceramic-on-polyethylene bearing surfaces. 
Hypoallergenic TKA implants can be grouped into 2 main categories: [40,41]
- Cobalt chrome implants that have been coated by a hypoallergenic material such as titanium nitride, zirconia nitride, or zirconium oxide
- Implants made from a material other than cobalt chrome
Coated cobalt chrome implants are either completely enveloped by the coating or have coating only on the articular surfaces. For example, the Columbus Knee System (Aesculap, Tuttlingen, Germany) is a cobalt chromium molybdenum alloy with multilayer coating consisting of chromium nitride and zirconium nitride.
The potential risk of exposure to metal surfaces exists if the coating is worn away or if non-coated regions of the implant are exposed to the patient’s immune system.  Ceramic femoral-sided components do not contain any metals and have demonstrated favorable short-term outcomes. [41-43] In addition, many systems have an all-polyethylene tibial component option. 
Although there is weak evidence to use hypoallergenic implants in patients who present with mild local skin reactions to nickel, cobalt, or chromium, some opinion leaders endorse these implants for patient who have demonstrated positive patch testing. It is currently unclear, however, if patients with known or suspected metal hypersensitivity should undergo patch testing or if these patients would benefit from a hypoallergenic implant as their primary implant, especially if they are known to have an allergy to a metal in the standard implant. [31, 39-41,44-48] Hypoallergenic implants should be considered for patients who have demonstrated severe cutaneous or systemic reactions to metals. [40,44,45,49]
Patients with an asymptomatic total joint who develop a positive skin patch test after being tested for another reason should not have their implants removed.  Patients should be worked up for a potential metal or cement allergy if they present with painful total joints within the first few months after implantation – but only after the workup has fully excluded osteolysis, infection, component malalignment, mid-flexion instability, inadequate sizing, and complex regional pain syndrome. [20,31,41,46,48] This workup may benefit from an allergy, rheumatology, or dermatology consult.  In addition, an arthroscopic biopsy may be considered for unclear cases.
Patients with findings indicative of a hypersensitivity reaction can then be offered a revision surgery, which would include explantation of implants and replantation of hypoallergenic implants. [27,31,39,45,46,48,50] In terms of component selection, many options are available.  Patients with a total knee failure from hypersensitivity who have undergone a revision with hypoallergenic implants have demonstrated satisfactory outcomes. [46,51-53] Similar improvement can be seen in patients with failed total hip replacements revised with hypoallergenic implants. 
It should be noted that several investigators doubt the existence of an allergic response to metal implants. They recommend against the use of hypoallergenic implants in patients who have metal allergies and against revising painful joints to hypoallergenic options. [33,55]
Currently, there are neither guidelines for addressing suspected or known metal allergy preoperatively nor evidence-based support for either preoperative testing or routine use of hypoallergenic implants.
Multiple diagnostic modalities are available for the workup of suspected metal hypersensitivity; however, the ability of these tests to diagnose disease and predict outcomes has not yet been elucidated. In addition, a variety of hypoallergenic implants exist, but no evidence-based guidelines for their use are available.
Further research is warranted to help understand the pathology, diagnosis, and treatment of metal hypersensitivity.
Nima Eftekhary, MD; Nicholas Shepard, MD; Daniel Wiznia, MD; Richard Iorio, MD; William J. Long, MD, FRCSC; and Jonathan Vigdorchik, MD, are from the Department of Orthopaedics at NYU Langone Health – Hospital for Joint Diseases, New York, New York.
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