Metal Release and Hypersensitivity in Total Joint Arthroplasty

While TKA largely has seen decades of successful outcomes, as clinicians we should focus on improving the number of patients who are satisfied after their TKA. Over the last two to three decades a focus on patient perceived outcomes has spotlighted that nearly 1 out of 5 patients may not be satisfied with their TKA result. About 15 years ago, dermatologists suggested that orthopaedic surgeons begin skin-patch testing (SPT) of patients before insertion of metal implants. It was then suggested that the patients with poorer outcomes could be suffering from a metal hypersensitivity reaction. Over the last two decades dermatologists have noted that nickel allergy in patients continues to climb when skin-patch testing results are compared over time. In North America, such sensitivity has been reported in over 18% of individuals. But several authors in this publication point out the inherent issues with relying on SPT when applied to the presence of an implant in deep tissue. (In 2011, along with Drs. Josh Jacobs and Stuart Goodman, we published a rebuttal to the first dermatology suggestion of SPT for all orthopaedic patients in AAOS Now (ref)). Today, there is still not enough data to suggest that this recommendation should be followed. In this issue of CeraNews, experts point out that SPT reactions rely on langerhan cells which are dendritic-derived cells, whereas deep-tissue reactions are driven by lymphocytes, monocytes, local cytokines, and antibodies. There also have been multiple reports where a SPT has converted after an implant was placed in a patient and cases where a patient with a nickel-positive SPT experienced a good clinical outcome after undergoing a primary TKA that had trace nickel in its alloy.
 
Many orthopaedic surgeons still consider metal hypersensitivity as a cause for pain and dissatisfaction after a TKA as a diagnosis of exclusion.  When a metal hypersensitivity reaction is suspected, surgeons should rule out all other common causes (i.e. infection, arthrofibrosis, suboptimal implant alignment) before going down the metal hypersensitivity pathway. Complaints of recurrent or constant effusion, continued pain, and never having a period of satisfaction  also are common symptoms of a septic low-level infection, which is why it is imperative that infection first be ruled out. In the U.S., we are limited in the tests that we can order. While a lymphocyte transformation test (LTT) is available in most laboratories, not all insurance companies will cover its cost and not all labs have consistent protocols, which makes it difficult to rely on some results. Dermatologists can perform a SPT, but these typically cost well over $1,000. Melisa tests are not readily available and genetic testing has not become available or approved in the USA. (As you will read in this issue, the test has had promising results and is being used in other countries.)  

Genetic testing is the newest diagnostic test on the scene, based mostly on the ALVAL determinants from our Metal on Metal (MoM) hip arthroplasty bearing surface experiences. ALVAL is now looking like a scenario that occurs more often in TKA revisions than previously thought, with up to 30% of TKA revision surgeries showing evidence of ALVAL. Taking into account the number of revisions in the first five years after primary TKA and then the fact that 30% of patients may show signs of ALVAL, this may represent a more true numerator of hypersensitivity reactions after TKA surgery. While a number of publications have shown improvements of metal hypersensitivity-diagnosed patients after undergoing revision TKA surgery with an alternative implant material (ceramic coatings, ceramicized metals, BIOLOX delta or Alumina implants), there also have been reports of patients who have not seen improvements after exchanging their implants for ones made of a nickel/cobalt chrome-free biomaterial.

Dr. Summer, from the Munich Implant Allergy group, reports in this edition that they advocate a multifaceted approach to diagnosis of implant hypersensitivity. Using SPT along with LTT results as well as IL1alpha and beta stimulation testing and genetic testing is beneficial. Their genetic testing focuses on identifying single nucleotide polymorphisms (SNP) of IL1RN. They think that by identifying these variants they can help predict which implants may be best on an individual basis. 
 
Dr. Caicedo, in this edition, discusses the fact that genetic testing is in its early stages. He says utilizing human leukocyte antigen (HLA) haplotypes in patients who had ALVAL reactions might help some patients, but that specific clinical outcomes based on these results may be challenging.

We performed a single nucleotide polymorphism study on 44 patients with symptomatic pain and high cobalt and chrome levels after MoM THA and could not find a correlation with any SNPs that were identified. (Mihalko et al ISTA 2015) There was a weak association with an SNP for IL-15 in some patients with high cobalt and chrome circulating blood levels, but it was found to not be consistent.
 

Other biomaterial by-products, however, also have been found in the synovial tissue at much higher rates in our repository study. Polymethylmethacrylate (PMMA) has been found in histology-prepared samples from this study group far more often than other metals (Figure 2).(ORS podium presentation 2025) 

A recent 2025 report on 50 nickel-allergy patients undergoing TKA found no correlation with poor outcomes and severity of nickel allergy (Chimento et al 2025). However, a recent meta-analysis that included eight articles and over 33,000 TKA patients found that metal-allergy patients had poorer reported outcomes (Soler et al 2024). Siljander et al just reported on 287 patients who had a self-reported nickel allergy and compared them with a large cohort of patients without a self-reported allergy and found no difference in revision rates or with outcomes (Siljander et al 2024). Clearly, the literature shows mixed results when it comes to nickel allergy and TKA outcomes.

While newer diagnostic tools, such as genetic testing, have been developed from what we learned during the MoM ALVAL reactions, a perfect correlation to TKA may not be evident. Also, the ALVAL reactions and circulating metal levels may not show a correlation with genetic testing. The Mayo Clinic in 2016 reported on 161 primary TKAs (127 patients, 56 SPT positive) after SPT compared them with a matched control group of 161 TKAs and found no difference in failures at 5 years or in outcomes. Clearly this study determined a positive SPT may not be consequential and revision may not always make a difference. I personally have seen patients in my practice with a painful and chronic effusion after a primary TKA with a diagnosis of exclusion and a positive SPT and LTT for nickel that had no improvement with revision surgery. Therefore, I inform patients that revision surgery cannot always be relied on for improved results.

While SPT, LTT, and lymphocyte proliferation testing have all been used for diagnosing metal allergy in TKA patients, there has not been a reported good correlation between these tests in the literature. (Dennis 2022, Malihias 2023) Careful assessment of genetic results should be taken into consideration. As has been explained above, a hypersensitivity reaction requires a pre-sensitized host. Previous exposure to the metal antigen triggers an initial immune cascade, and when re-exposed an exaggerated immunological reaction can occur. Sometimes it takes repeated exposure to an antigen before a true reaction occurs. Environmental and geographical location also have been shown to affect the patients’ sensitization to metals. Many reports in the literature have shown good outcomes after TKA in patients with self-reported or positive SPT, so there may not be a perfect correlation with a significant false positive rate of results. According to SPT results, metal sensitivity in the general population is approximately 18% nickel, 7% cobalt (cobalt chloride), 3% chromium (dichromate), and cross-reactivity between nickel and cobalt is thought to be common. That being said, I do not believe that surgeons feel that we are seeing 20% or higher rates of orthopaedic-implant patients with a metal hypersensitivity diagnosis. Clearly, the issue is more complicated and deep-tissue reactions may not be as prevalent. This brings up another issue with SPT because as mentioned above the metal byproducts utilized in SPT are not the same as those produced in the deep joint tissues from cobalt chrome or other orthopaedic implant alloys.

So local physiology combined with environmental exposure could be sensitizing patients after their TKA, which might cause local inflammatory response and a poor patient-reported outcome. We continue to follow these patients with high synovial fluid corrosion rates longitudinally to determine if there is a correlation with Knee Injury Osteoarthritis Outcome Score Joint Replacement (KOOSJR) scores. To date, the parameters found to correlate with outcome scores are higher volume of synovial fluid at the time of surgery and pH. 

There is clearly a void in that data we need to analyze to determine who truly has and who may develop a metal hypersensitivity reaction.  

I want to thank the authors for their expertise and reporting in this edition of CeraNews and their help in bringing a focus on this potential issue in TKA patients causing poor outcomes. I also want to acknowledge the ARCTIC study group for the insights reported above concerning metal release around TKA implants. I thank my collaborators in the Arthroplasty Retrieval and Cellular Tissue Investigation Consortium (ARCTIC) study group:

Steven Kurtz PhD, (Drexel University);
Michael Kurtz PhD (Drexel University);
Nicholas Piuzzi MD (Cleveland Clinic);
Jeremy Gilbert PhD (Clemson University);
Robin Pourzal PhD, (Rush University);
Deborah Hall PhD (Rush University).