Metal allergy: A clinical conundrum

More multicenter, randomized controlled trials are needed to validate metal hypersensitivity testing.

Modifiable patient factors, such as BMI, vitamin D levels and diabetes, can be optimized preoperatively to reduce the risk of infection and other postoperative complications. However, sometimes patient risk factors — and how to modify them — are not as clear cut.

One area of controversy in preoperative medical optimization is metal hypersensitivity, a delayed immune response thought to occur when a patient receives an orthopedic implant that contains a type of metal to which they are sensitive or allergic. In literature reports, about 10% of the general population were found to have metal hypersensitivity to nickel, cobalt, chromium or molybdenum, Leo A. Whiteside, MD, orthopedic surgeon at St. Luke’s Des Peres Hospital in St. Louis, told Orthopedics Today. After total knee replacement, he noted the incidence of metal hypersensitivity increases to 16% to 20%.

Diagnosis of metal hypersensitivity

Diagnosis of metal hypersensitivity can be challenging “because there is not much specificity to what has been generally considered symptoms of an allergic response to a metal implant,” according to Joshua J. Jacobs, MD, William A. Hark and Susanne G. Swift professor and chairman of the department of orthopedic surgery at Rush University Medical Center in Chicago.

Source: Susan M. Rapp, Orthopedics Today

In a review published in the Journal of Bone and Joint Surgery, Nima Eftekhary, MD, and colleagues noted that surgeons should be aware of cutaneous allergy symptoms to metal, which can include itching and eczematous dermatitis after contact with a wristwatch or other jewelry containing metal.

“In older literature, the classic manifestation of a hypersensitivity response to a metal implant is a rash that occurs following the implantation of the metal device,” Jacobs said.

Patients may also present with symptoms related to the joint itself, such as pain, swelling, stiffness and synovitis or an effusion. These symptoms can be more challenging to address as these can be related to a variety of pathologic conditions, according to Eftekhary and colleagues, which result in metal hypersensitivity being a diagnosis of exclusion.

Metal allergy is typically a cell-mediated delayed-type 4 hypersensitivity reaction. This can only occur if metal ions, which act as haptens, are sufficiently bioavailable to interact with the patient’s immune system, Jacobs said.

“Nickel, which is the most common allergen in orthopedic implants, is tied up in the metal alloy and would only be bioavailable in sufficient quanities if there is an aggressive wear or tribocorrosion process,” Jacobs told Orthopedics Today. “Furthermore, there is less than 1% nickel in the cobalt-alloy implants commonly used in joint replacement, making nickel allergy an unlikely phenomenon in the setting of total knee replacement, for example.”

David R. Lionberger, MD, orthopedic surgeon and assistant professor at Texas A&M University, said for patients to have a metal hypersensitive reaction to an implant, there needs to be a long enough time frame “to where it makes logical sense that byproducts of wear-stimulated [metal hypersensitivity] occur.”

“We would not assume a person who has a swollen, hot knee 1 month out to be caused from an allergic reaction,” Lionberger said.

When evaluating patients with persistent pain after joint replacement, Jacobs said surgeons should first rule out loosening, infection, instability, malrotation of components, extra-articular sources of pain (eg, lumbar radiculopathy) and chronic regional pain syndrome before considering the diagnosis of metal sensitivity.

“You certainly do not jump to metal sensitivity as the first reason that there is something wrong,” Lionberger said. “I think that is where it gets a black mark. It is not a big percentage out there. But, albeit, even though it is not a big percentage of the failures ... it ought to be something that comes to mind in a problem joint where nothing else can be found.”

Skin patch, lymphocyte testing

Once other diagnoses have been ruled out as possible causes, Lionberger said surgeons may want patients to undergo metal hypersensitivity testing, especially for women, who naturally have a higher risk of being sensitive to metal and patients who report having metal allergy and sensitivities. For patients undergoing shoulder surgery, Gerald R. Williams Jr., MD, the John M. Fenlin, MD, professor of shoulder and elbow surgery at the Kimmel Medical College, Thomas Jefferson University, and Rothman Orthopaedic Institute, said he has anyone who thinks they may be allergic to metal undergo metal hypersensitivity testing. The same goes for patients who have unexplained postoperative pain with an implant that otherwise looks normal.

“I am not routinely [testing] unless [patients] present to me with a strong history of allergies to metal materials,” Douglas A. Dennis, MD, of Colorado Joint Replacement and adjunct professor in the department of bioengineering at Denver University, said.

Currently, there are two main tests for metal hypersensitivity: a skin-patch test and the lymphocyte transformation test (LTT). Simple to perform and widely available, the skin-patch test (SPT) can be performed in the office by a dermatologist and allows for a number of potential offending agents to be assessed. It has been considered the gold standard of metal allergy testing with 83% of members of the American Contact Dermatitis Society and European Society of Contact Dermatitis who were surveyed reporting SPT as the diagnostic test of choice for metal hypersensitivity.

In contrast, there are literature reports that show many orthopedic surgeons see no relevant correlation between immunologic responses in and around the bone-implant interface and SPT, and instead prefer to use the LTT. A blood test that challenges peripheral blood lymphocytes and monocytes with a variety of metals, including aluminum, cobalt, chromium, molybdenum, nickel, vanadium and zirconium, the LTT is a quantitative test that eliminates the confounder of Langerhans cells, which are specific to the skin.

Testing caveats

Although both tests have shown promising results in the diagnosis of metal hypersensitivity, previously published studies have shown they also have disadvantages. The SPT has been found to be subjective and to produce false positives, Lionberger told Orthopedics Today. It is also unknown whether a skin reaction to certain metals translates to what may occur inside the body.

“A lot of the positive tests have been from skin-patch testing and the reactive cells that are present on the human skin are not present in the intra-articular environment of the knee,” said Dennis, who is an Orthopedics Today Editorial Board Member. “You may react on your skin, but you may not react with something that is inside your knee.”

Although it is more objective than the SPT, according to a review study by Teo and colleagues, the LTT is not standardized nor is it widely available for clinical use. It is reportedly more expensive, with sources citing costs for it that ranged from $400 to $2,000, and is not covered by insurance.

The LTT is also not validated. Therefore, sources said patients should be informed of the caveats associated with the test.

“I tell the patient that neither LTT nor patch testing is clinically validated. Further, these testing modalities have not been shown to be predictive of surgical outcomes. Even if the patient undergoes surgery with a so-called hypoallergenic implant, there is no guarantee they will not experience a hypersensitivity response to their implant,” Jacobs said.

Metal implant alternatives

According to Dennis, nickel is the “most commonly noted metal material to cause reactivity.” However, it is unknown how much nickel needs to be in an implant for patients to have a metal hypersensitive reaction.

“If we look at the femoral components that we put in, most of them have less than 1% nickel,” Dennis told Orthopedics Today. “One thing we do not know is, to react to anything, does it need to be 10% nickel? If it is 0.001% nickel, can it cause the same reaction?”

For patients identified as being sensitive to nickel prior to surgery, surgeons can reach out to implant manufacturers to see if they have a nickel-free implant, Williams said. However, he added not many companies have a nickel-free implant option.

In total shoulder replacement prostheses, titanium is the most common substitute for nickel, but it too has downsides, he said.

“The problem is that often the part that contains nickel is the bearing portion of the joint,” Williams told Orthopedics Today. “The reason we do not make the bearing surface out of titanium to begin with is because titanium is a relatively soft metal. It is not a good bearing surface; it has worse bearing characteristics.”

An alternative material that can be used in hip and knee replacement designs is Oxinium (Smith & Nephew) which uses oxidized zirconia instead of nickel. Dennis said Oxinium is nickel-free, but according to Lionberger, the tibial side of one of these knee components is non-coated titanium alloy with traces of other metals prone to free radical ionization on the synovial fluid.

“You are left with some titanium on the tibial side, which reduces or lessens the exposure of byproducts of wear, but it does not eliminate it,” Lionberger said.

Lionberger said Aesculap has developed an “advanced surface” technology made of cobalt ingot coated with ceramic that may reduce the potential for metal ion release. Despite its durable surface, Lionberger said the downside of the material is that the cobalt chrome used leads to a stiff stem that some surgeons may not find appealing.

Source: Sarah Cornelius, PA-C

“The stem is not made of more flexible titanium, but cobalt chrome instead. So, you have to counsel your patients that, yes, we will reduce your allergic load, but you may not like the implant because it is so stiff. As a result, you may experience stem pain from modulus mismatch,” he said.

Revision surgery

Despite a limited number of studies that have suggested good outcomes in patients who undergo revision surgery for metal hypersensitivity, Jacobs noted the sample sizes used are small, the studies are uncontrolled and retrospective, and they lack histologic confirmation that there was a tissue allergy present.

“Individuals can get better from revision surgery for a variety of reasons unrelated to metal allergy, such as the correction of subtle instabilities,” Jacobs said.

Although patients with metal hypersensitivity may benefit from revision surgery, Jacobs said to think twice before performing revision surgery for metal hypersensitivity because outcomes are unpredictable and there are real risks of postoperative complications, such as prosthetic joint infection.

“I consider revision surgery for a presumptive diagnosis of metal allergy as the last resort. It has to be undertaken after every other option has been exhausted and with the patient fully informed that the outcomes are unpredictable,” he said.

Surgeons have three options when it comes to performing revision surgery on patients with metal hypersensitivity, according to Williams.

“One is to rip everything out on a perfectly well-fixed shoulder which is a big deal and can cause a lot of problems,” he said. “You can ask the company to make a nickel-free implant in a custom way; or you can ask a different company to make a custom allergy-free implant [for that particular joint].”

Lionberger said surgeons should tell their patients the satisfaction rate will not be 100% and that it will not be an instantaneous fix.

“The figure on total knees that ... you do not have a reason for going in or revising except for the fact that they are not satisfied with them, those are running [a satisfaction rate of] about 60%,” Lionberger said.

He continued, “Our series of patients known to be sensitized to metal who have no other symptoms, such as infection, loosening or instability get about an 80% success rate, which speaks to the fact that the allergies do play a role in failed knees, albeit a small one.”

The LTT could potentially be used to select a revision implant that does not have alloying elements that the patient is sensitive to, Jacobs said.

If a surgeon is unwilling to perform the surgery, Whiteside said he or she likely will know another surgeon who may take on the case.

“Find out where you can get the implants that are made to address metal hypersensitivity and learn how to use them if you are willing to do [the surgery] or find somebody who will take them and is doing this referral work, because it is an entity,” Whiteside said. “I think you should know about it and have a plan.”

Take metal hypersensitivity seriously

Despite the controversies surrounding metal hypersensitivity from whether it should be tested for to whether it even exists, Williams stressed the fact that orthopedic surgeons need to take the diagnosis seriously.

“Everything is controversial about [metal hypersensitivity]. But, if you look at the literature and if you have been involved in joint replacement and have been willing to accept these patients and tried to treat them, you have to come to the realization that this is a real entity,” Whiteside said. “It is extremely important for some patients and we definitely need something that we can offer them.”

Due to the lack of multicentered randomized controlled trials that validate the different testing methods, sources told Orthopedics Today they would not recommend routine use of metal hypersensitivity testing.

“The studies that have [preoperatively tested for metal hypersensitivity] do not show any difference in outcomes of patients who are metal sensitive vs. not metal sensitive when you put that metal in with their total knee,” Whiteside said.

Williams contends that orthopedic surgeons should routinely ask patients about metal allergies, including if they are allergic to metals, if there are any types of jewelry they cannot wear and if they have any other joint replacements they have trouble with.

“If they have had a hip or knee replacement and it is perfect, they have no problems with it at all, it is exactly the same metal so the likelihood of them having hypersensitivity reaction to the metal with a perfectly functioning hip and knee is close to zero,” Williams said.

According to Dennis, research is needed to fully understand how metal hypersensitivity affects patients.

“There is more we do not know about implant hypersensitivity than we do know, in my opinion,” Dennis said. “I think we probably have inadequate tests to truly discern if it exists and what the true incidence is.” – by Casey Tingle

Editor’s note

This Cover Story is the second in a two-part series that focuses on optimizing patients for orthopedic surgery preoperatively to mitigate complications, poor outcomes and possibly avoid the need for revision surgery. In the December 2018 Orthopedics Today Cover Story, sources discussed co-management of such patient factors as obesity and albumin, testosterone and vitamin D levels. Click here to read part one of the series.

• References:
• Advanced surface technology. Available at: www.aesculapimplantsystems.com/products/orthopaedics/knee-arthroplasty/advanced-surface-technology. Accessed Dec. 6, 2018.
• Caicedo M. Metal hypersensitivity to TMJ implant materials. Available at: www.center4research.org/metal-hypersensitivity-tmj-implant-materials/. Accessed Dec. 10, 2018.
• Eftekhary N, et al. JBJS Rev. 2018;doi:10.2106/JBJS.RVW.17.00169.
• Oxinium. Available at: www.smith-nephew.com/key-products/orthopaedic-reconstr-uction/oxinium-oxidized-zirconium. Accessed Dec. 6, 2018.
• Teo WZW, et al. Dermatol Ther (Heidelb). 2017;doi:10.1007/s13555-016-0162-1.

• For more information:
• Douglas A. Dennis, MD, can be reached at 2535 S. Downing St., Suite 100, Denver, CO 80210; email: roseannjohnson@centura.org.
• Joshua J. Jacobs, MD, can be reached at 1611 W. Harrison St., Suite 201, Chicago, IL 60612; email: joshua.jacobs@rushortho.com.
• David R. Lionberger, MD, can be reached at 6560 Fannin St. #1016, Houston, TX 77030; email: dlionbergermd@gmail.com.
• Leo A. Whiteside, MD, can be reached at 1000 Des Peres Road, St. Louis, MO 63131; email: whiteside@whitesidebio.com.
• Gerald R. Williams Jr., MD, can be reached at 925 Chestnut St., 5th Fl., Philadelphia, PA 19107; email: richard.cushman@rothmanortho.com.

Disclosures: Jacobs reports he has stock options in Implant Protections and Hyalex; and his laboratory receives research funding from Zimmer Biomet, Medtronic and Nuvasive. Whiteside reports he is an employee of Signal Medical, receives research support from and stock options in Signal Medical Corp. and receives IP royalties from Smith & Nephew. Williams reports he is a designer of shoulder replacement products for DePuy Synthes and DJO. Dennis and Lionberger report no relevant financial disclosures.

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