Metal allergies and other reactions

When you hear the word “allergy” you might picture rapid and severe swelling of the face and throat from eating certain foods, or perhaps a bad skin rash or asthma. But there are other types of allergies, including Type IV, that have a delayed reaction. Metal allergies are typically Type IV allergies, with sensitisation beginning days after first exposure [1] in susceptible people and a time lag in the development of allergy after initial sensitisation [2]. Immediate-type allergies can also occur in response to metal but are not typical [3]. Allergy symptoms may include pain, swelling, decreased function and loosening of the implant. Sometimes an increase in systemic inflammatory cytokines from metal allergies causes other unusual symptoms remote from the surgical site, including pain in other joints, skin rash, fever and abdominal pain [4, 5].

Metal allergies are often overlooked as a potential cause of ongoing post-operative pain and stiffness and the topic is rarely discussed in the orthopaedic literature [6]. However, a recent large international study suggested that metal-related allergies can explain a proportion of ongoing problems after joint replacement and are potentially a significant contributor to implant failure [5]. Other inflammatory reactions can also be involved and are discussed below. In addition to joint replacements, metal is used in components such as screws, bolts and other fixings in a variety of joint surgeries including ACL reconstructions and fracture repair. Nonetheless, it’s important to note that having arthrofibrosis does not necessarily mean you have a metal allergy – this is only one of many potential causes of arthrofibrosis.

Allergy is an abnormal response by the body’s immune system to substances that are typically harmless for most people [7], and is one type of hypersensitivity response [1]. The terms “allergy” and “hypersensitivity” are used interchangeably, but “hypersensitivity” also includes autoimmune reactions [7]. The symptoms of both allergy and other hypersensitivity reactions can range from mild to very serious. The cause of these reactions is complex, but genetics is likely to play a key role [2, 8].

Nickel, cobalt, chromium and bone cement are the most likely to cause an allergic reaction but titanium, stainless steel and other materials are allergenic (create allergies) in some people with orthopaedic implants [6, 9].

Orthopaedic implants are often made of cobalt-chromium alloys, stainless steel (alloy), titanium alloys and zirconia [10]. Since almost all metallic components in implants are alloys (a mix of two or more metals) [5] it can be difficult to know what specific metals you’re exposed to. Individual metals can be allergenic even when they are part of an alloy [2] and it’s also common for people with allergies to react to more than one metal [4]. Titanium was once thought to be hypoallergenic (non-reactive) but titanium allergies are increasingly recognised, and may involve oxidative stress creating an inflammatory reaction in exposed tissues [5]. Around one-third of metal implants used in orthopaedic surgery contain some titanium [5].

Proposed investigation pathway from Chen and Kurmis 2024 [2]. See “Tests” below for more information. PJI is infection.

Mechanisms. Metal allergies and other inflammatory reactions can create problems after any surgery where foreign material remains in the body, including cardiac (heart) components, pacemakers and gastric and spinal stimulators [6]. In the case of orthopaedic surgery, joint prostheses (replacements), plates, nails, bolts, screws and surgical clips or staples can stimulate an excessive immune reaction [6]. Since there are no naturally occurring metal structures in the human body [2], metal implants, and the particles released from them, trigger the body’s “foreign body response” with the immune system leaping into action to destroy or seal away the metal [11]. Myofibroblasts (cells that create fibrosis) produce scar tissue in order to seal the metal away and prevent the “invader” from spreading [11]. This occurs in people with a normal immune system and is usually self-limiting.

Corrosion, wear and immune attack on implants cause degradation and the release of metallic ions and particles into the body [9].

The body’s reaction to these depends on the size of the particles and the type of metal [11] as well as genetics. There may be a localised inflammatory reaction from the innate immune system that has similar symptoms to an allergy [4]. As well as pain, metal particles can stimulate fibrosis and pseudotumours [4], creating what is termed “adverse reactions to metal debris” [12]. Pseudotumours are non-cancerous lumps, and in joints and tendons they usually have a fibrotic capsule and can become calcified (form bone) [13]. Free metal ions (molecules) released from implants bind to proteins in the body and form complexes that trigger immune cell activation [14] and an increase in cytokine production [15]. The immune systems of people with a genetic predisposition become increasingly sensitised, resulting in an allergic response [2] driven by T cells and macrophages (types of immune cells) [2, 12].

In extreme cases, damaged metal prostheses release so much metal debris that it becomes toxic, killing cells and tissues [8]. This toxicity is caused by free radicals, disruption of cell membranes and inhibition of enzymes [3]. In 2010 DePuy issued a worldwide recall of its metal-on-metal hip prostheses following “catastrophic complications”, including necrosis (tissue death) from the large quantities of metal particles released [8]. The synovial membrane and soft tissue surrounding these metal-on-metal implants were often fibrotic, with areas of dead tissue and sometimes pseudotumours [16]. The design of hip prostheses has changed since 2010, however, metal-on-metal hip prostheses continue to be used in some young people, despite serious concerns [12].

Testing for metal allergy. Skin patch tests are the most frequently performed test for metal allergies but are a controversial method for diagnosing reactions to implants. In this test metal particles are placed in a patch and left in continuous contact with the skin for 2 days, then the reaction is visually assessed. However, skin patch tests rely on metal solubility and the metal passing into the skin. Titanium doesn’t pass into skin efficiently, and skin patch testing for titanium allergies is frequently negative even when the person has an allergy [5]. In addition, skin allergic responses are driven by specific types of immune cells that are not present inside joints [2], so skin tests may not reflect immune reactions inside a joint. A recent review of allergies to orthopaedic implants suggests that skin patch tests and patient-reported skin sensitivities are not reliable indicators of implant metal allergies [2]. Likewise, high levels of metals in blood are probably not a reliable indication of metal allergies, since many people will not have an allergic reaction, and for others even very small amounts can induce allergy [3]. These tests could be used in combination with other assessments [2], although skin patch testing carries the risk of creating metal sensitisation or aggravating an existing allergy [3].

The best currently available test for implant allergies involves analysing the response of immune cells after a challenge with metal particles [5]. This is performed in a blood sample. The lymphocyte transformation test (LTT) measures the proliferation of T cells after stimulation with specific metals and can be used for people with symptomatic implants as well as for pre-implant screening [5]. It has a diagnostic efficiency of 87% for diagnosing nickel allergy [3] and has been used for decades to test for delayed-type allergies [3] in response to medications and other substances. However, people who are on corticosteroids or other immunosuppressant medications at the time the blood sample was collected may have false-negative results [17]. A modified form of LTT, the Memory Lymphocyte Immuno-Stimulation Assay (MELISA), is used specifically to diagnose Type-IV allergies to metals and may be more sensitive [2]. However, LTT and MELISA are not able to detect non-allergic hypersensitivity [17] and local inflammatory reactions and MELISA may not be widely available [2].

After other causes of arthrofibrosis, especially infection, are ruled out, some specialists use genetic screening to determine if there is a particular susceptibility to metal allergies [2]. Specific HLA genotypes, including HLA-B27, HLA-DR43, HLA-DQB1 and HLA-DRB1, have been associated with poor outcomes and metal allergy from prostheses [8].

Treatment. As discussed, the presence of arthrofibrosis is not, by itself, an indication of metal allergy. Many other factors, including other medical conditions, genetic predisposition, cutting bone and fat pads and aggressive physiotherapy can lead to arthrofibrosis even in the absence of metal implants, and the diagnosis is a process of exclusion using testing and imaging. However, if you have stiffness and unexplained persistent pain after surgery, and metal implants in or near the affected joint, it may be worth testing for metal allergies after other causes like infection and fracture have been excluded. If your symptoms are severe and a metal allergy is diagnosed, removal and (in the case of a prosthesis) replacement with a coated hypoallergenic alternative may be considered [2].

MELISA Diagnostics offer testing for metal allergies, see https://www.melisa.org/. The IAA has no connection or association, financial or otherwise, with this company and does not benefit from it in any way.

References

1. Watanabe, M., Liu, L. & Ichikawa, T. Are Allergy-Induced Implant Failures Actually Hypersensitivity Reactions to Titanium? A Literature Review. Dent J (Basel) 11 (2023). https://doi.org/10.3390/dj11110263

2. Chen, A. & Kurmis, A. P. Understanding immune-mediated cobalt/chromium allergy to orthopaedic implants: a meta-synthetic review. Arthroplasty 6, 1 (2024). https://doi.org/10.1186/s42836-023-00227-x

3. Bjorklund, G., Dadar, M., Chirumbolo, S., Aaseth, J. & Peana, M. Metals, autoimmunity, and neuroendocrinology: Is there a connection? Environ Res 187, 109541 (2020). https://doi.org/10.1016/j.envres.2020.109541

4. Roach, K. & Roberts, J. A comprehensive summary of disease variants implicated in metal allergy. J Toxicol Environ Health B Crit Rev 25, 279-341 (2022). https://doi.org/10.1080/10937404.2022.2104981

5. Chen, A. & Kurmis, A. P. Understanding immune-mediated titanium allergy to in situ orthopaedic implants: a narrative review of the current literature. ANZ J Surg 94, 1925-1934 (2024). https://doi.org/10.1111/ans.19167

6. Pacheco, K. A. Allergy to Surgical Implants. Clin Rev Allergy Immunol 56, 72-85 (2019). https://doi.org/10.1007/s12016-018-8707-y

7. Jutel, M. et al. Nomenclature of allergic diseases and hypersensitivity reactions: Adapted to modern needs: An EAACI position paper. Allergy 78, 2851-2874 (2023). https://doi.org/10.1111/all.15889

8. Sheridan, G. A. et al. Identification of protective and 'at risk' HLA genotypes for the development of pseudotumours around metal-on-metal hip resurfacings. Bone Jt Open 4, 182-187 (2023). https://doi.org/10.1302/2633-1462.43.BJO-2023-0003.R1

9. Frigerio, E., Pigatto, P. D., Guzzi, G. & Altomare, G. Metal sensitivity in patients with orthopaedic implants: a prospective study. Contact Dermatitis 64, 273-279 (2011). https://doi.org/10.1111/j.1600-0536.2011.01886.x

10. Podzimek, S. et al. Metal hypersensitivity and pro-inflammatory cytokine production in patients with failed orthopedic implants: A case-control study. Clin Immunol 245, 109152 (2022). https://doi.org/10.1016/j.clim.2022.109152

11. Gibon, E. et al. Friend or foe? Inflammation and the foreign body response to orthopedic biomaterials. J Biomed Mater Res A 112, 1172-1187 (2024). https://doi.org/10.1002/jbm.a.37599

12. Davis, T. P. Metal-on-Metal Hip Arthroplasty: A Comprehensive Review of the Current Literature. Cureus 15, e48238 (2023). https://doi.org/10.7759/cureus.48238

13. Paramesparan, K., Shah, A. & Rennie, W. J. Guide to pseudotumours and soft tissue tumour mimics. Orthopaedics and Trauma 31, 204-215 (2017). https://doi.org/10.1016/j.mporth.2017.03.010

14. Hallab, N. J., Caicedo, M., Finnegan, A. & Jacobs, J. J. Th1 type lymphocyte reactivity to metals in patients with total hip arthroplasty. J Orthop Surg Res 3, 6 (2008). https://doi.org/10.1186/1749-799X-3-6

15. Grayson, W., Flanagan, S., House, H. & Brown, N. M. Impact of nickel allergy on total knee arthroplasty outcomes. Journal of Orthopaedic Reports (2025). https://doi.org/10.1016/j.jorep.2025.100640

16. Palmer, W. et al. Glossary of terms for musculoskeletal radiology. Skeletal Radiol 49, 1-33 (2020). https://doi.org/10.1007/s00256-020-03465-1

17. Glassner, A., Dubrall, D., Weinhold, L., Schmid, M. & Sachs, B. Lymphocyte transformation test for drug allergy detection: When does it work? Ann Allergy Asthma Immunol 129, 497-506 e493 (2022). https://doi.org/10.1016/j.anai.2022.06.014