The influence of HLA genotype on the development of metal hypersensitivity following joint replacement

• Published in: Communications medicine Vol. 2; no. 1; p. 73
• Main Authors: Langton, David J., Bhalekar, Rohan M., Joyce, Thomas J., Rushton, Stephen P., Wainwright, Benjamin J., Nargol, Matthew E., Shyam, Nish, Lie, Benedicte A., Pabbruwe, Moreica B., Stewart, Alan J., Waller, Susan, Natu, Shonali, Ren, Renee, Hornick, Rachelle, Darlay, Rebecca, Su, Edwin P., Nargol, Antoni V. F.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.06.2022; Nature Portfolio
• Subjects: 45/23; 631/208/248/1512; 692/308/53/2423; 692/4023/1671/63; 692/699/1670/498; Medicine; Medicine & Public Health; Predictive markers; Bone; Genetic testing; Rheumatoid arthritis
• ISSN: 2730-664X; 2730-664X
• DOI: 10.1038/s43856-022-00137-0

Background Over five million joint replacements are performed across the world each year. Cobalt chrome (CoCr) components are used in most of these procedures. Some patients develop delayed-type hypersensitivity (DTH) responses to CoCr implants, resulting in tissue damage and revision surgery. DTH is unpredictable and genetic links have yet to be definitively established. Methods At a single site, we carried out an initial investigation to identify HLA alleles associated with development of DTH following metal-on-metal hip arthroplasty. We then recruited patients from other centres to train and validate an algorithm incorporating patient age, gender, HLA genotype, and blood metal concentrations to predict the development of DTH. Accuracy of the modelling was assessed using performance metrics including time-dependent receiver operator curves. Results Using next-generation sequencing, here we determine the HLA genotypes of 606 patients. 176 of these patients had experienced failure of their prostheses; the remaining 430 remain asymptomatic at a mean follow up of twelve years. We demonstrate that the development of DTH is associated with patient age, gender, the magnitude of metal exposure, and the presence of certain HLA class II alleles. We show that the predictive algorithm developed from this investigation performs to an accuracy suitable for clinical use, with weighted mean survival probability errors of 1.8% and 3.1% for pre-operative and post-operative models respectively. Conclusions The development of DTH following joint replacement appears to be determined by the interaction between implant wear and a patient’s genotype. The algorithm described in this paper may improve implant selection and help direct patient surveillance following surgery. Further consideration should be given towards understanding patient-specific responses to different biomaterials. Langton et al. identify HLA alleles associated with development of delayed-type hypersensitivity following hip arthroplasty. They train an algorithm to predict hypersensitivity which could improve implant selection and enable targeted patient surveillance following surgery. Plain language summary Millions of joint replacement surgeries are carried out across the world annually. In this surgery, the joint is replaced with an artificial implant. Most implants are made of cobalt chrome (CoCr). Some patients develop allergic responses to these implants, resulting in pain and tissue damage and repeat surgery. We identified patients who had developed allergies to their CoCr hip implants and compared their genes to those of patients who remained symptom-free. Having identified genes that increased the likelihood of a patient developing an allergic response, we invited additional patients to contribute samples for gene testing. Using the combined data, we used a computer algorithm to predict allergic responses based on a patient’s genes, age, and gender. The algorithm performed with sufficient accuracy to be usable in clinical practice to guide implant selection preoperatively and guide patient follow-up post-surgery.