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

Abstract

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.

Additively manufactured Ti‐29Nb‐21Zr shows improved oxide polarization resistance versus Ti‐6Al‐4V in inflammatory simulating solution

“…Phagocytic cells are hypothesized to engage in inflammatory cell induced corrosion. Recent studies link patient genotype to aseptic lymphocyte‐dominated vasculitis association lesion (ALVAL) susceptibility 60 . Improving fatigue performance in additively manufactured titanium alloys (particularly in β alloys) remains an ongoing issue.…”

An interleukin-1 polymorphism additionally intensified by atopy as prognostic factor for aseptic non-mechanical complications in metal knee and hip arthroplasty

“…In addition, the role of delayed type hypersensitivity (DTH) to metals may be complicated by different interpretation of the term "DTH" by allergists and surgeons. Langton et al reported in 2022 that variation in HLA class II phenotype influences susceptibility to DTH following implantation of MoM CoCr hip prosthesis (36).…”

“…Langton et al. reported in 2022 that variation in HLA class II phenotype influences susceptibility to DTH following implantation of MoM CoCr hip prosthesis ( 36 ). Patients who underwent revision of their MoM hip prosthesis had: assessment of metal ion concentration in blood, serum, joint fluid; assessment of explanted joint for volumetric wear; evaluation of periimplant tissue samples; HLA genotyping from buccal samples.…”

Periarticular metal hypersensitivity complications of hip bearings containing cobalt–chromium

“…HLA sequencing showed that DQA1*02:01, DQB1*02:02 and DRB1*07:01 were significantly positive with ALVAL. Additionally, DQA1*02:01–DQB1*02:02 had the highest affinity binding to the N-terminal sequence of albumin, while DQA1*01:01–DQB1*05:01 exhibited the lowest binding affinity, which was found in patients without ALVAL in a high frequency ( 54 ). Another study showed that in patients with MoM bearings, CD86 and HLA-DR molecule expression on the surface of APCs is increased, strongly implying the presence of an immune response ( 55 ).…”

“…Although NTS is not the primary (or even secondary) binding site for Co 2+ , it still can in theory bind to Co 2+ if these are present at sufficiently high levels. Furthermore, patients with an HLA class II genotype that encodes a protein with peptide-binding grooves possessing greater affinity for the N-terminal sequence of HSA have a greater risk of developing delayed-type hypersensitivity ( 54 ). Therefore, although yet to be proven, cobalt–HSA complexes are considered to be potential immunogens which can elicit ALVAL ( 101 ).…”