Metal Hypersensitivity in Total Joint Arthroplasty: Molecular Immunopathogenesis, Diagnostic Controversies, and Prospects for Precision Medicine

Implant-related metal hypersensitivity (MH) after total joint arthroplasty (TJA) is an uncommon and diagnostically challenging complication in which antigen-specific T-cell responses may coexist with nonspecific inflammatory reactions to wear and corrosion products. This narrative review critically summarizes current evidence on the molecular immunopathogenesis, clinical presentation, diagnosis, and management of suspected MH, with particular emphasis on HLA-associated susceptibility and the 2023 European Academy of Allergy and Clinical Immunology (EAACI) mechanistic nomenclature. A structured search of PubMed, Scopus, and Web of Science was used to identify relevant clinical, immunological, and consensus literature. Metal sensitization is substantially more common than clinically relevant implant-associated hypersensitivity, and positive patch or lymphocyte transformation tests do not by themselves establish causality. Current evidence supports selective, clinically contextualized testing after exclusion of infection and mechanical causes; routine preoperative screening in patients without a suggestive history is not recommended. HLA class II associations and metal–peptide–MHC/T-cell receptor interactions provide a plausible molecular basis for interindividual susceptibility, but available genetic data remain insufficient for clinical risk stratification or implant selection. Future studies should integrate standardized phenotyping, quantitative metal exposure, histopathology, and molecular immune profiling before implementing precision arthroplasty.