Adverse Reaction to Metal Debris in Patients with Metal-on-Metal Hip Replacements: Etiology & Pathogenesis

Third generation Metal-on-Metal (MoM) hip replacements were designed as a durable option, especially for young and active people. Traditional metal-on- polyethylene (MoP) would produce polyethylene wear and lead to osteolysis in these patients. Third generation MoM was introduced as a new, longer lasting bearing couple and high hopes were placed on it. Simulator studies showed encouragingly low rates of bearing wear. As a result, surgeons rapidly adopted MoM hip resurfacing and soon MoM total hip arthroplasty (THA) was introduced. However, evidence from clinical studies to support the use of MoM hip replacements was lacking.

More than one million MoM hip replacements were implanted during the early 2000s. First reports of emerging problems were published in 2006. These described periprosthetic soft-tissue lesions causing pain and implant failure leading to revision surgery. In 2007, the Australian Orthopaedic Association National Joint Registry Annual Report reported higher than expected revision rates for MoM hip resurfacings. Several more case series from hospitals were reported, and follow-up programs to identify patients in need of revision surgery were launched. The term Adverse Reaction to Metal Debris (ARMD) was created to describe the diverse findings seen in failed MoM hips.

Etiopathogenesis of ARMD has been of interest for more than a decade now but remains poorly understood. Failure is seen with both high and low wearing hip implants. High wear is, however, considered to be the primary cause of failure in most patients. Metal wear debris is thought to cause local soft tissue inflammation and necrosis in adjacent tissues. Mainly, three types of tissue responses have been suggested: lymphocytic type IV hypersensitivity mimicking response, which has also been termed Aseptic Lymphocyte-dominated Vasculitis-Associated Lesion (ALVAL). The two other types are foreign-body macrophage response and direct cytotoxic response from metal ions, leading to necrosis. Some evidence suggests that the foreign-body and cytotoxic responses are associated with high implant wear or blood metal ion levels, and the lymphocytic hypersensitivity/ALVAL response to low wear, but contradicting reports exist. Patient susceptibility has also been suggested as a major contributor to the development of soft tissue lesions and subsequent failure.

The aim of this dissertation is to investigate the etiology and pathogenesis of ARMD. In study I, we analyzed bearing wear, whole blood and synovial fluid metal ion levels in MoM hip resurfacings. We then investigated the possible associations of these with histological findings of the synovial tissue. In study II, metal concentrations in synovial tissue were determined and investigated in relation to histological findings, whole blood and synovial fluid metal ion levels. Hip resurfacings and total hip replacements were compared. In study III, we sought to find subtypes of ARMD using statistical cluster and latent class analyses for histological findings of synovial tissues. Imaging findings and metal ion levels were compared between the observed subtypes. In study IV, we aimed to investigate whether intrinsic, host-related factors affect the pathogenesis of ARMD in bilateral MoM hip replacement patients.

In study I, we found that bearing wear, WB and synovial fluid metal ion levels correlated with the degree of macrophage infiltration and necrosis. Further, WB and synovial fluid metal ion levels correlated with bearing wear volume and rate. In study II, we found that periprosthetic tissue metal concentrations were not associated with histological findings. Patients with MoM total hip arthroplasties evinced more necrosis and lymphocytes than did patients with hip resurfacings. In study III, four different subtypes of ARMD were identified. We found that ALVAL-type response is dualistic in nature – either wear-particle related or more of an immunological hypersensitivity response. Cytotoxic and foreign-body responses were also noted. In study IV, it was observed that bilateral patients evince similar histological and imaging findings on contralateral sides despite markedly different wear volumes between the sides.

Our results therefore suggest that ARMD is not one or two entities but four. Implant wear may lead to cytotoxic, foreign-body or wear-related ALVAL response. Some patients may also develop an ALVAL response in the presence of a low wearing hip replacement. Further, intrinsic host-related factors are likely central in the development of ARMD and may dictate the type of tissue response to a large degree. Extrinsic factors, such as wear volume, whole blood and synovial fluid metal ion levels, are associated with the degree of necrosis and the number of macrophages in the tissues. Periprosthetic tissue metal concentrations were not associated with histological features. Thus, the analysis of periprosthetic metal concentrations does not seem beneficial. As the literature regarding the associations between external factors and histological findings is very discrepant, intrinsic factors may be of more importance and lead to susceptibility to metal

debris. Also, taper debris in total hip arthroplasties is likely more immunogenic and/or cytotoxic compared with bearing wear debris. This finding has significance in terms of non-MoM (such as MoP, metal-on-polyethylene) total hip arthroplasties in addition to MoM total hip arthroplasties. In future, understanding why some patients are more susceptible than others and whether these patients can be identified is of great importance to properly allocate follow-up resources and to time revision surgery optimally.