Our results show that conformational change in the polyethylene bushing is strongly associated with large particulate polyethylene debris and a high prevalence of metal and polyethylene particles, confirming that conformational change in the bushing is due to loss of material, not just deformation. Of note, no difference was found between RA and non-RA patients in terms of the severity of device deformation, the composition or magnitude of wear debris, or the average pre-operative range of motion, suggesting that differences in the cellular and tissue reaction cannot be attributed to these factors. The only positive association with less conformational change and wear debris was having a primary TEA revised <4 years after implantation, regardless of underlying diagnosis.
We found an increase in the intensity of lymphocytic aggregates among untreated
RA patients, which correlated with the presence of metal and polyethylene particles. This suggests activation of the adaptive immune system in these patients. Analysis of the pattern of prosthetic wear revealed that the ulnar and humeral polyethylene bushings exhibited extensive wear and fragmentation, including metal particle formation related to unintended metal-on-metal wear. Previous studies reported the presence of an inflammatory cell infiltrate and multinucleated giant cells with regions of fibrosis and focal necrosis associated with extra- and intracellular metallic and polymeric particles within histiocytes [3
]. Only a minimal lymphocytic reaction was found in most cases, and no
difference in cellular characteristics was reported between patients with or without inflammatory arthritis. Our study suggests that while no increase occurred in the presence of lymphoplasmacytic infiltrates in patients with inflammatory arthritis, the degree of plasma cell infiltrates was significantly increased among those with diffuse lymphocytic aggregates.
The presence of plasma cells associated with metal wear debris is a characteristic histologic feature in patients undergoing revision surgery after metal-on-metal hip resurfacing [8
]. Diffuse aggregates of lymphocytes and plasma cells are associated with regions of tissue necrosis and extensive fibrin deposition. The reaction is thought to represent a hypersensitivity to the metal wear products. These findings differ substantially from those in our series and other TEA series [3
], and may represent a distinct clinical entity in a weight bearing joint. However, most of the patients on anti-TNF therapy in our study demonstrated a similar, high prevalence of plasma cells only in tissue sites with high metal debris, suggesting that metal debris may initiate the plasmacytic response. The presence of lymphocytic aggregates, however, was significantly associated with lower metal particle prevalence. This suggests that while metal might specifically bring about a plasmacytic response, polyethylene may be driving the broader lymphocytic response in these patients. Another possibility is that metal particles in the nanometer range, which have been previously described particularly in metal-on-metal implants and are not counted through visual identification, could cause an underestimation of the true metal particle burden and its contribution to a lymphocytic response [10
Fujishiro et al. recently reviewed a large series of patients undergoing revision surgery after total hip replacement for non-metal-on-metal implants [11
]. Their series was restricted to patients without known inflammatory arthritis, and included patients undergoing revision surgery for septic joints. They noted lymphocytic infiltrates in half of the patients with aseptic loosening, 62% of whom demonstrated a diffuse pattern of lymphocytic infiltration. They noted that the diffuse pattern was most commonly associated with regions of metal wear accumulation. Only 7% of aseptic cases had plasma cells associated with the lymphocytic aggregates. Their detection of plasma cells in a low number of non-RA patients is similar to our findings, and contrasts with the high prevalence of these cells in our RA patients.
Our findings confirm our earlier observations in RA patients undergoing revision surgery for failed total knee replacement [5
]. Although we detected the presence of lymphocytic infiltrates in the tissue from both RA and non-RA patients, the pattern of tissue distribution and extent of the infiltrates differed substantially between the two patient subsets. The infiltrates in non-RA patients were focal with predominantly perivascular localization and few plasma cells. In contrast, in RA patients the infiltrates exhibited both a perivascular and interstitial pattern of distribution and were often organized into sheet-like infiltrates with a high proportion of plasma cells. High polyethylene particle prevalence and large polyethylene particle size was associated with a high plasma cell prevalence within lymphocytic aggregates in RA patients. In contrast, no non-RA patients with many or large polyethylene particles in the peri-implant tissue had lymphocytic aggregates with a high plasma cell prevalence. The prevalence of plasma cells in treated
RA patients fell between these two groups, suggesting that the reduction in systemic and tissue inflammation associated with anti-TNF therapy results in attenuation of the pattern of cellular responses observed in RA patients.
Our results provide evidence that patients with RA exhibit a differential cellular reaction to inorganic metallic and polyethylene debris compared to patients without RA. The tissue reaction in the non-RA patients exhibited features of a non-immune granuloma. Lymphocytic infiltrates were scattered within the tissue and limited primarily to a perivascular location. In the untreated
RA patients, the presence of more generalized lymphocytic infiltrates containing abundant plasma cells are indicative of participation of cellular components of both the innate and adaptive immune system, a feature characteristic of an “immune granuloma.” These findings recapitulate the observations of Caplan and coworkers who described the presence of atypical pulmonary nodules in a series of coal miners [12
]. Histopathologic analysis of those nodules revealed the presence of immune granulomas with extensive lymphocytic infiltration with T and B cells. Importantly, these lesions were absent in miners without RA or in RA patients without exposure to coal dust, leading to the hypothesis that these findings reflected an aberrant immune response to the inorganic components of the coal dust in the RA patients.
The nature of the underlying immunologic mechanisms by which inorganic particles initiate an inflammatory reaction with cellular features of an immune granulomatous response remains speculative. Importantly, this reaction in both peri-implant tissues and “Caplan’s nodules” develops in the absence of articular cartilage. Cartilage matrix components have been implicated as potential immunogens in the pathogenesis of RA synovitis; our observations provide evidence that cartilage is not playing a role in the immune response [13
]. The association of anti-TNF therapy with diminished cellular features of the tissue reaction parallels its known effects in reducing inflammatory cell infiltrates in RA synovium [14
In addition, there was no difference in the presence of radiolucencies between patients treated and not treated with etanercept. While limited by a small sample size and the unavailability of three-dimensional imaging, these findings are consistent with other studies, which have not found anti-TNF medications to be protective against osteolysis [15
Our data show a trend towards the TEA lasting longer in RA patients compared with non-RA patients. This could be due to lower demands placed on the joint replacement by RA patients. However, treated RA patients show a length of implantation similar to non-RA patients and shorter than untreated RA patients. TNF users may have had better-controlled disease, enabling them to resume normal function with higher forces across the joint, accelerating prosthesis loosening.
Our study has limitations, including the small sample size and retrospective data collection. Data were collected cross-sectionally from the time of revision surgery, making it impossible to assign causation. Histopathologic analysis was also limited by the number of available slides. Etanercept was FDA approved in 1998. Patients with more severe RA operated on in the latter part of our cohort may have been more likely to receive a TNF inhibitor, a potential systematic bias. However, the fact that anti-TNF’s were not readily available until early 1999 prevented any confounding by indication for the first three years of our cohort.
In summary, we provide evidence that patients with RA exhibit a differential cellular response to prosthetic wear debris compared with non-RA patients, and that this reaction is mitigated by the use of anti-TNF inhibitors. The immune tissue reaction is similar to that observed in RA patients exposed to silica, another inorganic particle, and specifically consistent with earlier findings of Goldring et. al [5
]. Of note, this reaction develops in the absence of articular cartilage, which has been implicated in the immunopathogenesis of RA synovitis [13
]. These results provide evidence of a pathogenic activation of the adaptive immune response in RA and could have implications for the treatment of peri-implant osteolysis.