As reviewed above, three main types of tissue responses have been suggested in ARMD, and these may further overlap. Periprosthetic tissues show inflammatory changes, such as swelling, presence of macrophages, T-lymphocytes and necrosis, in different proportions (Grammatopoulos et al. 2013, Berstock et al. 2014). Other findings include occasional B-lymphocytes, plasma cells, neutrophils, granulomas and germinal centers (Natu et al. 2012, Grammatopoulos et al. 2013, Hasegawa et al. 2016). These different microscopic, tissue-level findings reveal important indirect information about the underlying pathological processes. It is for this reason that the histopathological analysis of tissues related to failed MoM hip replacements is important. (Athanasou 2016). Another, less commonly used method for evaluating the cellular response is flow-cytometry. This method uses specific cellular antigens to detect the exact amounts of different inflammatory cells and their subgroups present in a tissue sample (Brown and Wittwer 2000).
The most commonly scored histological features are the presence and extent of macrophages, lymphocytes and necrosis (Campbell et al. 2018b). Macrophages are considered a key component of the innate, non-specific response to foreign material. Lymphocytes, on the other hand, form the cellular basis of the adaptive immune response, which is antigen-specific and has an immunological memory.
(Athanasou 2016). Necrosis may be the result of the direct cytotoxic effects of metal wear but may also be due to lymphocytic inflammation (Mahendra et al.
2009, Campbell et al. 2010, Langton et al. 2011b). Innate and adaptive immunological responses are not exclusive. The adaptive response may then be provoked if foreign material (metal debris) is presented by antigen-presenting cells and recognized as a specific antigen by sensitized lymphocytes. Macrophages help maintain inflammation by secreting cytokines that gather and affect lymphocytes in many ways (Athanasou 2016). In regard to the ALVAL response, it has been suggested that the underlying mechanism is an adaptive, cell-mediated type IV response that leads to the accumulation of diffuse and perivascular lymphocytes (mainly T-lymphocytes), inflammation and necrosis of the periprosthetic tissues (Davies et al. 2005, Willert et al. 2005). It has been postulated that metal ions may
form complexes with host-proteins which would change their conjugation, be recognized as foreign antigens and lead to activation of the adaptive immunological cascade (Athanasou 2016, Eltit et al. 2019).
Histopathological findings may be further combined with clinical and retrieval information, such as implant wear, gender and time from primary operation to revision surgery, to better understand the underlying pathogeneses and their variations in individuals (Campbell et al. 2018b). Since ARMD is considered a consequence of wear debris, many studies have focused on the associations between metal wear burden and histopathological findings (Table 5) (Langton et al.
2010, Takamura et al. 2014). Some studies have directly measured wear from retrieved implants, and some have used indirect methods, such as blood/synovial metal ion concentrations or periprosthetic tissue metal concentration (Table 5). As becomes evident from the table, the results of these studies have been discrepant.
In a central study in 2010, Campbell et al. showed that the ALVAL response was associated with low implant wear. Conversely, a macrophage-dominant response was seen with high implant wear. This formed a basis for a hypothesis that the ALVAL response is due to hypersensitivity to metal debris and does not therefore require abnormal amounts of metal debris to be provoked (Campbell et al. 2010). This hypothesis has been supported by the majority of the research;
however, opposing results have also been published (Table 5). On a group-level, associations between metal wear burden and type of tissue response have mostly been weak. In some studies in which group-level associations were not found between metal wear burden and lymphocytes, the authors noted that a subset of patients presented features of ALVAL responses and had low wear, supporting the original hypothesis (Grammatopoulos et al. 2013, 2017a).
Campbell et al. suggested that high amounts of metal wear lead to a foreign-body, macrophage-dominated innate response (Campbell et al. 2010). Many of the studies have supported this finding (Table 5). Grammatopoulos et al. further observed that high wear was associated with both macrophages and necrosis (Grammatopoulos et al. 2013). They proposed a cycle where metal particles cause direct cytotoxic effects to cells which undergo cell-death. This leads to the accumulation of macrophages to clear the cell debris and results in the macrophages also facing cell-death. This subsequently leads to the recruitment of more macrophages. The direct cytotoxic effects of metal particles have also been suggested by another study (Mahendra et al. 2009). However, it remains unclear whether the foreign-body macrophage-response without necrosis is a separate entity.
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Other etiopathological factors, such as particle size and origin, patient susceptibility and gender, have also been suggested. Metal debris from the taper-interface is potentially more immunogenic and cytotoxic than debris from the bearing surfaces (Langton et al. 2013a, Xia et al. 2017). Xia et al. reported that taper debris led to more severe necrosis and lymphocytic infiltration than bearing wear despite smaller amounts of metals being present in the tissues. Another often proposed factor is patient susceptibility. It has been suggested that individual reactivity to metal debris is variable (Grammatopoulos et al. 2013). The existence of individual patient susceptibility is widely accepted (Campbell et al. 2014). There is, however, no direct evidence to support this belief. Studies have been conducted regarding clinical testing for metal hypersensitivity, but no clinically useful tests have been found (Teo and Schalock 2016). Women have been observed to be at higher risk for failure at similar levels of blood metal ions compared to men (Langton et al. 2013b). Other researchers have published similar findings, as discussed earlier in Chapter 2.4.3. Langton et al. also noted that the ALVAL response was overrepresented in women. They suggested that when compared to men, women may be more prone to mount adaptive immune responses leading to ARMD.
The pathogenesis of ARMD is still poorly understood. Several different mechanisms have been proposed, but many of the studies regarding etiopathogenesis have been in disagreement. Furthermore, the observed associations have mostly been relatively weak. In conclusion, there appears to be several different pathological entities which most often lead to ARMD in the presence of a high wearing implant. However, ARMD is also encountered in patients with low wearing implants, and the presence of an adaptive, lymphocytic ALVAL response in these patients is supported by the body of evidence. These responses often overlap and other, still unrecognized, responses may exist (Grammatopoulos et al. 2013, Berstock et al. 2014, Ricciardi et al. 2016)
Table 5. The reported associations between metal measurements and tissue responses in the
N Association between metal measurement & tissue response
wear Histology 25 Not associated Not associated Not associated Ebramzadeh et al.
2014 Linear wear Histology 119 High wear Low wear Not associated
Nawabi et al.
2014 Volumetric
wear Histology 94 - Low wear -
Campbell et al.
2018a Volumetric
wear Histology 165 High wear Not associated Not associated Lohmann et al.
Reito et al. 2015b Synovial fluid concentration s
Histology 163 Not associated High metal load High metal load Paukkeri et al.
Histology 38 Not associated Not associated Not associated
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3 AIMS
The purpose of this dissertation was to investigate the histopathological characteristics of ARMD, implant wear, clinical markers of implant wear, periprosthetic tissue metal ion levels, and to investigate the relationships between these characteristics in order to better understand the etiopathogenesis of ARMD.
The specific aims of the studies were to investigate:
Study I: Bearing wear and its association with histopathological findings in patients with failed ASR MoM hip resurfacings
Study II: The association between periprosthetic tissue metal ion levels, whole blood and synovial fluid metal ion levels and histopathological findings in patients with failed MoM hip replacements
Study III: The histopathological patterns and possible subgroups in ARMD Study IV: The role of host-specific factors in the pathogenesis of ARMD