Etiology and risk factors

Most risk factors for ARMD and related failure are similar to the risk factors for all-cause revision (of which most are due to ARMD). However, the different definitions of ARMD between studies makes the evaluation of the risk factors challenging. The reported risk factors for failure specifically related to ARMD and pseudotumor are listed in Table 3. ARMD can be understood as a complication arising from the generation of metal debris from the bearing surface or modular interface. The generation of metal debris leads to local tissue responses and typical clinical presentation (Mahendra et al. 2009, Langton et al. 2010, Haddad et al.

2011). ARMD, in its different forms, has been observed in patients with both high- and low-wearing prostheses (Campbell et al. 2010, Kwon et al. 2010, Langton et al.

2010, Ebramzadeh et al. 2011, Langton et al. 2011b, Matthies et al. 2012, Grammatopoulos et al. 2013, Ebramzadeh et al. 2014). Most failures appear to be related to excess wear, and it is therefore considered to be the most important cause of the development of ARMD (Langton et al. 2010, 2011a, 2011b, Matthies et al. 2011, Takamura et al. 2014). Moreover, high wear also results in high local concentrations of metal debris leading to cellular and immunological cascades, and ultimately manifesting clinically as ARMD (Athanasou 2016). However, ARMD has also been observed in patients with low implant wear. Sensitivity to metal debris, either type IV delayed adaptive immunity response or some other mechanism, has been suggested as a cause of ARMD in these patients (Campbell et al. 2010, Matthies et al. 2012, Park et al. 2018).

Metal ion levels in blood can be used to estimate the in vivo wear state of the implant and the need for revision surgery (De Smet et al. 2008, Langton et al.

2011b, Sidaginamale et al. 2013, Van Der Straeten et al. 2013). High metal ion levels are associated with higher risk for all-cause and ARMD revision when compared with low metal ion levels (Langton et al. 2010, Hart et al. 2011b, Langton et al. 2013b, Hart et al. 2014). However, there is no method for recognizing those who are at risk for revision despite low implant wear and low blood metal ion levels. Metal hypersensitivity mediated by type IV delayed response has been suggested as a cause, but there is no reliable test to predict the individual response to metal debris (Teo and Schalock 2016). It has been reported that women are at higher risk for ARMD and related failure (Glyn-Jones et al.

2009, Murray et al. 2012a, Langton et al. 2013b, Reito et al. 2013, Matharu et al.

2016). In addition, there is some evidence that metal hypersensitivity may be more frequent in women (Ebramzadeh et al. 2011) and previous exposure to metal ions from wearing jewelry has been suggested as a possible cause (Pandit et al. 2008a).

On the other hand, Langton et al. noted that ALVAL-type responses share many histological features with autoimmune diseases, such as rheumatoid arthritis, and these diseases are more frequent in women (Langton et al. 2013b). Thus, it could be that women are genetically more susceptible to ARMD. Patients with bilateral MoM hips have higher risk for failure due to ARMD compared with patients with unilateral MoM hips (Langton et al. 2016). Sensitization to metal debris caused by the first MoM hip was suggested by the authors. In addition to delayed-type hypersensitivity to metal debris, it is possible that the magnitude and type of host response, that is, patient susceptibility, is individually variable overall. This could lead to a difference in the thresholds of metal debris needed between patients to provoke an adverse reaction. Patient susceptibility has been suggested as a possible contributor to the development of ARMD in numerous previous studies (Campbell et al. 2010, Donell et al. 2010, Ebramzadeh et al. 2011, Hart et al. 2012a, Matthies et al. 2012, Ebramzadeh et al. 2014, Athanasou 2016, Langton et al.

2016), but no direct evidence to support this has been presented.

Other known risk factors for ARMD include those factors that affect the wear process of the prosthesis, and these factors can be divided into implant-specific factors and surgical factors. Hip resurfacings have a lower prevalence of ARMD than stemmed THA (Langton et al. 2011a, Reito et al. 2013). Wear debris from the trunnion-interface between the head and stem in THA was suggested by the authors as a contributor to the higher risk of failure due to ARMD. In addition to implant type, implant brand has also been shown to be associated with risk for failure due to ARMD (NJR 2017). The highest failure rates have been observed

54

with ASR XL and ASR resurfacing devices in data from both registries and clinical trials (Langton et al. 2011b, NJR 2017). It has been suggested that this high failure rate is due to the design of the ASR cups, that is, small arc of cover leading to edge loading and increased wear (Langton et al. 2011b). In some studies utilizing univariable analyses, a small head size in hip resurfacing patients has been identified as a risk factor for ARMD (Glyn-Jones et al. 2009, Ollivere et al. 2009, Langton et al. 2011b, Murray et al. 2012a, Reito et al. 2013), but in analyses controlling for gender, a similar association has not been found (Glyn-Jones et al.

2009, Murray et al. 2012a, Reito et al. 2013, Matharu et al. 2016). Thus, it is likely that the results of the univariable analyses are confounded by the fact that women have smaller components and that female gender is associated with higher risk for ARMD. Conversely, in THA, a large head size has been identified as an independent risk factor for ARMD (Reito et al. 2015a). It has been suggested that increments in head size lead to increases in the lever arm between the trunnion and the head and/or increased frictional torque in bearing, which may translate in to greater micromotion and subsequent wear at the trunnion. This could therefore serve to explain the risk associated with larger head sizes (Langton et al. 2012).

Surgical factors associated with increased risk for ARMD include malpositioning of the cup, namely excessive inclination and excessive or insufficient anteversion of the cup (De Haan et al. 2008, Langton et al. 2011b). Excessive inclination leads to increased bearing wear, which is considered to be the root cause of ARMD (Hart et al. 2013).

Table 3. The risk factors for revision specifically related to ARMD or pseudotumor in single-center cohorts in patients with metal-on-metal hip replacements.

Risk factor Study

Female gender Glyn-Jones et al. 2009, Murray et al. 2012b, Reito et

al. 2013

Acetabular component malpositioning De Haan et al. 2008, Grammatopoulos et al. 2010, Langton et al. 2011b

High component wear Kwon et al. 2010, Glyn-Jones et al. 2011

High blood metal ion levels Langton et al. 2010, 2013b

Bilateral hip replacement Langton et al. 2016

Total hip replacement (vs. hip resurfacing) Langton et al. 2011a

Large head-size in THA Reito et al. 2015a

Age < 40 Glyn-Jones et al. 2009