Where Are We Now?
The development of abnormal soft-tissue lesions in the vicinity of the operated joints in some patients has called into question the use of metal-on-metal (MoM) bearings in THA. These pseudotumors had been noted early on in patients with older MoM implants , but their clinical importance in terms of causing persistent pain or more deleterious effects was only appreciated in the previous decade, when use of MoM THA experienced a steep rise. Today, it is the leading reason why MoM THA has been all-but abandoned.
We still do not know what causes pseudotumors. While delayed (Type IV) T-lymphocyte-mediated metal hypersensitivity was initially suggested , more-recent immunohistologic and flow cytometric studies [6, 12, 14] suggested that metal debris may trigger a B-lymphocyte-dominated immunological reaction or exert a foreign-body, hypoxia-like, cytotoxic effect, with macrophages being heavily involved in the necrotic appearance of pseudotumor tissue. From a technical standpoint, hard-on-hard bearings are technically more demanding and less forgiving. Edge loading caused by malpositioning of the acetabular component is not well tolerated, increasing the amount of metal debris generated, and edge loading has been implicated in pseudotumor formation. However, pseudotumors have been noted in well-positioned cups and painless hips, and with a prevalence similar to that of patients with painful MoM THAs .
Such perplexing findings have led some investigators to theorize there may be an element of individual susceptibility that contributes, over and above anything else, to some patients reacting unfavorably to metal debris . Research on the subject of genetically defined individual susceptibility to pseudotumor formation after MoM THA is not available to date ; the current study by Kilb and colleagues is the first ever of which I am aware that explores this subject.
Where Do We Need to Go?
Given the favorable wear characteristics of MoM bearings in the laboratory, but also the technical difficulties of hip resurfacing for the average surgeon , it seems logical to me to continue offering stemmed, large-diameter, MoM THA to younger, active patients. To do this safely, there is an absolute need to develop preventative measures that will reduce the incidence of pseudotumor formation. Although regular postoperative followup after MoM THA is strongly recommended [1, 10], this is less than satisfactory since it allows for early detection of pseudotumors but does nothing to diminish their formation. Ideally, physicians would screen before surgery and confidently counsel a priori each patient whether he/she may be at risk for adverse reactions to metal, even with a well-implanted prosthesis. Current technology is limited in this regard: Skin patch and lymphocyte transformation testing are of little help, since Type IV, T-lymphocyte delayed hypersensitivity is not the dominant immune reaction in many patients .
Although Kilb and colleagues conducted their study on patients who already had surgery, its main value probably lies in the potential applicability of such testing as a preoperative tool. Similar “candidate gene approach studies” on the risk of loosening after metal-on-polyethylene THA have been published , and it appears that predictive testing using genetic material of patients, although still in its infancy, holds promise as a powerful preoperative screening tool for the future. Should this become a reality in the everyday clinical setting, it would be a breakthrough in the field of adult hip reconstructive surgery.
Kilb and colleagues did not examine the genotype of patients with asymptomatic pseudotumors, as the authors were concerned this phenotype represented a grey zone between their two distinct groups (symptomatic pseudotumor and no pseudotumor). There were also far fewer women in the control group (18% vs. 50%). Women have been reported to fare worse after MoM THA  and hip resurfacing  for anatomic, biomechanical and biological reasons [3, 9, 13]. Although sex has been statistically treated as an independent covariate in the present study, future studies with balanced sex distributions in the comparator groups are needed. Lastly, still unanswered remains the important question pertaining to the frequency of the examined alleles in patients of different racial origins, since the study population was composed of white patients.
How Do We Get There?
With 26 patients and 28 controls, the findings of the present study must be regarded as preliminary. Nevertheless, they indicate that further research in the field of predictive genetic testing of patients with MoM THA is worth undertaking in order to improve our understanding of the true influence of genetic predisposition to adverse reactions to metal debris.
A graduated approach to further research on this subject would require similar studies with larger numbers of patients as the best first step forward. To do this, collaborative work from centers having specialized in MoM THA in the past, is necessary. A larger sample size with an appropriate spectrum of participants will almost surely ameliorate any discrepancies in gender between case and control groups and will include patients of different races. Larger multicenter studies may even be statistically robust enough to enroll a third group, comprising patients with asymptomatic pseudotumors, for analysis.
As a second step, and provided present findings are substantiated, the possibility of using genetic markers prospectively might be considered. Of course, patient recruitment in a randomized controlled manner (that is, patients tested preoperatively vs. a group with no testing) would be ideal, but strong ethical concerns may arise with such a study design. Alternatively, and more easily, prospective studies, possibly of the investigational device exemption type, on patients undergoing MoM THA once their genetic profile has been preoperatively confirmed to be favorable for this type of implant, appear safer and more justified ethically. Followed over time, the incidence of pseudotumors in such cohorts can provide fairly reliable data that will enable researchers to validate this kind of prognostic/predictive testing by calculating traditional features such as sensitivity and specificity or by better defining its diagnostic accuracy using receiver-operating characteristic analysis .
In the event studies of those sorts deliver promising results, the pharmaceutical industry may wish to become involved to produce commercially available gene assays for easier clinical use. Similar studies to those described above would then be required for these kits, and cost-effectiveness analyses would predate widespread clinical use.
This study suggests genetic screening may someday facilitate everyday practice and prove beneficial to millions of patients who will undergo THA. An obvious obstacle to further progress in this area is the availability of genetic material from patients. It appears the time has come for national registries to start collecting not only clinical data, but genetic material, as well, from arthroplasty patients. Unpublished data from the Norwegian arthroplasty registry suggest this may be neither too difficult nor too costly to implement. I hope the world’s other registries will follow suit.
2. De Smet K, Calistri A. Hip resurfacing: Expectations and limitations. Acta Orthop. 2009;80:625–626.
3. Hallab N, Merritt K, Jacobs JJ. Metal sensitivity in patients with orthopaedic implants. J Bone Joint Surg Am. 2001;83A:428–436.
4. Hallab NJ. CORR
: Do patients with a failed metal-on-metal hip implant with a pseudotumor present differences in their peripheral blood lymphocyte subpopulations? Clin Orthop Relat Res. 2015;473:3915–3917.
5. Hart AJ, Satchithananda K, Liddle AD, Sabah SA, McRobbie D, Henckel J, Cobb JP, Skinner JA, Mitchell AW. Pseudotumors in association with well-functioning metal-on-metal hip prostheses: A case-control study using three-dimensional computed tomography and magnetic resonance imaging. J Bone Joint Surg Am. 2012;94:317–325.
6. Hasegawa M, Iino T, Sudo A. Immune response in adverse reactions to metal debris following metal-on-metal total hip arthroplasty. BMC Musculoskelet Disord. 2016;17:221.
7. Jones DA, Lucas HK, O'Driscoll M, Price CH, Wibberley B. Cobalt toxicity after McKee hip arthroplasty. J Bone Joint Surg Br. 1975;57:289–296.
8. Kwon YM, Thomas P, Summer B, Pandit H, Taylor A, Beard D, Murray DW, Gill HS. Lymphocyte proliferation responses in patients with pseudotumors following metal-on-metal hip resurfacing arthroplasty. J Orthop Res. 2010;28:444–450.
9. Latteier MJ, Berend KR, Lombardi AV Jr., Ajluni AF, Seng BE, Adams JB. Gender is a significant factor for failure of metal-on-metal total hip arthroplasty. J Arthroplasty. 2011;26:19–23.
10. Lombardi AV Jr., Barrack RL, Berend KR, Cuckler JM, Jacobs JJ, Mont MA, Schmalzried TP. The Hip Society: Algorithmic approach to diagnosis and management of metal-on-metal arthroplasty. J Bone Joint Surg Br. 2012;94:14–18.
11. Matthies AK, Skinner JA, Osmani H, Henckel J, Hart AJ. Pseudotumors are common in well-positioned low-wearing metal-on-metal hips. Clin Orthop Relat Res. 2012;470:1895–1906.
12. Mittal S, Revell M, Barone F, Hardie DL, Matharu GS, Davenport AJ, Martin RA, Grant M, Mosselmans F, Pynsent P, Sumathi VP, Addison O, Revell PA, Buckley CD. Lymphoid aggregates that resemble tertiary lymphoid organs define a specific pathological subset in metal-on-metal hip replacements. PLoS One. 2013;8:e63470.
13. Murray DW, Grammatopoulos G, Gundle R, Gibbons CL, Whitwell D, Taylor A, Glyn-Jones S, Pandit HG, Ostlere S, Gill HS, Athanasou N, McLardy-Smith P. Hip resurfacing and pseudotumour. Hip Int. 2011;21:279–283.
14. Paukkeri EL, Korhonen R, Hamalainen M, Pesu M, Eskelinen A, Moilanen T, Moilanen E. The inflammatory phenotype in failed metal-on-metal hip arthroplasty correlates with blood metal concentrations. PLoS One. 2016;11:e0155121.
15. Stelmach P, Wedemeyer C, Fuest L, Kurscheid G, Gehrke T, Klenke S, Jager M, Kauther MD, Bachmann HS. The BCL2 -938C>A promoter polymorphism is associated with risk for and time to aseptic loosening of total hip arthroplasty. PLoS One. 2016;11:e0149528.
16. Willert HG, Buchhorn GH, Fayyazi A, Flury R, Windler M, Koster G, Lohmann CH. Metal-on-metal bearings and hypersensitivity in patients with artificial hip joints. A clinical and histomorphological study. J Bone Joint Surg Am. 2005;87:28–36.
17. Zou KH, O'Malley AJ, Mauri L. Receiver-operating characteristic analysis for evaluating diagnostic tests and predictive models. Circulation. 2007;115:654–657.