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Confirmation of Sexual Dimorphisms in Metal Hypersensitivity and Joint Pain Following Total Joint Arthroplasty: Commentary on an article by Marco S. Caicedo, PhD, et al. “Females with Unexplained Joint Pain Following Total Joint Arthroplasty Exhibit a Higher Rate and Severity of Hypersensitivity to Implant Metals Compared with Males. Implications of Sex-Based Bioreactivity Differences”

Schwarz, Edward M. PhD*

doi: 10.2106/JBJS.16.01496
Commentary and Perspective
Disclosures
Related Article

University of Rochester Medical Center, Rochester, New York

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Commentary

Complications following total joint arthroplasty (TJA) secondary to implant wear remain a limitation of this highly prevalent procedure. While investigators have made great strides in our understanding of the pathology resulting from chemically inert nonmetallic particles1, the nature of the host response to metal wear and ions is less clear2. Additionally, the broad spectrum of metallosis signs and symptoms remains enigmatic, particularly with respect to suspected sex differences, which are aligned with epidemiology demonstrating that females have higher rates of rheumatoid arthritis and osteoarthritis and undergo more TJAs compared with males3. Recent studies have also indicated that females are at increased risk of adverse local tissue reactions, aseptic loosening, and revision after primary metal-on-metal (MoM) hip resurfacing arthroplasty4. However, the underlying biological mechanisms responsible for these sexual dimorphisms remain unclear. While some of these effects might be explained by anatomical and biomechanical sex differences, it is also likely that inherent immunological reactions to implant debris exist. Thus, to better understand the etiology of metallosis following TJA, it is first necessary to confirm the anecdotal evidence of sex differences in the rate and severity of joint pain following TJA, and confirm that the increases observed among females are associated with a commensurate increase in the rate and severity of hypersensitivity to implant metals. To this end, Caicedo and colleagues completed a retrospective study to test the hypothesis that females referred for metal-sensitivity testing because of joint pain following TJA with no evidence of infection have a higher rate and greater level of sensitization to implant metals compared with their male counterparts, as determined with use of a blood test (metal-lymphocyte transformation test [metal-LTT]).

In this Level-III study, Caicedo et al. completed a retrospective analysis of the rate of metal sensitization (i.e., metal allergy) to cobalt, chromium, and/or nickel among 1,038 male subjects and 1,575 female subjects with unexplained joint pain following TJA who were referred for metal-sensitivity testing. Joint pain was determined according to the patients’ self-assessed pain using an established visual analog scale (VAS), scored from 0 to 10. The rate and severity of metal sensitivity were determined with use of the metal-LTT blood test, in which the percentage of TJA subjects within each group with a stimulation index (SI) of ≥4 (reactive) or ≥8 (highly reactive) to nickel (as NiCl2), cobalt (CoCl2), and/or chromium (CrCl2) was quantified.

The retrospective analysis revealed that a similar majority of males (62%) and females (56%) with joint pain following TJA were referred for metal-sensitivity testing within 2 years of surgery and that >75% were referred within 5 years of TJA. This is consistent with a hypersensitive host response, as the painful symptoms occurred earlier than may be expected for aseptic loosening. The authors also confirmed several sex differences. In terms of self-reported pain by VAS, the average severity level at the time of metal-sensitivity testing was significantly greater for females than for males (6.8 compared with 6.1; p < 0.0001). However, the clinical importance of this difference is questionable, and the authors acknowledge that this result needs to be confirmed with the use of more sensitive instruments, for example, the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index). In terms of metal sensitivity, the authors found that (1) females had a significantly greater rate of self-reported cutaneous metal allergy (e.g., to jewelry) prior to testing compared with males; (2) the overall rate of metal-LTT hypersensitivity was significantly greater among females (49% of females compared with only 38% of males); and (3) the degree of metal hypersensitivity was significantly higher among females than among males (median SI of 3.5 compared with 2.8).

Now that significant sexual dimorphism with respect to joint pain following TJA has been confirmed, there are 2 important limitations that need to be addressed. The first is causation. While the authors argue that the rate of metal sensitivity is positively correlated with pain in subjects who underwent TJA, they do not have direct evidence to substantiate this claim. More importantly, the question of whether there are biological interventions that can inhibit complications from metal hypersensitivity remains untested. While candidate therapies exist5, it is likely that basic science research to elucidate the molecular and cellular mechanisms responsible for metallosis is a prerequisite toward a clinical solution.

* On the Disclosure of Potential Conflicts of Interest form, which is provided with the online version of the article, the author noted funding support from the NIH and NIAMS (P30AR069655, P50AR054041, R01DE019902, and R01AR070613) relevant to the current work and checked “yes” to indicate that he had a relevant financial relationship in the biomedical arena outside the submitted work (http://links.lww.com/JBJS/C263).

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References

1. Gibon E, Córdova LA, Lu L, Lin TH, Yao Z, Hamadouche M, Goodman SB. The biological response to orthopedic implants for joint replacement. II: polyethylene, ceramics, PMMA, and the foreign body reaction. J Biomed Mater Res B Appl Biomater. 2016 . [Epub ahead of print].
2. Gibon E, Amanatullah DF, Loi F, Pajarinen J, Nabeshima A, Yao Z, Hamadouche M, Goodman SB. The biological response to orthopaedic implants for joint replacement: part I: metals. J Biomed Mater Res B Appl Biomater. 2016 . [Epub ahead of print].
3. Cram P, Lu X, Kaboli PJ, Vaughan-Sarrazin MS, Cai X, Wolf BR, Li Y. Clinical characteristics and outcomes of Medicare patients undergoing total hip arthroplasty, 1991-2008. JAMA. 2011 ;305(15):1560–7.
4. Haughom BD, Erickson BJ, Hellman MD, Jacobs JJ. Do complication rates differ by gender after metal-on-metal hip resurfacing arthroplasty? A systematic review. Clin Orthop Relat Res. 2015 ;473(8):2521–9.
5. Smith RL, Schwarz EM. Are biologic treatments a potential approach to wear- and corrosion-related problems? Clin Orthop Relat Res. 2014 ;472(12):3740–6.

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