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.

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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).
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