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

Caicedo, Marco S. PhD1; Solver, Edward BS1; Coleman, Latasha BS1; Jacobs, Joshua J. MD2; Hallab, Nadim J. PhD1,2,a

Journal of Bone & Joint Surgery - American Volume: 19 April 2017 - Volume 99 - Issue 8 - p 621–628
doi: 10.2106/JBJS.16.00720
Scientific Articles

Background: Recent studies indicate that females demonstrate an increased risk of experiencing adverse local tissue reactions, aseptic loosening, and revision after primary metal-on-metal hip resurfacing arthroplasty compared with males; the underlying biological mechanisms responsible for sex discrepancies in implant failure remain unclear. In addition to anatomical and biomechanical sex differences, there may be inherent immunological disparities that predispose females to more aggressive adaptive immune reactivity to implant debris, i.e., metal sensitivity.

Methods: In this retrospective study, we analyzed sex-associated rates and levels of metal sensitization in 1,038 male and 1,575 female subjects with idiopathic joint pain following total joint arthroplasty (TJA) who were referred for in vitro metal-sensitivity testing.

Results: Females demonstrated a significantly higher rate and severity of metal sensitization compared with males. The median lymphocyte stimulation index (SI) among males was 2.8 (mean, 5.4; 95% confidence interval [CI], 4.9 to 6.0) compared with 3.5 (mean, 8.2; 95% CI, 7.4 to 9.0) among females (p < 0.05). Forty-nine percent of females had an SI of ≥4 (reactive) compared with 38% of males, and the implant-related level of pain was also significantly (p < 0.0001) higher among females (mean, 6.8; 95% CI, 6.6 to 6.9) compared with males (mean, 6.1; 95% CI, 6.0 to 6.3).

Conclusions: In a select group of patients who had joint pain following TJA and no evidence of infection and who were referred for metal-sensitivity testing, females exhibited a higher level of pain and demonstrated a higher rate and severity (as measured by lymphocyte SI) of metal sensitization compared with males.

Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

1Orthopedic Analysis, Chicago, Illinois

2Departments of Orthopedic Surgery (J.J.J. and N.J.H.) and Immunology (N.J.H.), Rush University Medical Center, Chicago, Illinois

E-mail address for N.J. Hallab: nhallab@rush.edu

Article Outline

More total hip arthroplasties (THAs) are performed in female patients than in male patients1,2. This is not surprising given the higher rates of developmental dysplasia, rheumatoid arthritis, and osteoarthritis among females. The number of total joint arthroplasties (TJAs) performed yearly in the United States continues to rise (4 million per year by 2030)3, and commensurately, the number of implant failures as a result of aseptic loosening, infection, osteolysis, and pain of unknown etiology is also expected to increase4,5.

Previous studies indicated that sex discrepancies exist with respect to perioperative complications and implant failures6-15. Studies involving the use of the National Joint Registry for England and Wales found that women who undergo metal-on-metal THA have a higher rate of implant failure16-18. While acetabular and femoral head sizes accounted for some of these discrepancies, the Canadian Arthroplasty Society showed that sex differences exist regardless of head size19.

A more recent systematic review of complication rates by sex after metal-on-metal hip resurfacing arthroplasty found that women exhibit increased risk of experiencing adverse local tissue reactions (odds ratio [OR], 5.70), implant dislocation (OR, 3.04), aseptic loosening (OR, 3.18), and revision (OR, 2.50) after primary metal-on-metal hip resurfacing arthroplasty compared with males15. A separate study also found that the risk of aseptic revision after metal-on-metal and metal-on-polyethylene THA, including dislocation and periprosthetic fractures, was 32% higher among females than among males, while the risk of septic revision was only 17% higher4.

While these studies indicate that female patients may have a higher risk or failure rate, it remains unclear, aside from well-documented mechanical factors, what biological aspects may influence this discrepancy. There are several potential biological factors that have been previously described and attributed to aseptic implant failures20-25. Excessive innate and adaptive immune reactivity to implant debris26-31, aseptic lymphocyte-dominated vasculitis-associated lesions32, and metal toxicity33-35 are biological mechanisms that have been shown to influence aseptic implant failure rates. It is also well established that delayed-type hypersensitivity to metal can trigger excessive aseptic inflammatory responses around the bone-implant interface20,21,24,25,36-40, which may be responsible for a subgroup of patients undergoing revision for unexplained pain. This is also consistent with previous studies noting the prevalence of metal hypersensitivity in 10% of the general population, in 20% of people with well-performing implants, and in 60% of those with failing implants40.

Are more aggressive adaptive immune responses, such as metal sensitivity, a biological factor that contributes to the greater risk of aseptic implant failure among females compared with males? We hypothesized that, in a cohort of subjects referred for metal-sensitivity testing because of joint pain following TJA with no evidence of infection, females would demonstrate a higher rate and a higher level of sensitization to implant metals compared with their male counterparts as determined by a metal-lymphocyte transformation test (metal-LTT). We tested this hypothesis by retrospectively analyzing the rate of metal sensitization (i.e., metal allergy) to cobalt (Co), chromium (Cr), and/or nickel (Ni) in 1,038 male subjects and 1,575 female subjects with unexplained pain following TJA who were referred for metal-sensitivity testing.

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Materials and Methods

Subject Groups and Parameters

Blinded, de-identified data from a cohort of 2,613 patients who underwent TJA (knee and/or hip) and were tested for metal hypersensitivity using an in vitro LTT were approved for study by the Rush University institutional review board. The data were retrospectively analyzed. Male (n = 1,038) and female (n = 1,575) subjects who had pain following TJA and were referred for metal-sensitivity testing were compared for sex-specific statistical differences with respect to joint type (i.e., hip or knee); age at the time of testing; implant time in situ at the time of testing; self-reported history of metal allergy; self-reported history of drug allergy; and self-determined pain at the time of blood draw for LTT testing, assessed using a visual analog scale (VAS) scored from 0 to 10, which has been established as a general measure of inflammation-related pain41-44 (Table I). The male and female TJA groups were further subdivided as follows: no pain (controls), low pain (a score of 1 to 3 on a scale of 10), moderate pain (4 to 7), and high pain (8 to 10). The “no pain” control group consisted of age-matched control subjects who were tested prior to TJA implantation and had no reported history of metal allergy (n = 318).

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Sample Collection and LTT

Whole blood was collected by venipuncture from patients who had undergone TJA and were referred for metal-sensitivity testing from health-care facilities representative of 48 U.S. states. A specialized blood collection kit was used to ensure the quality of blood draw supplies and sample temperature stability during transport. All samples were transported to the testing facility by priority overnight status and processed within 24 hours of initial collection. Peripheral blood mononuclear cells (PBMCs) were collected from 30 mL of peripheral blood by Ficoll gradient separation. Collected PBMCs (white buffy coat) were washed in phosphate-buffered saline (PBS) solution and resuspended in RPMI-1640 medium with 10% autologous serum and cultured with soluble nickel (NiCl2), cobalt (CoCl2), and chromium (CrCl2) at 0.001 mM, 0.01 mM, and 0.1-mM concentrations in 5% CO2 and at 37°C for 6 days. At day 5 of culture, 3H-thymidine was added. At day 6, 3H-thymidine incorporation in unchallenged (control) and metal-treated PBMCs was analyzed using a beta scintillation counter. A stimulation index (SI) of reactivity was calculated by dividing scintillation counts per minute of metal-challenged cells by those of untreated controls. An SI of <2 was considered nonreactive, 2 to <4 was mildly reactive, 4 to <8 was reactive, and ≥8 was highly reactive.

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Rates and Levels of Sensitization

The rate of in vitro metal sensitivity in males versus females with TJA implants was compared by calculating the percentage of subjects in each group with an SI of ≥4 (reactive) or ≥8 (highly reactive) to NiCl2, CoCl2, and/or CrCl2 at any of the concentrations tested. The group mean of sensitization was calculated by obtaining the mean SI of the highest lymphocyte stimulation inducers (sensitizers) found for each individual.

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Statistical Analysis

D’Agostino-Pearson omnibus and Kolmogorov-Smirnov normality tests were performed to determine normality for each of the data sets. The data sets were determined not to be normally distributed. Male versus female groups were analyzed for significant differences with respect to joint type (knee or hip), age, implant time in situ, and self-reported pain score at the time of metal-sensitivity testing using a nonparametric Mann-Whitney test (2-tailed). Significant differences in the rates of males and females with LTT results of reactive (SI of ≥4) and highly reactive (SI of ≥8), including self-reported pain subgroups, were analyzed using a Z test for population proportions. The rates of self-reported metal allergy and LTT results were also analyzed for significance using a Z test for population proportions. Sex differences in LTT results were analyzed using a multiple-comparison, nonparametric Kruskal-Wallis test with a Dunn post-test comparing all pairs of groups. Groups were considered significantly different at the level of p < 0.05.

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We reviewed 2,613 TJA cases that were referred for metal-sensitivity testing because of recurrent idiopathic joint pain with no evidence of infection, implant malpositioning, or radiographically evident osteolysis. A higher number of female subjects (1,575 females compared with 1,038 males) were referred for testing. The rates of procedures were similar between males and females, with 22% of the male subjects and 21% of the female subjects having undergone THA and 78% of the male subjects and 79% of the female subjects having undergone total knee arthroplasty (Table I). The average implant time in situ at the time of testing was 2.8 years (95% confidence interval [CI], 2.6 to 3.0 years) for males, while a slightly higher average time of 3.2 years (95% CI, 3.0 to 3.4 years) was noted for females (p = 0.05). For the majority of both males (62%) and females (56%), the implant time in situ was <2 years, and in more than three-quarters of all cases, it was ≤5 years (Fig. 1). Twenty-nine percent (95% CI, 26% to 31%) of the female subjects self-reported a history of cutaneous metal allergy (i.e., jewelry or metal allergy) prior to testing compared with only 4% (95% CI, 2.0% to 5.0%) of the male subjects. Similarly, the female subjects had a higher rate of self-reported allergy to ≥1 medication, at 36% (95% CI, 33% to 38%), compared with only 15% (95% CI, 13% to 17%) for males (Table I). Both of these differences were significant (p < 0.05). In addition, the severity of self-reported joint pain at the time of testing was significantly higher among the females than among the males (p < 0.0001), where females had an average pain score of 6.8 (95% CI, 6.6 to 6.9) and males had an average score of 6.1 (95% CI, 6.0 to 6.3) on a scale of 0 to 10 (Table I).

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Metal Sensitivity Responses

While 49% (95% CI, 46% to 51%) of the females who were referred for metal-sensitivity testing were reactive (SI of ≥4) to Co+2, Cr+2, and/or Ni+2, only 38% (95% CI, 34% to 40%) of the males showed this level of reactivity (p < 0.05). When both groups were compared with their respective age-matched controls (no implant or history of metal allergy), there were marked differences in the rate of sensitivity. Only 14% (95% CI, 9% to 21%) of male controls demonstrated metal reactivity (SI of ≥4), while among females, the rate was higher, although not significantly so, at 21% (95% CI, 16% to 28%) (Fig. 2-A). To determine if sex differences exist in the rate of metal sensitivity on the basis of self-reported pain levels following TJA, the low-pain, moderate-pain, and high-pain subgroups were analyzed. The rate of females demonstrating reactivity (SI of ≥4) was significantly higher than that of males for each of the 3 pain levels analyzed (p < 0.05) (Fig. 2-B). Even when using a more stringent parameter of high metal reactivity (SI of ≥8), a higher rate of females than males demonstrated this level of sensitivity (25% [95% CI, 22% to 26%]) compared with only 16% [95% CI, 15% to 20%]) (Fig. 2-C). Similarly, there was a marked difference (p < 0.05) between the age-matched controls, with 4% of the males (95% CI, 2% to 9%) compared with 11% of the females (95% CI, 7% to 17%) demonstrating high metal reactivity. Higher rates of females than males also exhibited high reactivity according to the different pain levels (p < 0.05) (Fig. 2-D).

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Severity of Metal Sensitivity

To further test whether sex differences in metal sensitization exist among people with joint pain following TJA, we analyzed each person-specific lymphocyte SI of reactivity to cobalt, chromium, or nickel—whichever was highest—in males versus females with joint pain following TJA and in controls. Females not only exhibited a greater sensitivity as reported above but also demonstrated higher in vitro metal SI levels (i.e. level of reactivity) compared with males (Fig. 3-A). While the median SI among males (n = 1,038) tested for metal sensitivity was 2.8 (mean, 5.4; 95% CI, 4.9 to 6.0), the median SI among females (n = 1,575) was significantly higher at 3.5 (mean, 8.2; 95% CI, 7.4 to 9.0) (p < 0.05) (Fig. 3-B). Similarly, the severity of in vitro lymphocyte stimulation in the no-implant control group was significantly (p < 0.05) lower for both males and females, with a median SI of 1.34 (mean, 3.2; 95% CI, 1.7 to 4.6) and 1.36 (mean, 4.3; 95% CI, 2.2 to 6.4), respectively. There were marked significant differences between male and female subjects who underwent TJA compared with their respective no-implant control groups (p < 0.001) (Fig. 3-B). The SI levels for cobalt and chromium were higher for females, but because of high variability, only those for nickel differed significantly between males and females (p < 0.05).

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In Vitro Metal Sensitivity Compared with Self-Reported Metal Allergy

It was previously reported that females (preoperatively) demonstrate higher rates of cutaneous metal allergy45. To examine whether reporting biases manifest sex differences in rates of metal sensitivity in people with idiopathic joint pain following TJA, we compared rates of self-reported cutaneous metal sensitivity (e.g., jewelry, metal buttons, clasps, belt buckles, tattoos, deodorant, and wearable fitness trackers) with in vitro metal sensitivity results in males compared with females (Fig. 4). We found that 29% (95% CI, 26% to 31%) of females with joint pain following TJA reported a history of cutaneous metal allergy compared with only 4% (95% CI, 2.0% to 5.0%) of males (Fig. 4 and Table I). Interestingly, the rates of in vitro metal sensitivity were significantly higher than those of self-reported history for both males and females (p < 0.001); the rate of in vitro metal sensitivity to cobalt, chromium, and/or nickel (SI of ≥4) was 38% (95% CI, 34% to 40%) for males and 49% (95% CI, 46% to 51%) for females (Fig. 4). Thus, there was a nearly 10-fold difference for men compared with a <2-fold difference for women with respect to individual assessment based on history compared with LTT results.

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As determined by LTT, we found a higher rate and severity of metal sensitization to soluble nickel (NiCl2), cobalt (CoCl2), and/or chromium (CrCl2) among females compared with males with unexplained joint pain following TJA. This supports both our hypothesis and previous reports that females may have a higher risk of adverse responses to implant metals4,15,19. This higher rate and level of sensitization found among females also correlates with a higher mean self-reported pain score (females, 6.8; males, 6.1). However, a limitation of this study (self-determined pain assessment using a VAS, scored from 0 to 10)41-44 is that it lacked the specificity to determine the association between patient activity level and pain level. Future investigations with more detailed pain measures (e.g., WOMAC [Western Ontario and McMaster Universities Osteoarthritis Index]) may determine larger (clinically meaningful) sex-dependent differences in pain associated with lymphocyte reactivity. Although the female subjects had a slightly longer time in situ (mean of 3.2 compared with 2.8 years), regression analysis showed no significant correlation between implant time in situ and level of sensitization (SI) in male subjects (R2 = 0.0017) or female subjects (R2 = 0.018).

Females showed significantly higher (p < 0.05) rates of metal sensitivity regardless of pain intensity, and when using a more stringent threshold for metal sensitivity (SI of ≥8), the pain-level subgroups exhibited differences in the rates of metal sensitivity, with the rate of females being significantly higher than that of males (Fig. 2-D). These current findings are consistent with our previous study indicating that the prevalence of metal sensitivity is positively correlated with pain in subjects who have undergone TJA46.

Previous reports found that females exhibit higher rates of rheumatoid arthritis and osteoarthritis and increased risk of experiencing adverse local tissue reactions and aseptic loosening after metal-on-metal hip resurfacing arthroplasty15,16, which may have an adaptive immunological basis24,47. Supporting this contention, we found that females demonstrated a remarkable and significant increase in the in vitro SI of reactivity to metals when compared with males. Implant time in situ did not differ significantly between males and females (p = 0.05), and thus, this relative increase in metal reactivity is not likely related to time in situ. Females with unexplained joint paint following TJA not only had a higher rate of metal sensitivity but also exhibited a higher intensity of lymphocyte metal sensitization in vitro. Whether this was caused by intrinsic biological factors (i.e., hormonal milieu, overactive immune cell populations) or environmental exposure to metals (e.g., jewelry, cosmetics, metal implants) remains incompletely understood.

Previous investigations reported a higher frequency of self-reported cutaneous metal sensitivity among females and advocated that prostheses free of cobalt, chromium, or nickel could be used for so-called allergic individuals45. While this precaution may mitigate a pathogenic adaptive immune response, it would overlook sensitivity to other common implant metals (e.g., aluminum, titanium, zirconium, and niobium)46. We found that 29% of females reported having a history of cutaneous metal sensitivity compared with only 4% of males prior to in vitro testing. However, the actual rate of metal sensitivity according to metal-LTT results (SI of ≥4) was 49% for females and 38% for males. When a higher threshold of reactivity was used (SI of ≥8), the rate of metal sensitivity dropped to 25% for females and to 18% for males (Table I); however, it has been established that drug-induced LTTs with SI levels as low as 2 correlate with clinical symptoms (i.e., erythema multiforme, maculopapular exanthema, and anaphylaxis) in drug-allergic individuals48. Therefore, use of a self-reported history of cutaneous metal sensitivity for the diagnosis of metal allergy may grossly underestimate the adaptive immune responses to metal challenge in vivo. One limitation of this portion of the study was the reliance on the ability of a patient to recognize and self-report cutaneous allergic reactions to metals (jewelry, buckles, occupational exposure, etc.), which were not confirmed clinically (e.g., patch testing). However, the large number of patients included in this investigation partially mitigates this limitation.

These data have important implications to understanding what factors may influence any sex-based disparity in total joint replacement outcomes. While these results provide evidence that females referred for metal allergy testing have higher pain scores and a greater rate and severity of sensitization to implant metals (as measured by LTT), due to the retrospective nature of this study we cannot determine if these findings represent a preexisting condition prior to TJA, the responsiveness was induced after TJA, or a combination of both of these factors. Also, while unlikely, we cannot rule out that sex differences in sensitization may be due to sex differences in physician referral for testing. Another important limitation of the current study is the lack of more specific operative information (e.g., implant type and composition); due to the restrictions of using de-identified bulk data, more targeted prospective investigation is required to undertake more specific subgroup analysis of reactive (positive metal-sensitive) individuals versus clinical outcomes.

In summary, our data indicate that among those with unexplained joint pain following TJA referred for metal-sensitivity testing, females exhibited higher pain scores and a greater rate and severity of metal sensitization as determined by LTT compared with males. These findings may explain, at least in part, the sex disparity in the outcomes of certain TJA implant designs.

Investigation performed at Rush University Medical Center, Chicago, Illinois

A commentary by Edward M. Schwarz, PhD, is linked to the online version of this article at jbjs.org.

Disclosure: Funding for this study was provided by Orthopedic Analysis; three of the authors (M.S.C., E.S., and L.C.) are employees. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work and “yes” to indicate that the author had other relationships or activities that could be perceived to influence, or have the potential to influence, what was written in this work (http://links.lww.com/JBJS/C258).

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