Background: Multidirectional Instability (MDI) and fibrosis associated with nickel allergies have been described in 1.5% of all primary total knees. The symptoms of MDI include pain getting up from the sitting position, audible clunking on varus and valgus stressing, feelings of instability in gait, increasing pain, and joint effusion. Hypoallergenic implants have been designed to alleviate this issue. One, the Genesis II primary knee replacement from Smith and Nephew contains very little nickel (<0.0035% for the zirconium femoral component and <0.1% for the titanium baseplate). We believe that, even with the small amount of nickel in the titanium baseplate, that it demonstrates all the findings that were seen with other implants in presentations of MDI and nickel allergies.

Methods: All patients referred with clinical MDI following a primary total knee joint with the Genesis II prosthesis underwent the Metal-Lymphocyte Transformation Test (metal-LTT) for metal allergies. Patients had symptomatology of MDI. They underwent routine labs including CBC, CRP, and ESR as well as staging studies including X-rays, tri-phase bone scan, WBC scan, and CT scan. Surgical revision using a fully constrained hinge coated with zirconium or niobium nitride was the treatment option.

Results: 20 patients with clinical symptoms of MDI associated with the Genesis II prosthesis were investigated. Fifteen patients were female, 5 were male with an average time to failure of 36 months (range of 5 to 96 months). Imaging revealed hypervascular synovitis, as demonstrated by the bone scan, with a large effusion with minimal prosthetic uptake.

Conclusion: Although the Genesis II prosthesis was believed to be hypoallergenic, we found that 20 of our patients with the Genesis II prosthesis and nickel allergies still had clinical symptoms of MDI. All patients required hinge revision with hypoallergenic implants.

•    Primary total knee arthroplasty
•    Knee revision
•    Metal allergy
•    Prosthetic failure

Kennard N, Mohammadi D, Srinivasaraghavan A, Mixon A, Maale GE (2021) Multidirectional Instability Following Primary Total Knees Associated With Zirconium Femurs and Titanium Tibial Baseplates in Patients with Nickel Allergies. Ann Orthop Rheumatol 8(1): 1095.

MDI: Multidirectional Instability, TKA: Total Knee Arthroplasty, WBC: White Blood Cell, CRP: C-Reactive Protein, PCR: Polymerase-Chain Reaction; LTT: Lymphocyte Transformation Testing; Zr-Ti: Zirconium; Distal Femoral Knee Prosthesis; Oxinium: Oxidized Zirconium; XR: X-Ray

The Total Knee Arthroplasty (TKA) is one of the most commonly performed orthopedic surgical procedures in the United States [1]. Increased life expectancy as well as increased prevalence of obesity has resulted in higher rates of osteoarthritis in the United States population today, the annual number of TKA’s is continuously rising [1,2]. For example, between 1999 and 2008, the number of TKA procedures increased 134% and current statistics show continued increase in need for primary total knees [2]. Unfortunately, more annual cases equate to more patients with associated problems related to the implant, such as arthrofibrosis, pain, and swelling leading to impairments with functional mobility [1]. Etiologies related to the problems with primary knee arthroplasties include infection, instability, increased wear and debris response, and aseptic loosening [3]. Additionally, some literature reports the phenomenon of Multidirectional Instability (MDI) as an etiology of knee implant failure [1,4]. MDI of the knee joint is a clinical syndrome involving increased laxity of the MCL (define) LCL, and cruciate deficiency leading to effusion and hyperemia around the joint. Clinical MDI following a primary TKA is characterized by increasing pain when standing from the seated position, audible clunking of the implant, feeling of instability during gait and opening of the joint after varus and valgus stress [4]. Physical exam demonstrates the degree of laxity with anterior and posterior drawer signs of the knee joint is directly related to the level of force applied during varus and valgus stress testing [4]. However, there now exists a growing body of literature finding a correlation between metal hypersensitivity with arthrofibrosis and problems associated with primary knee arthroplasties [5,6].

Additionally, current data suggests that between 1-15% [1] of the general population has metal allergies [5]. Of the metal allergic population, the most common sensitizer is nickel [7]. Metal hypersensitivity in patients with a primary knee arthroplasty present months to years after the TKA procedure via a delayedtype hypersensitivity reaction [5]. Symptoms associated with the hypersensitivity reaction include joint effusion, erythema, pain, and difficulty with mobility [5-7, quotes MDI]. The symptoms from metal hypersensitivity mimic infection on physical exam and with certain lab markers. Specifically, the physical exam can show grossly swollen knees with increased warmth and a cellulitic appearance, and lab work can demonstrate elevated White Blood Cell (WBC) count and C-reactive protein (CRP) [1]. Additionally, imaging studies like triple phase bone scans and WBC scans show abnormally increased uptake similar to what can be seen in infection [6,8,9]. However a couple factors differentiate the two etiologies [5-7]. In patients with a metal hypersensitivity, neither the joint aspirate nor blood sample culture, stain, or polymerasechain reaction (PCR) amplify any species of bacteria [5-7]. Also, Lymphocyte Transformation Testing (LTT), an in-vitro method for allergen sensitivity testing, will show a high sensitivity to specific metals in patients with a metal hypersensitivity [9].

Due to the increased awareness of metal hypersensitivity as a possible reason for TKA failure, biomedical companies are starting to produce ‘hypoallergenic’ metal implants (Table 1-2) [7,8]. Examples of the ‘hypo-allergenic’ metal implants include titanium, zirconium, and niobium-based implants [7,8]. Some of the ‘hypoallergenic’ implants still contain small amounts of nickel, and as a result, patients are failing after their primary TKA’s due to MDI when providers attempt to control for the known metal hypersensitivity [7,10]. For comparison, other non-hypoallergenic prostheses containing CrCoMo, such as those made by Zimmer, Biomet, Johnson & Johnson, and Stryker, have failure rates of 1.5% [1].

In this study, we aim to report a correlation between failed primary TKA’s associated with metal hypersensitivity reactions that mimic periprosthetic joint infections (PJI) in patients with the zirconium distal femoral knee prosthesis (Genesis II), which contain a small amount of nickel, approximately 0.0035% [11]. Furthermore, we propose a clinically-based diagnosis of MDI along with pain, as the main presenting symptoms for patients experiencing metal hypersensitivity reactions involving their TKA implant.

Study design and setting

This study was retrospective and case controlled. The 20 patients included in this study were referred between December 2015 and March 2020 with issues regarding their primary TKA with a specific implant, the Genesis II primary knee replacement from Smith and Nephew. This prosthesis is made of a titanium alloy and an oxidized zirconium alloy (Table 3-4).

These patients were subjected to a physical exam and extensive questioning regarding the timeline of their symptoms. The clinical syndrome of MDI presents as pain when getting up from a sitting position, audible clunking in the primary TKA when walking in full extension, effusion with hypertrophic synovium, feelings of instability during gait, and medial and lateral opening of the prosthetic joint upon varus and valgus stress. Primary TKA patients presenting with the clinical symptoms of MDI were evaluated with metal allergy testing along with routine labs (CBC, CRP, and ESR), and staging studies (X-ray, CT Scan, Triple Phase Bone Scan, and WBC Scan) in order to rule out prosthetic loosening and infection as the source of symptomatology.

The Metal-Lymphocyte Transformation Test is a proliferation assay. Proliferation of cells is measured by [3H]-thymidine incorporation into DNA in a 96-well microplate. The average for each treatment is normalized to that of the negative control (no treatment) producing a ratio, generally termed a proliferation factor/index/ratio or stimulation index (SI). The SI is used to compare lymphocyte reactivity among different metals. The lower limit of this stimulation index is zero indicating all cells stopped dividing before addition of [3H]-thymidine, after 5 days. Proliferation assays using Ficoll separated peripheral blood mononuclear cells (PBMCs) collected from 30-40 milliliters of peripheral blood. These isolated PBMCs are cultured in 96-well cell-culture plates (Sigma), at a density of 0.1-0.3x106 cells/well for a period of 6 days in 150 mL of DMEM/well, 10% autologous serum at 37°C and 0.5% CO2 , with metal treatments, a positive control (0.01 mg/ml PHA) and a negative control (untreated). Each treatment is conducted in triplicate (3 wells/treatment). [3H]-thymidine is added during the last 12 hours of incubation after 5 days of treatment. At day six [3H]-thymidine uptake (1 m Ci/culture well) is measured using liquid scintillation. SI is calculated using measured radiation counts per minute (cpm): Simulation Index = (mean cpm with treatment) / (mean cpm without treatment). Six days of incubation are chosen to reproduce the DTH response. Stimulation indices of 2-4 indicate mild reactivity, 5-8 moderate reactivity and above 8 high reactivity to metals [12].

The Genesis II prosthesis is a low-friction arthroplasty that has a zirconium (hypoallergenic) for the femoral component with a titanium baseplate. The device contains a low percentage of nickel with less than 0.1% in the titanium baseplates [11].

Titanium has been thought to be hypoallergenic and was used in patients with metal allergies in total hips [1]. Any patients presenting with clinical MDI of their primary TKA associated with metal hypersensitivity were noted in the Electronic Health Record for data analysis.

Description of treatment

For patients with MDI associated with a metal hypersensitivity, and no evidence of another cause of MDI, the patient was recommended a surgical revision of the prosthetic device with a fully-constrained Zirconium or Niobium nitride coated replacement. All of the primary joints were well cemented without evidence of loosening on x-ray or CT. The primary joints were removed followed by debridement and excision of the hypertrophic capsule. The inflamed collateral and cruciate ligaments were also excised. The metal implant, determined based on the individual patient’s allergy, was revised with a revision hinge. All components but the patellar button were exchanged. Each component was fit specifically to the physical dimensions of bone loss caused by the revision in the patient.

Description of follow-up routine

Patients electing for the revision were placed on standard dosing antibiotics and calcium sulfate hemihydrate biodegradable antibiotic carriers to reduce the risk of infection with revisions. Patients followed up postoperatively two weeks, three months, six months, and one year with clinical exams, labs, and x-rays. After that, the patient is followed up on a yearly basis. During each follow-up, patients were asked a variety of questions regarding the functionality of their new implant and quality of life.

Variables, outcome measures, data sources, and bias

The variables studied were (1) if patients with a Genesis II implant presented with MDI following a primary TKA, (2) if the patient was hypersensitive to nickel or other metals in one patient, and (3) which specific metal caused the hypersensitivity. Metal hypersensitivity was determined based on metal allergy testing described above. In addition, routine labs and staging studies were performed to rule out potential confounders such as infection or prosthetic loosening. Varus and valgus stress, applied by board certified orthopedic surgeons, was used to note if the primary TKA opened. MDI was diagnosed by accounting for each patient’s history, symptoms, physical examinations, and diagnostic/laboratory reports.

Statistics

The statistical analysis involved measuring the mean, range, and Fisher’s exact test of significance for variables in question. The p-value was set at 0.01.

Table 1: Available Hypoallergenic Primary TKA Systems.

Table 2: Available Hypoallergenic Hinge TKA Systems.

Table 3: Genesis II Metal Composition - Zirconium alloy.

Table 4: Genesis II Metal Composition-Titanium alloy.

In this study group, 20 patients have been confirmed as failed primary TKA with the Genesis II prosthesis. 5 of these patients were males, 15 were females. These patients have all been diagnosed with clinical MDI as well as nickel allergies, most commonly with a sensitivity to nickel (19/20). The average time to failure was 36 months, with a range of 5 to 96 months.

XR and CT did not demonstrate prosthetic loosening (Figures 1-2). The bone scan shows significantly increased activity in the capsule on the vascular flow phase indicating a synovial reaction, which can be correlated to inflammation of the capsule (Figure 3). The delayed phase of the bone scan demonstrated only minimal activity around the prosthesis. Additionally, the WBC scan shows, at most, mild increased uptake in the tissues around the joint, indicative of inflammatory response (Figure 4). All patients with these characteristics underwent intraoperative open biopsy to confirm lack of infection followed by debridement of the inflamed synovial tissues, periosteum, and surrounding ligaments. This was followed by revision to a fully constrained hypoallergenic prosthesis (either Waldemar Link Porex hinge or Aesculap hinge).

As a revision center, many of the patients referred to us with failed well-fixed primaries. The first patient noticed to have MDI associated with the failed Genesis II primary knee arthroplasty was in December of 2015. Since then, 19 additional patients were appreciated to have both MDI and metal allergies with the Genesis II. The patient population age ranges from 41 years to 73 years, with an average age of 60 years at time of revision. The average time to implant failure is 36 months with a range between 5 and 96 months. Using the primary knee revision rate in the Khan et al. which quoted a 5% incidence of failure, Fisher’s exact test of significance comparing the primary Genesis II prosthesis failure rate and the control was performed and yielded p<.01. Of the 20 failed implants, 15 patients were female and 5 were male. Comparing the gender distribution of the number of failed Genesis II prosthesis to the number of non-failed primary Genesis II prosthesis, Fisher’s exact test of significance is 0.7832.

Although the Genesis II primary total knee is thought to be hypoallergenic and safe to use in patients with metal allergies, 20 of our patients with nickel allergies have experienced significant pain and hindrance due to the clinical MDI associated with the device. The makeup of the prosthesis is titanium and an oxidized zirconium alloy. The titanium contains less than 0.1% nickel [11], yet it seems to be capable of producing an allergenic reaction to the metal allergy in the total joint.

The failure rate of the primary zirconium titanium implant in patients with primary TKAs was statistically significant with a p-value <0.01. The average time to failure in our study, 36 months, is alarming given the average lifetime of a knee implant Figure 4 Indium labeled WBC scan indicating increase of radiotracer around the prosthesis (black arrows) compatible with inflammation. historically is between 10-15 years with an annual 1% failure rate [13], and the risk of revision prior to that timeframe is less than 5% [14]. Every patient in our cohort required a revision TKA to a zirconium or niobium nitride coated prosthesis in order to eradicate symptomatology and promote function. Most of the patients reported relief of their pre-surgical pain by the second day post-operatively.

The gender distribution of failed implants in our patient population is skewed towards females. When compared to the overall gender distribution of primary zirconium titanium implant cases, the p-value is statistically insignificant. This means that the failures of the Genesis II prosthesis necessitating a hypoallergenic implant are following the same gender distribution prevalence as previously reported in metal allergies [15-17].

All of the patients in our cohort presented with MDI. When evaluating our study group, patients presented with a variety of symptoms. Most of our patients noted increasing pain, impaired function and instability as well as complications like erythema and edema, mimicking infection. All patients requiring revision reported significant pain at rest and that woke them up at night. Furthermore, the XR, CT imaging, triple phase bone scans, and indium labeled WBC scans all showed evidence of inflammation, synovial thickening, and increased vascularity in the tissues adjacent to the implant. Current literature has shown pain, inflammation, and component loosening as common reasons for implant failure [16,17].

Although this study reports a clear clinical significance related to the abnormally high incidence of Genesis II prosthesis failures in patients with nickel allergies, this study did have limitations. First, although postoperative follow-up was the same for all patients, we were not aware of the problems with the implant early on, which may indicate prevalence bias [18]. Prior to the realization of the issue, patients with pain or swelling may have been treated more conservatively instead of with additional revision surgery. Because most of these patients were referral patients, it took longer to make the association with the device itself. As a result, the failure rate may be higher than what we found. More symptomatic patients who received implants earlier on may not have been revised at all or were not revised by our practice. Second, not all of our patients were compliant with their follow up appointments which may cause attrition bias [19]. If patients began to have symptoms indicative of implant failure but did not come to their appointments, the data may not be reflective of the actual number of failures. These debris particles could compound the reaction seen in response to the nickel allergy.

The use of hypoallergenic implants may improve the quality of life in patients with metal allergies and MDI. However, the Genesis II, although thought to be hypoallergenic, can fail in patients with metal allergies. This study is meant to report the association of nickel allergies with the Genesis II prosthesis. Since titanium has less than 0.1% nickel, as opposed to the 0.0035% in zirconium femur, it is thought that the titanium base plate is the source of the manifestations of the metal allergy.

1. Maale GE, Mohammadi DK, Calderon II FA, Kennard N, Montgomery WK. Clinical Multi-Directional Instability Associated with Metal Ion Allergy Mimicking Infection Following Primary Total Knee Arthroplasty. Ann Orthop Rheumatol. 2020; 7: 1091.

2. Momoli A, Giarretta S, Modena M, Micheloni GM. The painful knee after total knee arthroplasty: evaluation and management. Acta Biomed. 2017; 88: 60-67.

3. Losina E, Thornhill TS, Rome BN, Wright J, Katz JN. The dramatic increase in total knee replacement utilization rates in the United States cannot be fully explained by growth in population size and the obesity epidemic. J Bone Joint Surg Am. 2012; 94: 201-207.

4. Hossain F, Patel S, Haddad FS. Midterm assessment of causes and results of revision total knee arthroplasty. Clin Orthop Relat Res. 2010; 468: 1221-1228.

5. Navlet MG, Asenjo-Gismero CV. Multidirectional Instability: Natural History and Evaluation. Open Orthop J. 2017; 11: 861-874.

6. Lachiewicz PF, Watters TS, Jacobs JJ. Metal Hypersensitivity and Total Knee Arthroplasty. J Am Acad Orthop Surg. 2016; 242: 106-112.

7. Anand A, McGlynn F, Jiranek W. Metal hypersensitivity: can it mimic infection? J Arthroplasty. 2009; 245: 826.e825-828.

8. Dietrich KA, Mazoochian F, Summer B, Reinert M, Ruzicka T, Thomas P. Intolerance reactions to knee arthroplasty in patients with nickel/ cobalt allergy and disappearance of symptoms after revision surgery with titanium-based endoprostheses. J Dtsch Dermatol Ges. 2009; 75: 410-413.

9. Zondervan RL, Vaux JJ, Blackmer MJ, Brazier BG, Taunt CJ Jr. Improved outcomes in patients with positive metal sensitivity following revision total knee arthroplasty. J Orthop Surg Res. 2019; 141: 182.

10. Akil S, Newman JM, Shah NV, Ahmed N, Deshmukh AJ, Maheshwari AV. Metal hypersensitivity in total hip and knee arthroplasty: Current concepts. J Clin Orthop Trauma. 2018; 91: 3-6.

11. No authors listed. Smith and Nephew materials composition letter. Smith and Nephew.

12. No authors listed. Smith and Nephew implant components. Smith and Nephew.

13. No authors listed. Metal-LTT Technical Protocol. Orthopedic Analysis.

14. Hightower CD, Hightower LS, Tatman PJ, Morgan PM, Gioe T, Singh JA. How often is the office visit needed? Predicting total knee arthroplasty revision risk using pain/function scores. BMC Health Serv Res. 2016; 161: 429.

15. Khan M, Osman K, Green G, Haddad FS. The epidemiology of failure in total knee arthroplasty. The Bone and Joint Journal. 2016; 98-B1: 105-112.

16. Nam D, Li K, Riegler V, Barrack RL. Patient-Reported Metal Allergy: A Risk Factor for Poor Outcomes after Total Joint Arthroplasty? J Arthroplasty. 2016; 319: 1910-1915.

17. Lachiewicz PF, Watters TS, Jacobs JJ. Metal Hypersensitivity and Total Knee Arthroplasty. J Am Acad Orthop Surg. 2016; 242: 106-112.

18. Jager KJ, Tripepi G, Chesnaye NC, Dekker FW, Zoccali C, Stel VS. Where to look for the most frequent biases? Nephrology Carlton. 2020; 25: 435-441.

19. Tripepi G, Jager KJ, Dekker FW, Wanner C, Zoccali C. Bias in clinical research. Kidney Int. 2008; 732: 148-153.