The Genetic Risk for Joint Replacement Failure

About five million joint replacements are performed globally every year. Hip replacements make up two million of these, a treatment proven to be successful to treat end-stage hip arthritis.

Conventional hip replacements use a metal femoral head that articulates against a polyethylene cup or liner. However, the lifespan of these can be limited in younger, more active patients. During the activities of daily life, the harder metal head can wear away the plastic component. Release of wear debris over time increases the likelihood of an adverse immune response, which can lead to wear-induced osteolysis—compromise of the bony architecture surrounding the implant, loosening the components.

Metal-on-metal hip resurfacing prostheses were reintroduced at the turn of the century to address this. Hip resurfacing removes the damaged articular surface from the native femoral head replaced by a hollow, cobalt chrome (CoCr) that articulates against a CoCr acetabular component. The hope was the removal of softer polyethylene would reduce wear debris. The technology was then adapted for total hip replacements.

Although many patients are satisfied with their surgery’s results using the new CoCr hip replacement composition, a significant number of joint replacements fail early as a result of adverse immune responses. When small particles from CoCr joints leach into the blood, it can lead to an immune response that causes pain and joint failure in some patients.

“Essentially, the immune system attacks the implant in a process similar to how a patient rejects an organ transplant,” David Langton, Ph.D. explained to Genetic Engineering & Biotechnology News. “How quickly this happens is variable and unpredictable, but it appears to be dependent on the type of material, the amount of wear debris released, and other patient-specific factors.”

One of the patient-specific factors appears to be their genetics. Specifically, a variation in HLA class II genotype that influences a patient’s susceptibility to delayed-type hypersensitivity (DTH) responses to CoCr implants. According to a study headed by Dr. Langton published in Communications Medicine in late June, development of DTH after joint replacement appears to be determined by the interaction between the implant and the patient’s genotype.

Using next-generation genetic sequencing, Dr. Langton and his team determined the HLA genotypes of 606 patients, 176 of which had undergone failure of their prostheses. 430 were asymptomatic at a mean follow-up of twelve years. It was demonstrated that DTH is associated not only with patient age, gender, and magnitude of metal exposure, but also the presence of certain HLA class II alleles.

During the course of the study, the researchers trained and validated an algorithm that incorporated patient age, gender, HLA genotype, and blood metal concentrations to predict DTH development. They explained the predictive algorithm generated from the investigation performs at an accuracy suitable for clinical use, with weighted mean survival probability errors of 1.8% and 3.1% for pre-op and post-op models, respectively.

Dr. Langton is the director of ExplantLab, a firm that combines surgical, bioengineering, and medical knowledge to understand performance of implants that have been removed from the body (explants). The company uses advanced technology to reverse engineer explants to accurately determine their original shape. The company then compares the reconstructed, original surfaces with their shape after removal to calculate how much material was removed while in the body. ExplantLab can then map wear patterns and relate them to several design, patient, and surgical factors.

Located in Newcastle Upon Tyne, England, the company was established in 2011 and claims to be the “largest independent retrieval unit in Europe.”

Working with bioengineers, medical staff, and patients from collaborating institutions, ExplantLab developed Orthotype, a test that uses a patient’s genotype to build a risk profile of developing CoCr hypersensitivity.

Orthotype was the test developed and validated from Dr. Langton’s study.

The Orthotype test can be used pre- or post-op. Pre-op, blood or saliva samples can be taken that then undergo genetic sequencing to predict likelihood of a metal sensitivity reaction developing following surgery. (The saliva test can be done either at home or in the clinic). Post-op, ExplantLab provides testing kits for two blood samples that are genetically sequenced with ICP-MS to determine blood metal concentrations.

This could begin a new era where genetic testing prior to receiving medical implants becomes routine. Orthotype can help identify patients more likely to react following joint replacement made of CoCr components, helping surgeons choose an implant based on a manufactured material more suited to the patient.

“This represents a significant advance in orthopedic care for patients,” said Dr. Langton, “with potentially significant financial repercussions for global healthcare systems, through the avoidance of repeat surgery.”