Researchers at Hospital for Special Surgery (HSS) in New York City have identified a unique gene signature in patients who developed stiffness after knee replacement surgery. The findings, available online as part of the AAOS 2020 Virtual Education Experience, could help surgeons better identify patients at risk of developing complications after surgery and potentially lead to targeted treatments to prevent these complications.

Knee replacement surgery, or total knee arthroplasty (TKA), is one of the most common orthopedic operations, with more than 600,000 performed annually in the United States. Although TKA is a very successful procedure, up to 20% of patients report dissatisfaction after surgery, including debilitating stiffness and pain that may eventually lead to a second (revision) surgery.

“In some cases we can identify potential reasons for the development of stiffness, but a subset of patients develop stiffness and pain for reasons that we can’t identify,” said Miguel Otero, PhD, assistant scientist in the Orthopedic Soft Tissue Research Program and co-director of the Derfner Foundation Precision Medicine Laboratory at HSS. These patients are said to have arthrofibrosis, a condition marked by excessive formation of scar-like tissue that is associated with restricted movement in the joint and pain in the surgically repaired knee.

For the study titled “RNAseq Analyses of Neo-Synovial Tissues Retrieved at the Time of Revision Surgery from Patients with Stiff Knees Uncovered Arthrofibrosis-Specific Gene Signatures,” Dr. Otero and his colleagues integrated clinical outcomes of TKA patients with imaging studies and genomic information to see if they could identify unique gene signatures in patients who developed arthrofibrosis.

They enrolled 80 HSS patients undergoing revision knee surgery after experiencing complications following TKA. The researchers separated patients with stiffness into two groups based on whether the problem was linked to a known reason, such as a mechanical issue, or an unknown cause (arthrofibrotic group). A third group, including patients who underwent revision not accompanied by stiffness, for complications including instability or aseptic loosening, served as control.

Dr. Otero’s team analyzed tissue samples taken from the joints of patients during their revision surgery to see if they could find changes in gene expression between the different groups. They identified 435 genes differentially expressed in tissues from patients with stiffness for identifiable reasons relative to the control group. Importantly, they found more pronounced differences (1,509 differentially expressed genes) comparing the arthrofibrosis and non-stiff groups.

“Think about surgery as a massive injury. The body needs to heal the damage, and scars are often a consequence of that healing process,” Dr. Otero said. “The excessive scarring and fibrosis that we see in patients with arthrofibrosis is an overreaction to that injury, but we don’t yet know why they are overreacting or why their reaction is different from other patients who also developed stiffness after TKA.”

Dr. Otero and his colleagues hope to winnow their large pool of genes to a much smaller subset that will serve as a more precise signature of arthrofibrosis after TKA. “We want to identify cellular and molecular signatures with therapeutic and prognostic value, so that we can develop preventative therapies targeting specific genes or pathways, and also identify patients who are at risk of developing arthrofibrosis following TKA,” he said.

One goal of the research, he said, is to find targeted and specific ways to prevent the development of arthrofibrosis in patients undergoing TKA. “Even though all patients with stiffness have scarring and limited joint motion, patients with arthrofibrosis do not necessarily behave the same as other patients with stiffness,” Dr. Otero said. “The hope is to implement precision medicine approaches so that, potentially, we can match at-risk patients with specific treatment options and prevent this debilitating problem.”