Following the Law for the Promotion of Regenerative Medicine on Safety of Regenerative Medicine, our submission “Treatment for Osteoarthritis by APS Injection” was accepted by the Health and Welfare Bureau of the Ministry of Health, Labor and Welfare after being reviewed by the Committee for Specific Approval of Regenerative Medicine. Additionally, this study has been submitted to the ethical review board of our hospital and has been approved as a retrospective study to evaluate the safety and efficacy of the 12-month follow-up results. All data were handled following the Declaration of Helsinki.
Patient selection and study design
This retrospective study consists of 12-month clinical outcomes from consecutive 228 knees that are diagnosed with KOA and treated with APS intra-articular injection at our institution from August 2018 to October 2019.
The main inclusion criteria were ages of 45–85 years, KOA diagnoses with KL grades 2–4 in standing anterior–posterior radiographs, and a history of conventional conservative treatment for at least 3 months (e.g., physical therapy, oral analgesics, and intra-articular injection of HA) that did not provide sufficient benefit. Excluded from the study were patients with rheumatoid arthritis or arthritis secondary to other inflammatory or metabolic diseases, a history of cancer treatment, psychiatric disorders, and other regenerative medicine treatments (PRP, mesenchymal stem cell injections, etc.).
KL grade was assessed by an orthopedic surgeon with > 15 years of experience. The classification was repeated for randomly selected 50 knees by the same examiner to evaluate the reliability and reproducibility of the assessment and other examiners to assess the intraobserver and interobserver reproducibility. The concordance rate were 0.91 and 0.92.
APS is prepared using the nSTRIDE APS Kit (Zimmer Biomet). In the first step, 55 mL of blood and 4 mL of anticoagulant citrate dextrose solution A (Citra Labs, Braintree, MA) are injected into the nSTRIDE Cell Separator, and approximately 6 mL of PRP is separated after centrifugation at 3200 rpm for 15 min. The prepared PRP is then transferred to the second step, the nSTRIDE Concentrator, where it is exposed to polyacrylamide beads and filtered by centrifugation at 2000 rpm for 2 min to produce approximately 2–3mL of APS.
Intra-articular APS injection was performed with a 21G needle within 30 min of creation. After the joint puncture, joint fluid was first aspirated, as much as possible, and then APS was injected. After injection, the patient was instructed to rest at home on the procedure day. The patient is instructed to cool the affected area if knee swelling and pain developed after the injection to relieve the pain, and they were allowed to take one celecoxib tablet as rescue medication if the pain remained strong. For the next day, no activity restrictions were applied, and patients were allowed to gradually resume sports and recreational activities according to their pain tolerance.
No additional conservative treatment, such as medication or joint injections, was given after APS injection in these cases, but any medication given before APS injection was not discontinued. Aspiration of joint effusion was restricted for 1 month after the APS therapy to prevent its effect on APS injection. Aspiration was performed in cases with joint effusion > 1 month after APS injection. The patient was instructed to return for a follow-up examination if joint effusion continues and the patient wants to have the joint fluid aspirated to monitor the joint fluid volume. HA joint injections were resumed in eight knees.
The incidence and duration of acute local inflammatory reaction (AIR), a swelling and burning sensation with pain in the knee joint after APS injection, and the presence of other adverse events were examined to evaluate the safety of APS.
The Knee Injury and Osteoarthritis Outcome Score (KOOS) was collected before and 1, 3, 6, and 12 months after the APS injection to measure the change from baseline to each time point to evaluate the clinical efficacy of APS. The Outcome Measures in Arthritis Clinical Trials–Osteoarthritis Research Society International (OMERACT-OARSI) criteria were used to determine the effect of the APS injection10. KOOS and efficacy rates were separately compared by KL grade.
Additionally, we examined the details of cases that dropped out from the follow-up within the 12 months. The patients who dropped out of the follow-up were surveyed via telephone to check for changes in their symptoms. Specifically, patients who were judged as a responder at the last follow-up examination and did not come to the hospital because their condition remained unchanged were considered a responder. Patients who were judged as nonresponders at the last follow-up examination and did not come to the hospital because their condition did not improve were considered nonresponders. Thus, the overall estimated responder rate of the OMERACT-OARSI criteria was recalculated assuming no change in symptoms, and the subsequent efficacy was continued to be determined at the last visit for the clinical evaluation, including the cases who dropped out.
Furthermore, as a worst-case scenario, all the cases that dropped out of the follow-up within the 12 months were considered not effective. The estimated effective rate of the OMERACT-OARSI criteria in the worst-case scenario was also calculated.
Data were described as means and standard deviations (SDs) for continuous variables and as frequency counts and percentages for discrete variables. The Friedman tests were used to detect differences in repeated multiple measures of the KOOS. Dunnett's test was used to compare the KOOS at multiple time points with that at baseline. The Steel–Dwass test was used for the comparison of KOOS among the KL grades. Chi-square tests were used to compare the follow-up rate and efficacy rates in OMERACT-OARSI criteria by KL grades; p-values of < 0.05 were considered statistically significant. All analyses were performed using the statistical software JMP® ver.15 (SAS Institute Inc., Cary, NC, USA).