Discussion
knee infections, arthritis, pain
ADVERSE REACTION, ARTHRITIS, HAND SWELLING
This study demonstrated no superiority of any cell therapy over corticosteroids at 1 year when VAS and KOOS were compared. In addition, other measures including EQ-5D and PROMIS also showed no superiority among cellular therapies over CSI. As such, the primary hypothesis was rejected. Given the complexity of the study, patients and cells involved, no direct knowledge was attained from our primary analysis about the personalization of cellular injections for patients.The question of the most beneficial cellular treatment, and the assumption of superiority over CSI, has been debated for some time. However, large randomized clinical trials have been difficult to perform. Previously, the discussion over which source of cells are superior has been predominantly based on laboratory data analyzing MSCs, colony-forming units or other secretory factors. This type of approach is complicated by the large amount of heterogeneity among autologous and allogeneic products based on the donors who supply these cells. Based on in vitro analysis, the consensus is that birth tissue products will produce the higher number of true MSCs, but questions over the manufacturing, processing and efficacy of such treatments have been raised as most of the commercial products that have been available for use show no live MSCsA benefit of this large study was the evaluation of the safety of these procedures. Since this was a US Food and Drug Administration (FDA)-approved study, every adverse reaction, from pain and swelling in the joint to hospitalizations for illnesses unrelated to the study intervention, was recorded in real time. There were no study-related serious AEs or symptomatic knee infections noted in any of the treatment groups at any point during follow-up. The study-related AEs of procedural and post-procedural pain were highest in the SVF cohort followed by BMAC, and there were very few related AEs, none of which was severe. Almost all of the reported AEs recovered by the 1-week follow-up visit. This is consistent with previous reports of two large case series: one by Centeno et al in 2016 (ref. As none of the treatment groups was superior to another, it was deemed important to subgroup patients on the basis of their grade of arthritis. The use of KL scoring preinjection was used to classify patients accordingly. Despite having three types, II, III and IV, the KL grade was not a reliable predictor of success. The literature often points to a direct correlation between KL grading and specific product efficacy in small cohortsSignificant measures were taken to eliminate potential bias in our study, including blinding of authors to original data before final analysis. The primary analyses and the sensitivity analyses allowed us to evaluate all scenarios including subject loss, as we designed the study as intent to treat. However, selection bias may arise from differences between participants who selected to start the trial and those who did not. With interventions for knee OA, there is a well-described placebo effect that we must acknowledge. When trying to account for this placebo effect, one must look at studies where saline was used. It is debatable as to whether saline is a true control or has some therapeutic effect by diluting and washing away inflammatory mediators as well as aspiration of joint fluid, which occurs before any intervention. It is unclear whether different solutions and cellular therapies have this same dilution effect or if there is a reactionary byproduct from cellular injectates over saline. This placebo effect has been studied extensively in this area, with overall data suggesting there could be upwards of 50% response rate as well as up to 6 months improvement in pain and possibly even longer improvement in functionAlthough no study is perfect, our study identified that at 1 year post injection there was no cellular therapy that was more effective than CSI for knee OA. In addition, the study demonstrates in a large cohort the relative safety of these cellular procedures without evidence of severe AEs. It should be noted that a multiarm clinical trial evaluating the safety and efficacy of cellular biologics as compared to corticosteroid is exceedingly complex with multiple viewpoints and perceptions. A large team of scientists including expert opinion, critiques and requirements from the FDA shaped this study into its current form. Additional conclusions and responder analyses will be discussed more in future papers.