Treatment of Knee Osteoarthritis With Autologous Mesenchymal Stem Cells

Osteoarthritis is the most prevalent joint disease and a frequent cause of joint pain, functional loss, and disability (1). Osteoarthritis often becomes chronic, and conventional treatments have demonstrated only modest clinical benefits, without lesion reversal (2). Cell-based therapies have shown encouraging results in both animal studies and a few human case reports. We have recently published the results of a pilot clinical trial designed to assess the feasibility and safety of osteoarthritis treatment with bone marrow–derived mesenchymal stromal cells (MSCs) in 12 patients with chronic knee pain unresponsive to conservative treatments and radiologic evidence of osteoarthritis (3). The patients were treated with autologous expanded bone marrow MSCs by intra-articular injection (40×106 cells), and clinical outcomes, including evaluations of pain, disability, and quality of life, were followed up for 1 year. Articular cartilage quality was assessed by quantitative magnetic resonance imaging (MRI) T2 mapping (3). Feasibility and safety were confirmed, and strong indications of clinical efficacy were identified. Patients exhibited rapid and progressive improvement of algofunctional indexes that approached 65% to 78% by 1 year. This outcome compared favorably with the results of conventional treatments. In addition, MRI T2 relaxation measurements demonstrated a significant improvement of cartilage quality, in 11 of 12 patients (3). Now, we report the results of follow-up at 2 years from the intervention. No serious adverse effects appeared during the second year. Figure 1A–D summarizes the evolution of the clinical results. The pain improvement observed by the end of the first year was maintained with no significant modifications 1 year later, as exemplified for the Visual Analogue Scale (VAS) measurements during both daily and sport-associated activities (Fig. 1A). The therapeutic efficiency estimated from the pain relief–versus–initial pain score plot (4) was 0.71 (over a maximum of 1) for VAS (Fig. 1B). For Lequesne severity index, the efficiency was 0.66 (Fig. 1C). Regarding the Western Ontario and McMaster Universities Osteoarthritis Index, the estimated therapeutic efficiency varied between 0.44 and 0.78 for the different components of the test (Fig. 1D).FIGURE 1: Pain and cartilage quality improvement resulting from MSC treatment. (A) Graph showing evolution of knee pain, as measured by VAS, over time. Mean±SE of the values of daily activity of 11 patients (VAS-DA, filled circles) or the values of sports activity of 7 patients (VAS-SA, open circles). All the values at 3, 6, 12, and 24 months were significantly smaller than the baseline value (P<0.001 in all the cases; analysis of variance; Bonferroni test). (B–D) Correlation between improvement of knee pain 2 years after treatment with MSCs and initial pain score, as measured with different tests. The “perfect” treatment (dotted line with a slope of 1) is shown for comparison. The best-fitting lines are shown with values for the slope and linear regression coefficient (r) at the right. In case D, the four components of the Western Ontario and McMaster Universities Osteoarthritis Index test are shown with different signs (codes at top). The fitted line shown corresponds to the “total” component. (E and F) Cartilage quality was assessed by MRI T2 mapping and is quantified as the Poor Cartilage Index (PCI) (computed as the percentage of sample points with a T2 relaxation value > 50 milliseconds). The worse possible value for PCI is 100, and healthy cartilage should approach 5. (E) Graph showing the temporal evolution of PCI; mean±SE values of 12 patients treated with MSCs. Significance for differences with baseline value: *P<0.05. **P<0.01. ***P<0.001 (analysis of variance; Bonferroni test for paired values). (F) Correlation between PCI improvement at 2 years and initial PCI for the 12 patients included in this study. The best-fitting line is shown with values for the slope and linear regression coefficient (r) at the right. The “perfect” treatment (dotted line with a slope of 1) is shown for comparison.The cartilage quality evolution is shown in Figure 1E–F. The values of the Poor Cartilage Index (PCI; maximum value, 100; normal value, 5) (3) improved during the second year from 14.3±1.8 (36% of maximum) to 13.0±1.7 (45% of maximum) (Fig. 2A). This decrease of PCI was not statistically significant, but the overall improvement with regard to the baseline value (19.5±2.3) was highly significant (P<0.001). The PCI improvement–versus–initial PCI plot (4) is shown in Figure 2(B). There was a significantly (P<0.01, r=0.70) positive correlation between both parameters, with a slope of 0.57. The fitted line cut the abscissa axis at PCI of 8%, a value not far from the theoretical one of 5% (3). The results of the 2-year follow-up reaffirm the conclusions from the first-year results on the feasibility and safety of our MSC treatment. A recent meta-analysis gathering together 844 procedures with a mean follow-up of 21 months also concluded that the procedure is safe (5). We also find strong indications of clinical efficacy with improvements of the algofunctional indexes that reach 65% to 78% 1 year after the intervention and are maintained during the second year. The results of other clinical trials on treatment of osteoarthritis with expanded MSC declared in the data base clinicaltrials.gov have not been published yet, but the results of several series and case reports (6–8) were generally optimistic and consistent with our results. The quantitative MRI results on cartilage quality improvement are especially encouraging. There was a significant improvement 1 year after the intervention (3), and we find now at the 2-year follow-up that the quality of cartilage has further improved. Although the difference with the 1-year value was not statistically significant, the profile of the improvement, affecting 11 of the 12 patients was very convincing (Fig. 2B). Overall, our results reaffirm that MSC may be a valid alternative for the treatment of knee osteoarthritis because it attains effective and durable pain relief and objective cartilage improvement. The intervention is simple, but cell preparation is expensive. Future research should confirm results in large series of patients and look for modifications of cell production to make possible generalization of cell therapy. Lluis Orozco 1 Anna Munar1 Robert Soler1 Mercedes Alberca2 Francesc Soler3 Marina Huguet4 Joan Sentís5 Ana Sánchez2 Javier García-Sancho2 1 Institut de Teràpia Regenerativa Tissular (ITRT), Centro Médico Teknon Barcelona, Spain 2 Instituto de Biología y Genética Molecular (IBGM), University of Valladolid and CSIC, Valladolid, Spain 3 Orthopedic Surgery Department EGARSAT, Terrassa, Barcelona, Spain 4 Department of Magnetic Resonance Imaging, CETIR Clínica del Pilar Barcelona, Spain 5 Departament of Public Health, Medical School, University of Barcelona Barcelona, Spain ACKNOWLEDGMENTS The authors thank Mr. Jesús Fernández, IBGM, and Ms Carmen Barbero, ITRT, for the technical support. They also thank Dr. Juan Carlos Vilanova, Centro Diagnóstico por la Imagen, Girona, Spain, and Dr. Sigfried Trattnig, Medical University of Vienna, Austria, for the help with the T2 mapping. They also thank Dr. Xavier Peirau, traumatology consultant at ITRT.

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