Meta-analysis of preclinical studies of mesenchymal stromal cells to treat rheumatoid arthritis

Abstract

Background: This study aims to evaluate the quality of preclinical data, determine the effect sizes, and identify experimental measures that inform efficacy using mesenchymal stromal (or stem) cells (MSC) therapy in animal models of rheumatoid arthritis (RA).

Methods: Literature searches were performed on MSC preclinical studies to treat RA. MSC treatment effect sizes were determined by the most commonly used outcome measures, including paw thickness, clinical score, and histological score.

Findings: A total of 48 studies and 94 treatment arms were included, among which 42 studies and 79 treatment arms reported that MSC improved outcomes. The effect sizes of RA treatments using MSC, when compared to the controls, were: paw thickness was ameliorated by 53.6% (95% confidence interval (CI): 26.7% -80.4%), histological score was decreased by 44.9% (95% CI: 33.3% -56.6%), and clinical score was decreased by 29.9% (95% CI: 16.7% -43.0%). Specifically, our results indicated that human umbilical cord derived MSC led to large improvements of the clinical score (-42.1%) and histological score (-51.4%).

Interpretation: To the best of our knowledge, this meta-analysis is to quantitatively answer whether MSC represent a robust RA treatment in animal models. It suggests that in preclinical studies, MSC have consistently exhibited therapeutic benefits. The findings demonstrate a need for considering variations in different animal models and treatment protocols in future studies using MSC to treat RA in humans to maximise the therapeutic gains in the era of precision medicine.

Funds: NIH [1DP2CA195763], Baylx Inc.: BI-206512, NINDS/NIH Training Grant [Award# NS082174].

Keywords: Clinical trials; MSC; Mesenchymal stromal (or stem) cells; Meta-analysis; Pre-clinical study; Rheumatoid arthritis.

Fig. 1

Forest plots showing the normalised mean difference (MD) and 95% CI of the clinical score for each study included in the meta-analysis. The graph was generated using the meta package in R. All results have been normalised with sham control group as described in the methods. For all the plots, the vertical line indicates no effect, left hand side indicates favouring MSC treatment while right side indicates favouring PBS control treatment. The size of the box indicates the weighting of each study, and the thin horizontal whisker indicates the 95% CI. Random-effects model was used to summarise the effect sizes. Heterogeneity is denoted by the Ι² and τ².

Fig. 2

Forest plots showing the normalised mean difference (MD) and 95% CI of (a) histological score, (b) paw thickness for each study included in the meta-analysis. The graphs were generated using the meta package in R. All results have been normalised with sham control group as described in the methods. For all the plots, the vertical line indicates no effect, left hand side indicates favouring MSC treatment while right side indicates favouring PBS control treatment. The size of the box indicates the weighting of each study, and the thin horizontal whisker indicates the 95% CI. Random-effects model was used to summarise the effect sizes. Heterogeneity is denoted by the Ι² and τ².

Fig. 3

Forest plots showing normalised mean difference (MD) of clinical score changes and 95% CI for the subgroup of MSC donor species. The graph was generated using the meta package in R. All results were normalised with the sham control group as described in the methods. For all the plots, the vertical line indicates no effect, left hand side indicates favouring MSC treatment while right side indicates favouring PBS control treatment. The size of the box indicates the weighting of each study, and the thin horizontal whisker indicates the 95% CI. Random-effects model was used to summarise the effect sizes. Heterogeneity is denoted by the Ι² and τ².

Fig. 4

Forest plots showing normalised mean difference (MD) of clinical score changes and 95% CI for the subgroup of transplant types. The graph was generated using the meta package in R. All results were normalised with the sham control group as described in the methods. For all the plots, the vertical line indicates no effect, left hand side indicates favouring MSC treatment while right side indicates favouring PBS control treatment. The size of the box indicates the weighting of each study, and the thin horizontal whisker indicates the 95% CI. Random-effects model was used to summarise the effect sizes. Heterogeneity is denoted by the Ι² and τ².

Fig. 5

Forest plots showing normalised mean difference (MD) of clinical score changes and 95% CI for the subgroup MSC tissue of origin. The graph was generated using the meta package in R. All results were normalised with the sham control group as described in the methods. For all the plots, the vertical line indicates no effect, left hand side indicates favouring MSC treatment while right side indicates favouring PBS control treatment. The size of the box indicates the weighting of each study, and the thin horizontal whisker indicates the 95% CI. Random-effects model was used to summarise the effect sizes. Heterogeneity is denoted by the Ι² and τ². Mixed* indicates the treatment arm contains more than one type of MSC tissue of origin.

Fig. 6

Forest plots showing normalised mean difference (MD) of clinical score changes and 95% CI for the subgroup of routes of administration. The graph was generated using the meta package in R. All results were normalised with the sham control group as described in the methods. For all the plots, the vertical line indicates no effect, left hand side indicates favouring MSC treatment while right side indicates favouring PBS control treatment. The size of the box indicates the weighting of each study, and the thin horizontal whisker indicates the 95% CI. Random-effects model was used to summarise the effect sizes. Heterogeneity is denoted by the Ι² and τ².

Fig. 7

Regression model with regression line is shown in (a) single MSC injection treatment, (b) multiple MSC injections treatment (linear regression), and (c) multiple MSC injections treatment (quadratic regression). The size of the dot is proportional to number of injections. The dashed lines in (a, b, and c) represent the 95% CIs. The red line represents the trend of interactions between dosage of MSC and normalised difference in clinical score changes. The size of the dot is proportional to the weighting given to the study and the detailed weighting of each study could be found in Fig. 1. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 8

Funnel plot for (a) clinical score, (b) histological score, and (c) paw thickness. The funnel plots used either a model without regression (horizontal axis is the normalised mean difference), or a model after regression (horizontal axis is the residual value). Each dot in the figure represents a study, with the y-axis signifying study quality and the x-axis showing the study results.