Efficacy and safety of mesenchymal stem cells in the treatment of systemic sclerosis: a systematic review and meta-analysis

Abstract

Background: Systemic sclerosis (SSc) is an autoimmune disease with high morbidity and mortality characterized by fibrosis of the skin and internal organs. Some studies have investigated the use of stem cells to treat SSc. Herein, a systematic review and meta-analysis was conducted to determine the efficacy and safety of mesenchymal stem cells (MSCs) in the treatment of SSc.

Methods: PubMed, Embase, Cochrane Library, Web of Science, OVID, China National Knowledge Infrastructure and Wanfang databases were searched up to February 1, 2021. Literature screening, data extraction and quality assessment were conducted independently by two researchers in according to the inclusion and exclusion criteria. The discrepancies were resolved by a third researcher.

Results: A total of 9 studies encompassing 133 SSc patients were included in the study. Compared to the baseline after treatment with MSCs: 1. The modified Rodnan skin score (mRSS) was significantly reduced in patients with SSc (P < 0.00001). 2. MSCs decreased the number of digital ulcer, mouth handicap scale, and visual analog scale of hand pain in SSc patients (P = 0.0007 and P = 0.03, respectively). 3. No statistical differences were detected in Raynaud's condition score and Cochin hand function scale score at 6 months of MSCs therapy (P = 0.5 and P = 0.62). 4. After 12 months of follow-up, MSCs improve carbon monoxide diffusing capacity and forced vital capacity of SSc patients (P < 0.05). 5. Overall, MSCs application was safe; a few cases exhibited swelling at the injection site, diarrhea and arthralgia, which had self-recovery, and no severe adverse events occurred in the included trials.

Conclusions: MSC therapy improves the degree of skin thickening, lung function, and mouth opening and relieves finger ulcers and pain in patients with SSc without severe adverse events. Thus, MSCs or MSCs combined with plasma and traditional medicine might be an effective and promising treatment of SSc patients. PROSPERO registration number: CRD42020200350.

Keywords: Mesenchymal stem cells; Meta-analysis; Systemic sclerosis; Treatment.

Fig. 1

Flow chart of the selection process. Flow chart describing the selection steps of the systematic review and meta-analysis of comparing the efficacy and safety of mesenchymal stem cells in patients with systemic sclerosis, showing the number of studies excluded at each step, as well as the reasons for exclusion. *PubMed (n = 100), Ovid (n = 98), Cochrane (n = 11), Web of Science (n = 194), Embase (n = 186), Wanfang Data (n = 23), and China National Knowledge Infrastructure (n = 61). Ultimately, a total of 673 were retrieved from the seven database, and 5 articles were obtained by manual retrieval. Of these 678 studies, nine articles were finally identified, including 7 quantitative studies

Fig. 2

Forest plot of mRSS changes before and after treatment with MSCs at different time points. The mRSS of SSc patients after MSCs treatment was significantly lower than pretreatment at different follow-up times involving 3, 6, and 12 months (P < 0.05), especially at 12 months. No significant heterogeneity was observed in any of the three groups, and a fixed-effects model was used for statistical analysis. In the plane rectangular coordinate system, the forest plot takes a vertical invalid line (scale of abscissa is 0) as the center, describes the effect quantity and 95% CI of each study by using multiple line segments parallel to the horizontal axis, and describes the effect quantity and confidence interval of multiple studies by using a diamond. mRSS, modified Rodnan skin score; MSCs, mesenchymal stem cells; CI, confidence interval; SMD, standardized mean difference

Fig. 3

Forest plot of mRSS changes before and after treatment with MSCs of different cell origins. The results showed mRSS score was significantly lower than pretreatment at 6 months of MSCs from different sources treatment (P < 0.05). No significant heterogeneity was observed in any of the three groups, and a fixed-effects model was used for statistical analysis. In the plane rectangular coordinate system, the forest plot takes a vertical invalid line (scale of abscissa is 0) as the center, describes the effect quantity and 95% CI of each study by using multiple line segments parallel to the horizontal axis, and describes the effect quantity and confidence interval of multiple studies by using a diamond. SVF, stromal vascular fraction; MSCs, mesenchymal stem cells; UC-MSCs, umbilical cord mesenchymal stem cells; BMSCs, bone marrow-derived mesenchymal stem cells; mRSS, modified Rodnan skin score; CI, confidence interval; SMD, standardized mean difference

Fig. 4

Forest plot of RCS changes before and after treatment with MSCs. Only two studies comparison of RCS value and they were significant heterogeneity (I² = 93%). Hence, a random-effects model was used for analysis and no significant difference was observed at 6 months (P > 0.05). In the plane rectangular coordinate system, the forest plot takes a vertical invalid line (scale of abscissa is 0) as the center, describes the effect quantity and 95% CI of each study by using multiple line segments parallel to the horizontal axis, and describes the effect quantity and confidence interval of multiple studies by using a diamond. RCS, Raynaud's condition score; MSCs, mesenchymal stem cells; CI, confidence interval; SMD, standardized mean difference

Fig. 5

Forest plot of DU changes before and after treatment with MSCs. Four studies showed after treatment with MSCs, DU numbers in SSc patients were significantly lower than pretreatment at 6 months (P < 0.05). No significant heterogeneity was observed, and a fixed-effects model was used for statistical analysis. In the plane rectangular coordinate system, the forest plot takes a vertical invalid line (scale of abscissa is 1) as the center, describes the effect quantity and 95% CI of each study by using multiple line segments parallel to the horizontal axis, and describes the effect quantity and confidence interval of multiple studies by using a diamond. However, the confidence interval was large, which might due to small sample size. DU, digital ulcer; MSCs, mesenchymal stem cells; CI, confidence interval

Fig. 6

Forest plot of VAS changes before and after treatment with MSCs. Three studies showed after treatment with MSCs, VAS score in SSc patients was significantly lower than pretreatment at 6 months (P < 0.05). Since significant heterogeneity was observed (I² = 94%), a random-effects model was used. In the plane rectangular coordinate system, the forest plot takes a vertical invalid line (scale of abscissa is 0) as the center, describes the effect quantity and 95% CI of each study by using multiple line segments parallel to the horizontal axis, and describes the effect quantity and confidence interval of multiple studies by using a diamond. VAS, visual analogue scale; MSCs, mesenchymal stem cells; CI, confidence interval; SMD, standardized mean difference

Fig. 7

Forest plot of MHISS changes before and after treatment with MSCs. Only two studies showed after treatment with MSCs, MHISS score in SSc patients was significantly lower than pretreatment at 12 months (P < 0.05). Since heterogeneity was observed (I² = 57%), a random-effects model was used. In the plane rectangular coordinate system, the forest plot takes a vertical invalid line (scale of abscissa is 0) as the center, describes the effect quantity and 95% CI of each study by using multiple line segments parallel to the horizontal axis, and describes the effect quantity and confidence interval of multiple studies by using a diamond. MHISS, mouth handicap in systemic sclerosis scale; MSCs, mesenchymal stem cells; CI, confidence interval; SMD, standardized mean difference

Fig. 8

Forest plot of CHFS changes before and after treatment with MSCs. Only two studies showed after treatment with MSCs, CHFS score in SSc patients was significantly lower than pretreatment at 6 months (P < 0.05). Since significant heterogeneity was observed (I² = 95%), a random-effects model was used. In the plane rectangular coordinate system, the forest plot takes a vertical invalid line (scale of abscissa is 0) as the center, describes the effect quantity and 95% CI of each study by using multiple line segments parallel to the horizontal axis, and describes the effect quantity and confidence interval of multiple studies by using a diamond. CHFS, Cochin hand function scale; MSCs, mesenchymal stem cells; CI, confidence interval; SMD, standardized mean difference

Fig. 9

Publication bias. Funnel plot generated for the primary outcome using Begg's test (P = 0.806) and Egger's test (P = 0.349) suggested that there was no publication bias