Multiple sclerosis (MS) is considered to be a central nervous system (CNS) chronic inflammatory demyelinating disease, affecting more than 2 million individuals worldwide. In this meta-analysis, we aimed to assess the safety and efficacy of autologous mesenchymal stem cells (aMSCs) in treating MS patients. The PubMed, Embase, Cochrane, Web of Science, and Clinical Trial databases were searched in September 2019. The analysis was conducted for three endpoints: transplant-related mortality (TRM), rate of disease progression, and no evidence of disease activity (NEDA) status. RevMan and the metaprop command of the meta package in R was used in assessing the efficacy and safety of aMSCs. Subgroup analyses were performed for exploration of heterogeneity regarding outcomes. Nine studies comprising 133 patients were included in the meta-analysis. The pooled estimate of TRM was 0% (95% confidence interval (CI) 0%–0.3%). The rate of progression was 16% at 6 months (95% CI 10%–27%) and 35% at 1 year (95% CI 27%–46%). Lower 6-month and 1-year progression rates were significantly associated with intrathecal injection (
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease in the central nervous system (CNS), leading to demyelination, neurodegeneration, and gliosis [
Mesenchymal stem cells (MSCs) are derived from bone marrow (BM) and other tissues, including fat, muscle, umbilical cord blood (UCB), dermis, and dental pulp [
Therefore, the aims of this meta-analysis were to evaluate the efficacy and safety of MSCs by systematically collecting and summarizing all the evidence published about the outcomes including disease activity, Expanded Disability Status Scale (EDSS), and adverse events.
We systematically searched all the published studies reporting aMSCs for MS on PubMed, Embase, Web of Science, Cochrane, and Clinical Trials (published up to September 25, 2019). Our search strategies including free words and MeSH terms (multiple sclerosis [MeSH] and transplantation [MeSH] and patient [MeSH]): (a) “mesenchymal stem cells” or “MSCs”, and (b) “multiple sclerosis” or “MS”, (c) patient. In addition, other included studies were collected manually from references of eligible studies or other articles related to this topic. The abstracts were examined independently by two authors (Y Zhou and X Zhang).
Inclusion criteria for this meta-analysis were as follows: any study (a) on MS; (b) on patients receiving aMSC transplantation; (c) including data on efficacy of aMSC transplantation; (d) reporting mortality and clinical follow-up; (e) including more than 5 patients; and (f) published in English.
The exclusion criteria were as follows: the study (a) did not meet the inclusion criteria; (b) was an editorial, review, case report, or abstract, or was from a clinical conference, comments, or congresses; and (c) involved nonhuman studies.
The extracted data from eligible studies were as follows: (a) identity: authors, years, number of included patients; (b) baseline characteristics of patients (age, EDSS, proportion of patients with SPMS, disease duration, and relapses in the previous year); (c) treatments: transplantation methods, cell doses, follow-up period; and (d) outcomes: EDSS, mortality, and disease activity. The data from included articles were independently extracted and processed by two authors (Y Zhou and X Zhang). Any disagreement between the two authors was settled by consultation with a third author.
The following endpoints were used to assess the safety and efficacy of aMSC on transplantation MS patients. The transplant-related mortality (TRM) was defined as death within 100 days of aMSCs transplantation, and the data of overall mortality (OM) was derived from the entire follow-up of all included studies. Progression events were defined as increasing 1 point (baseline
The meta-analysis was completed using RevMan5.3 (The Cochrane Community, London, United Kingdom) and the metaprop command of the meta package in R to assess the safety (the transplant-related mortality) and efficacy (progression rate and the proportion of no evidence of disease activity). We used odds ratio (OR) and related 95% CI to analyze the data and log transformation to calculate pooled proportions under the fixed and random effects model. The chi-squared value test and inconsistency index statistic (
Written informed consent was acquired from all patients, and original data was approved by the local ethics committees. Any identifiable patient data were not found in this meta-analysis.
The search strategy retrieved 16, 22, 69, 46, and 9 studies from the PubMed, Embase, Web of Science, Cochrane, and Clinical Trials databases, respectively. A total of 82 duplicated studies were excluded, and the titles and abstracts of the remaining articles were screened by two reviewers. Subsequently, 25 studies with full text were evaluated. Among these studies, 3 were excluded due to less than 5 cases, 3 due to lack of full texts, 5 due to being review and conference articles, and 5 due to relevant data not being extractable. Finally, in this meta-analysis, 9 studies [
Flow diagram of the study selection process.
The included 9 studies, along with the basic characteristics and sample sizes, are summarized in Table
Basic demographics and clinical characteristics of each included study.
Authors | Sample size, |
Follow-up, month | Age, year | EDSS | MS subtype, % | MS duration, year | Cell source | Transplantation way |
---|---|---|---|---|---|---|---|---|
Bonab et al. | 10 | 19 (13-26) | 33 (22-40) | 5.15 (3.5-6) | SPMS (80%) PPMS (20%) | 11.2 (3-21) | Bone marrow | Intrathecal injection |
Karussis et al. | 15 | 6 | 6.7 (4-8) | NA | 10.7 (5-15) | Bone marrow | Intrathecal and intravenous injection | |
Yamout et al. | 7 | 12 | 42 (34-49) | 6.5 (4.5-7.5) | SPMS (100%) | 19.9 (11-39) | Bone marrow | Intrathecal injection |
Bonab et al. | 22 | 12 | 35.2 (23-50) | 6.2 (5.5-7) | SPMS (91%) PRMS (9%) | 8.68 (5-14) | Bone marrow | Intrathecal injection |
Connick et al. | 10 | 12 | 48.8 (40–53) | 6.1 (5.5–6.5) | SPMS (100%) | 14.4 (5–26) | Bone marrow | Intravenous injection |
Harris et al. | 6 | 88.8 (48-96) | 43 (28-64) | 7.3 (6.5-9) | SPMS (67%) PPMS (33%) | 17 (7-27) | Bone marrow | Intrathecal injection |
Cohen et al. | 6 | 12 | 6 (3–6.5) | SPMS (58%) RRMS (42%) | Bone marrow | Intravenous injection | ||
Fernández et al. | 19 | 12 | SPMS (100%) | Adipose | Intravenous injection | |||
Harris et al. | 20 | 12 | 49 (27-65) | 6.8 (3.5-8.5) | SPMS (80%) PPMS (20%) | 18.8 (10-32) | Bone marrow | Intrathecal injection |
Nine studies containing 133 cases reported common adverse effects which included transient low-grade fever, slight headache, backache, nausea/vomiting, iatrogenic meningitis, and urinary/respiratory infection. However, the results showed that no transplant-related deaths were observed during follow-up. There were 2 deaths in the overall studies, which occurred 8 and 40 months after completing the study (one due to severe spastic quadriplegia, the other by choking on food) [
After MSC transplantation, seven studies containing 99 cases reported the change of EDSS at 6 months [
(a) Forest plot for 6 months progression rate in each study and pooled estimates. (b) Forest plot for 1 year progression rate in each study and pooled estimates.
During the follow-up, 99 patients were reported as having reached NEDA in seven studies. The percentage of NEDA patients was 72% at 6 months (95% CI 58%–89%,
Forest plot for proportion of patients with no evidence of disease activity (NEDA) at 6 months.
Forest plot for proportion of patients with no evidence of disease activity (NEDA) at 1 year.
We performed subgroup analysis based on age, EDSS, MS duration, and transplantation method. The subgroup analysis of disease progression rates at 6 months indicates intrathecal injection was more beneficial than intravenous injection on the disability progression rates (
Forest plot of subgroup meta-analysis of the rates of disease progression at 6 months. (a) Subgroup analyses of intrathecal injection versus intravenous injection. (b) Subgroup analyses of baseline
Forest plot of subgroup meta-analysis of the rates of disease progression at 1 year. (a) Subgroup analyses of intrathecal injection versus intravenous injection. (b) Subgroup analyses of baseline
The assessment of publication bias cannot be conducted due to the number of included studies being less than 10.
In recent years, the increase in reported MS patients treated with aMSC transplantation has led to debates about this therapeutic approach as a progressive MS treatment [
In this meta-analysis, we used different software to analyze the efficacy and safety of aMSCs for MS. However, there are some limitations: (1) the studies used different MSC types and sources which included adipose tissue and bone marrow, and the MSC transplantation procedure was not uniform in each study; (2) the characteristics of MS patients in each study were different: the majority of patients in the study were SPMS patients and the degree of disability was relatively advanced. Some studies even only included SPMS patients, and this type is highly likely to continue to progress after MSC transplantation; (3) the doses and transplantation methods of MSCs were different in each study; (4) this study included only 9 studies and 133 patients and was unable to perform some important subgroup analyses, such as different disease subtypes and cell sources; (5) the EDSS in assessing disease progression was significantly subjective, had poor reproducibility and low consistency, and it is difficult to compare and combine disease progression in different states [
In this meta-analysis, we chose to use the rate of disease progression and percentage of NEDA as the main efficacy endpoints. The rate of disease progression was 16% at 6 months, while the rate reached 35% at 1 year. However, the 2-year disease progression rate was only 17.1% in the meta-analysis of autologous hematopoietic stem cell transplantation (aHSCT) for MS, and the 5-year disease progression rate was only 23.3% [
In terms of safety, no transplant-related deaths were observed in all included studies. However, in the meta-analysis of aHSCT for MS, the pooled estimate of transplant-related mortality (TRM) was 2.1% [
In fact, subgroup analysis shows that the rate of disability progression of aMSC transplantation with intrathecal injection was less than that with intravenous injection both at 6 months and 1 year, and there was statistical difference (
Animal studies on MS have shown that MSCs suppressed pathogenic effector CD4+ T cells, increased numbers of Tregs, and modulated effector CD8+ T cell subsets [
In this meta-analysis, we demonstrate the safety of aMSCs for the treatment of MS patients. However, the efficacy of aMSC transplantation in MS should be interpreted cautiously compared with those reported treatment regimes, and more random clinical trials are needed to clarify the efficacy of MSCs for treating MS. This meta-analysis also shows the significant association of aMSC intrathecal injection with lower disability progression rate. All in all, comprehensive consideration of results indicate that aMSC transplantation is safe, and to better evaluate the efficacy more studies need to be investigated in the future.
Cell transplantation with aMSCs for treatment of MS is safe, with a largest benefit profile being obtained in patients with aMSC intrathecal injection.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Zhou Yang and Zhang Xin contributed equally to drafting the manuscript. Zhou Yang, Zhang Xin, and Xue Hang reviewed the literatures. Zhou Yang, Zhang Xin, Liu Lingling, and Jie Zhu collected and analyzed the data. Jin Tao designed and supervised the study. All authors read and approved the final manuscript. Yang Zhou and Xin Zhang contributed equally to this work.
This work was supported by grants from the General Program of the National Natural Science Foundation of China (No. 81671177), Natural Science Foundation of Jilin Province Science and Technology Development Plan Project (20190201043JC), the Technology Innovation Program of Jilin Provincial Health and Family Planning Commission of China (No. 2016J040), and the grants from the Swedish Research Council (No. 2015-03005) and grants from the First Hospital, Jilin University of China.