Clinical Efficacy And Safety Of Stem Cell Therapy For Knee Osteoarthritis

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Correspondence: Meng Xu, The Second Hospital of Jilin University, Changchun, Jilin China (e-mail: xumeng@jlu.edu.cn).

Received 2019 Sep 17; Revised 2019 Dec 11; Accepted 2020 Feb 5; Collection date 2020 Mar.

This is an open access article distributed underneath the phrases of the Creative Commons Attribution-Non Commercial License 4.Zero (CCBY-NC), the place it is permissible to obtain, share, remix, rework, and buildup the work provided it is correctly cited. The work cannot be used commercially with out permission from the journal. http://creativecommons.org/licenses/by-nc/4.Zero

Background:

We performed a meta-evaluation of the efficacy and safety of stem cell therapy as a clinical therapy of knee osteoarthritis. This meta-evaluation is predicted to provide evidence of the efficacy of stem cell therapy, which is at the moment controversial, as a conservative therapy for knee osteoarthritis.

Methods:

A web based seek for related articles was conducted in the PubMed, EMBASE, and Cochrane Library databases. The search phrases had been "stem cells" and "osteoarthritis." We conducted a quality assessment of the included articles and extracted the following indicators: Visual Analogue Scale (VAS) score, Subjective International Knee Documentation Committee (IKDC) score, Western Ontario and McMaster Universities (WOMAC) subscales, and adversarial events. The RevMan5.Three software program was used for determining effect sizes.

Results:

Nine randomized controlled trials involving 339 patients were included. VAS score and IKDC rating from baseline to 24 months had been improved in the stem cell therapy group compared to these in the control group. However, no significant distinction was noticed between the 2 groups in IKDC rating changes from baseline to 6 and 12 months, as well as in WOMAC-Pain, WOMAC-Stiffness, and WOMAC-Physical Function score changes at every go to level.

Stem cell therapy is certainly superior to traditional remedies in the conservative treatment of KOA; it significantly reduces ache with no apparent further side effects.

Keywords: knee osteoarthritis, meta-analysis, stem cell therapy

Knee osteoarthritis is a chronic degenerative bone metabolic illness that commonly happens in middle-aged and older adults; it impacts patients’ each day activities and even causes disability.[1,2] Its clinical features primarily include cartilage degenerative lesions, with clinical manifestations comparable to joint swelling, pain, and deformity. Thus, the main therapeutic purposes of knee osteoarthritis are to reduce or remove pain, correct joint deformities, and improve joint perform by way of cartilage restore.[3]

In recent years, replacement of broken articular cartilage by chondrocytes or cartilage tissue has been thought of a potential approach for treating knee osteoarthritis. Studies have shown that it's feasible to induce human pluripotent stem cells to differentiate into chondrocytes; therefore, stem cell therapy has change into a new technique for native treatment of knee osteoarthritis. For instance, mesenchymal stem cells (MSCs) have multi-directional differentiation potential and may be differentiated into osteoblasts and chondrocytes below specific induction conditions in vitro and in vivo, thereby repairing bone and articular cartilage.[4,5] However, there is still a dispute on the clinical effects of stem cells,[6-8] for which a mess of clinical trials and meta-analyses have been carried out.[9,10]

We herein present a meta-evaluation of the controversial efficacy and safety of stem cell therapy as a clinical remedy of knee osteoarthritis. This research is markedly distinguished from earlier meta-analyses[9,10] as a result of it targeted on bone marrow MSCs, peripheral blood stem cells, and amniotic fluid free stem cells. In addition, we used updated knowledge from several latest high-stage randomized managed trials (RCTs).[11,12] This meta-analysis is anticipated to provide an proof of the efficacy of stem cell therapy as a conservative therapy of knee osteoarthritis.

2. Methods

All analyses had been based mostly on previous published research; thus, no ethical approval and patient consent are required.

2.1. Study choice

In accordance with the popular Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) assertion,[13] 2 researchers independently screened the literature, as well as extracted and cross-checked the relevant knowledge. If disagreements occurred, a call relating to data extraction was made by a 3rd researcher.

2.2. Search strategy

We conducted the search in PubMed (1970-May 2019), Embase (1970-May 2019), and The Cochrane Library (1970-May 2019) databases for related articles, with "stem cells" and "osteoarthritis" as search phrases. We additionally manually screened related Chinese and English language journals and reference lists to include potential research. The search strategy for PubMed is detailed herein for instance: ((("Stem Cells"[Mesh]) OR ((((((((((((((Cell, Stem[Title/Abstract]) OR Stem Cell[Title/Abstract]) OR Progenitor Cells[Title/Abstract]) OR Cell, Progenitor[Title/Abstract]) OR Cells, Progenitor[Title/Abstract]) OR Progenitor Cell[Title/Abstract]) OR Mother Cells[Title/Abstract]) OR Cell, Mother[Title/Abstract]) OR Cells, Mother[Title/Abstract]) OR Mother Cell[Title/Abstract]) OR Colony-Forming Unit[Title/Abstract]) OR Colony Forming Unit[Title/Abstract]) OR Colony-Forming Units[Title/Abstract]) OR Colony Forming Units[Title/Abstract]))) AND ((((((((((((((Osteoarthritides[Title/Abstract]) OR Osteoarthrosis[Title/Abstract]) OR Osteoarthroses[Title/Abstract]) OR Arthritis, Degenerative[Title/Abstract]) OR Arthritides, Degenerative[Title/Abstract]) OR Degenerative Arthritides[Title/Abstract]) OR Degenerative Arthritis[Title/Abstract]) OR Osteoarthrosis Deformans[Title/Abstract]) OR Polyarthritides[Title/Abstract]) OR Arthritides[Title/Abstract]) OR Polyarthritis[Title/Abstract]) OR Arthritis[Title/Abstract])) OR "Osteoarthritis"[Mesh]).

2.3. Eligibility standards

The study inclusion standards included:

- (1)research involving patients with knee osteoarthritis;

- (2)studies together with stem cell therapy as the test group, in addition to placebo, hyaluronic acid, and steroid remedies as the control groups;

- (3)RCTs;

- (4)research that used a minimum of considered one of the next indicators: Visual Analogue Scale (VAS) score, Western Ontario and McMaster Universities (WOMAC) subscale, International Knee Documentation Committee (IKDC) rating, and incidence of antagonistic events.

Studies have been ineligible in the event that they met any of the next circumstances:

- (1)studies that used animals or cadavers as analysis objects;

- (2)research that were unable to extract or convert valid information;

- (3)retrospective studies, literature critiques, or convention papers with no full textual content.

2.4. Data extraction

Data had been extracted independently by 2 researchers using a predesigned information sheet. Valid knowledge have been transformed as per the Cochrane Handbook for Systematic Reviews of Interventions,[14] within the case where commonplace deviation couldn't be acquired. If disagreements occurred, the choice regarding knowledge extraction was finished by the third reviewer. Each RCT was concurrently assessed with risk of bias.

2.5. Outcome measures

VAS is a scoring scale that intuitively quantifies the intensity of ache within the knee. A decrease score signifies milder pain.

The WOMAC subscale is a ranking scale that assesses the construction, stiffness, and perform of the knee in pain A decrease rating indicates higher knee condition.

IKDC is a subjective scale for assessing the knee joint. The next score signifies higher signs, features, and bodily activities of the knee joint.

Adverse occasions seek advice from therapy-associated hostile reactions, together with joint effusion, stiffness, and pain.

2.6. Statistical evaluation

Statistical analysis was carried out using the RevMan 5.Three software (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). The chi-sq. check was used to assess inter-research heterogeneity. I2>50% indicated heterogeneity. A random results mannequin was used; otherwise, a fixed effects mannequin was used. Relative risk and standardized mean difference had been used for assessing binary variables and steady variables, respectively. The 95% confidence interval estimates and hypothesis testing outcomes for every variable were listed in a forest plot. For each endpoint with excessive heterogeneity, a sensitivity analysis, by which the included studies have been eliminated one at a time, was conducted to screen the source of heterogeneity. A publication bias evaluation utilizing a funnel plot was carried out if there were no less than 10 studies included.

3. Results

3.1. Literature search

We retrieved 7054 relevant articles, and in the end included 9 RCTs[11,12,15-21] involving 399 patients (Fig. 1). In the studies by Kuah,[12] Lamo-Espinosa,[16] and Thomas Vangsness et al,[19] there have been 2 parallel check teams, namely the excessive- and low-dose groups, in comparison with the control group. Therefore, for each study mentioned above, we performed statistical analyses in 2 RCTs: high-dose vs management and low-dose vs management.

Flowchart of literature retrieval.

3.2. Study characteristics

There were 203 patients in the stem cell therapy group and 196 patients in the management group. The precise options and Jadad scores of the patients[22,23] are listed in Table 1. The Jadad scale is a 7-point scale that includes random sequence generation, randomized hiding, blind technique, withdrawal, and dropout.

Main traits of all the eligible research included in the analysis.

3.3. Clinical outcomes

3.3.1. VAS

From baseline to three months, 4 studies[12,15,16,20] had been included, involving 6 RCTs with 87 patients in the stem cell group and 79 patients within the management group Fig. 2. There was no heterogeneity (I2=0%) between the research; thus, the fastened effects mannequin was used for the analysis. In accordance with Figure 2, SMD (standardized imply distinction)=−0.36, 95% CI (confidence interval)[−0.67, −0.05], and P=.02. The VAS score within the stem cell group was significantly decrease than that within the control group.

Forest plot of the change of VAS score. VAS=visible analogue scale rating.

From baseline to six months, four studies[12,15,16,20] had been included, involving 6 RCTs with 87 patients within the stem cell group and seventy nine patients within the control group. Because there was a excessive heterogeneity (I2=86%) between the studies, the research by Bhattacharya et al[20] was removed from the sensitivity evaluation, and the I2 worth was decreased to 0%. The mounted results mannequin was used. According to Figure 2, SMD=−0.86, 95% CI [−1.21, −0.52], and P
From baseline to 12 months, three studies[12,16,21] were included, involving 5 RCTs with 51 patients in the stem cell group and 43 patients within the management group. There was a low heterogeneity (I2=8%) between the studies, and thus the fastened effects model was used. Based on Figure 2, SMD=−0.86, 95% CI [−1.30, −0.43], and P=0.0001. The VAS rating in the stem cell group was significantly lower than that in the control group.

3.3.2. WOMAC-Pain

From baseline to 3 months, 2 research[12,16] have been included, involving 4 RCTs with 36 patients within the stem cell group and 28 patients within the management group Fig. 3. There was a low heterogeneity (I2=40%) between the studies, and thus the fixed results model was used. In response to Figure 3, SMD=−0.22, 95% CI [−0.73, 0.30], and P=.41. There was no significant difference in WOMAC-Pain score between the groups.

Forest plot of the change of WOMAC-Pain score. WOMAC=Western Ontario and McMaster Universities subscore.

From baseline to 6 months, 2 research[12,16] were included, involving 4 RCTs with 36 patients within the stem cell group and 28 patients within the management group. There was a low heterogeneity (I2=48%) between the studies, and thus the mounted results model was used. In line with Figure 3, SMD=−0.08, 95% CI [−0.59, 0.44], and P=.77. There was no vital distinction in WOMAC-Pain score between the teams.

From baseline to 12 months, three studies[12,16] have been included, involving 4 RCTs with forty three patients in the stem cell group and 39 patients in the control group. There was no heterogeneity (I2=0%) between the studies, and thus the mounted effects model was used. According to Figure 3, SMD=−0.09, 95% CI [−0.53, 0.36], and P=.70. There was no important difference in WOMAC-Pain rating between the groups.

3.3.3. WOMAC-Stiffness

From baseline to 3 months, 2 research[12,16] have been included, involving 4 RCTs with 36 patients in the stem cell group and 28 patients within the management group Fig. 4. There was no heterogeneity (I2=0%) between the research, and the mounted effects mannequin was used. According to Figure 4, SMD=−0.51, 95% CI [−1.02, 0.01], and P=.05. There was no significant distinction in WOMAC-Stiffness rating between the groups.

Forest plot of the change of WOMAC-Stiffness rating. WOMAC=Western Ontario and McMaster Universities subscore.

From baseline to 6 months, 2 studies[12,16] had been included, involving 4 RCTs with 36 patients within the stem cell group and 28 patients in the control group. There was a low heterogeneity (I2=36%) between the research, and the mounted results model was used. In line with Figure 4, SMD=−0.25, 95% CI [−0.76, 0.27], and P=.35. There was no significant difference in WOMAC-Stiffness rating between the teams.

From baseline to 12 months, 2 research[12,16] had been included, involving 4 RCTs with 36 patients in the stem cell group and 28 patients within the control group. There was a low heterogeneity (I2=9%) between the studies, and the fixed results model was used. In response to Figure 4, SMD=−0.46, 95% CI [−0.98, 0.05], and P=.08. There was no important distinction in WOMAC-Stiffness score between the groups.

3.3.4. WOMAC-Function

From baseline to 3 months, 2 studies[12,16] had been included, involving four RCTs with 36 patients in the stem cell group and 28 patients in the management group Fig. 5. There was no heterogeneity (I2=0%) between the research, and the fixed results mannequin was used. In response to Figure 5, SMD=0.15, 95% CI [−0.35, 0.66], and P=.55. There was no important difference in WOMAC-Function rating between the groups.

Forest plot of the change of WOMAC-Function. WOMAC=Western Ontario and McMaster Universities subscore.

From baseline to six months, 2 research[12,16] were included, involving 4 RCTs with 36 patients within the stem cell group and 28 patients in the control group. There was a low heterogeneity (I2=29%) between the studies, and the fixed effects model was used. Based on Figure 5, SMD=0.43, 95% CI [−0.09, 0.95], and P=.1. There was no important difference in WOMAC-Function score between the groups.

From baseline to 12 months, 2 research[12,16] were included, involving 4 RCTs with 36 patients in the stem cell group and 28 patients within the control group. There was no heterogeneity (I2=0%) between the research, and the fastened results model was used. According to Figure 5, SMD=0.18, 95% CI [−0.33, 0.68], and P=.49. There was no important difference in WOMAC-Function score between the groups.

3.3.5. IKDC

From baseline to six months, 2 studies[17,18] were included, involving 2 RCTs with fifty three patients in the stem cell group and fifty two patients within the control group Fig. 6. There was a excessive heterogeneity (I2=51%) between the research, and the random effects model was used. Based on Figure 6, SMD=0.16, 95% CI [−0.39,0.72], and P=.56. There was no significant distinction in IKDC score between the groups.

Forest plot of the change of IKDC score. IKDC=International Knee Documentation Committee.

From baseline to 12 months, 2 studies[17,18] were included, involving 2 RCTs with 53 patients within the stem cell group and fifty two patients in the management group. There was a high heterogeneity (I2=83%) between the studies, and the random results mannequin was used. In keeping with Figure 6, SMD=0.36, 95% CI [−0.58, 1.31], and P=.45. There was no important difference in IKDC score between the groups.

From baseline to 24 months, 2 studies[17,18] have been included, https://stemcellprocedurescanada.com/ involving 2 RCTs with 53 patients in the stem cell group and fifty two patients in the control group. There was a high heterogeneity (I2=75%) between the research, and the random effects model was used. In line with Figure 6, SMD=0.53, 95% CI [−0.25, 1.32], and P=.18. There was no vital distinction in IKDC score between the teams.

3.3.6. Adverse occasions

There have been 2 included studies,[11,12] involving three RCTs with 28 patients within the stem cell group and 20 patients within the control group Fig. 7. There was a excessive heterogeneity (I2=73%) between the studies, and thus the random effects model was used. In keeping with Figure 7, SMD=1.54, 95% CI [0.57, 4.19], and P=.40. There was no important distinction in incidence of adverse events between the teams.

Forest plot of the change of adverse events.

4. Discussion

4.1. Key findings

Changes in VAS and IKDC scores from baseline to 24 months were superior within the stem cell group than within the control group, whereas there were no statistical variations within the altering trend of other indicators between the 2 teams, together with the modifications in IKDC scores at 6 months, IKDC score at 12 months, WOMAC-Pain score, WOMAC-Stiffness rating, WOMAC-Function rating, WOMAC-Pain rating, and incidence of hostile events.

Pain relief is key to treating knee osteoarthritis, with VAS scores as an vital endpoint for ache assessment. Kuah et al[12] discovered that relative to placebo, stem cell therapy significantly relieved ache at 3, 6, and 12 months after treatment. This conclusion has been confirmed in our meta-analysis. We discovered that the VAS scores within the stem cell group have been significantly lowered at every go to point. Inflammatory response is called one of the causes of pain. MSCs can launch anti-inflammatory components, thereby relieving ache. Lamo-Espinosa et al[16] believed that stem cells have a paracrine function and their anti-inflammatory properties contribute to pain relief. In addition, studies have found that in an acute renal failure model, MSCs can promote recovery of renal function by releasing anti-inflammatory elements and inhibiting production of professional-inflammatory cytokines, reminiscent of interleukin-1β, tumor necrosis issue, and interferon-γ.[24] Similar findings have been noticed in a pulmonary fibrosis mannequin, by which MSCs release IL-1 receptor antagonist (IL-1RA) to inhibit interleukin-1α-producing T cells and TNF-producing macrophages, indicating that MSCs have anti-inflammatory properties.[25] WOMAC-Pain scores showed no statistical difference between the 2 teams at each visit level, however these data relating to WOMAC-Pain score have been obtained solely from three research;[12,16,21] due to this fact, additional studies with bigger pattern sizes are warranted to confirm these findings.

Functional improvement of the knee joint is considered one of the final word purposes of knee osteoarthritis treatment. In this examine, we used WOMAC-Stiffness, WOMAC-Function, and IKDC scores to comprehensively assess knee joint perform. Statistical analysis outcomes confirmed that there was no important distinction between the 2 groups in IKDC scores at 6 and 12 months, in addition to in WOMAC-Stiffness and WOMAC-Function scores at every visit point. Studies have discovered that mesenchymal stem cell implantation achieves better outcomes in patients with grade 3 knee osteoarthritis than those in patients with grade four knee osteoarthritis.[26] We thus concluded that treatment with MSCs are effective in preventing or limiting the development of knee osteoarthritis on the early stage. In the research by Kuah[12] and Lamo-Espinosa et al,[16] patients with grade three osteoarthritis or higher accounted for 75% and over 80% of the entire patients, respectively. Most patients developed knee osteoarthritis on the middle and late stages, for whom remedy with MSCs had no vital efficacy and was not conducive to practical recovery. Moreover, in most tissue engineering strategies, MSCs are mixed with cell scaffolds containing chondrogenic progress components to type fully useful hyaline cartilage. Such a regimen is commonly utilized in small-animal models of surgically induced cartilage or osteochondral defects, however cannot be used for repairing large-space cartilage defects associated with knee osteoarthritis.[27] As well as, Centeno,[28] Emadedin,[29] and Vangsness et al[19] pointed out that remedy with roughly 2×107 stem cells can afford good clinical outcomes. Kuah[12] and Lamo-Espinosa et al[16] reported that a stem cell dose of lower or greater than 2×107 might also affect the therapeutic efficacy of stem cells. In addition, the change in IKDC score at 24 months was higher within the stem cell group than in the management group; nevertheless, these knowledge were extracted from only 2 research. Therefore, additional investigation with a larger sample dimension is warranted.

For hostile occasions, we sent an e-mail to the authors of the relevant analysis[18,19,21] to acquire information on the number of patients who skilled remedy-related adversarial occasions, including arthralgia, joint effusion, and joint stiffness, in both the stem cell and control teams. Because of the lack of response from the opposite research, only 2 studies[11,12] had been included, involving three RCTs. There were no statistical differences in hostile events between the 2 groups, indicating that stem cell treatment has no apparent side effects. A examine addressing 87 patients with lupus erythematosus[30] confirmed no antagonistic occasions associated with transplantation after 4 years of follow-up. Similarly, no graft-related hostile events occurred in many patients undergoing stem cell therapy for other diseases.[31-35] These findings indicated that the human body has good tolerance to MSCs, and that stem cell treatment has no vital negative effects.

4.2. Limitations

Differences in the unique RCT protocols led to inadequate representation of some end result indicators. Thus, high-quality, massive-scale RCTs are required to verify our findings. As well as, there was no uniform normal within the preparation and use of stem cells, which can cause sure heterogeneity.

In comparison with conventional methods, stem cell treatment has a certain superiority as a conservative therapy of knee osteoarthritis, in terms of markedly decreasing ache without inducing side effects.

Conceptualization: Rui Huang.

Data curation: Rui Huang, Wei Li, Ying Zhao.

Formal analysis: Rui Huang, Wei Li, Ying Zhao, Fan Yang.

Investigation: Rui Huang, Wei Li, Ying Zhao.

Methodology: Rui Huang, Wei Li, Fan Yang.

Project administration: Meng Xu.

Software: Rui Huang, Wei Li, Ying Zhao, Fan Yang.

Supervision: Rui Huang, Wei Li, Ying Zhao, Meng Xu.

Validation: Ying Zhao, Fan Yang, Meng Xu.

Visualization: Rui Huang, Wei Li, Fan Yang.

Writing - unique draft: Rui Huang, Wei Li.

Writing - assessment & enhancing: Ying Zhao, Meng Xu.

Abbreviations: Ad-MSCs = adipose-derived mesenchymal stem cells, BMAC = bone marrow aspirate concentrate, BM-MSCs = bone marrow mesenchymal stromal cells, Cl = confidence interval, HA = hyaluronic acid, HTO = excessive tibial osteotomy, IKDC = International Knee Documentation Committee, IL-1RA = IL-1 receptor antagonist, MSCs = mesenchymal stem cells, PBSC = peripheral blood stem cells, PRG = progenza, PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analysis, PRP = platelet-poor plasma, RCTs = randomized managed trials, SMD = standardized imply distinction, VAS = Visual Analogue Scale, WOMAC = Western Ontario and McMaster Universities.

Tips on how to cite this text: Huang R, Li W, Zhao Y, Yang F, Xu M. Clinical efficacy and security of stem cell therapy for knee osteoarthritis: A meta-analysis. Medicine. 2020;99:11(e19434).

The authors have no conflicts of interests to disclose.

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