Medical Policy

 

Subject: Mesenchymal Stem Cell Therapy for the Treatment of Joint and Ligament Disorders, Autoimmune, Inflammatory and Degenerative Diseases
Document #: TRANS.00035 Publish Date:    04/24/2019
Status: Reviewed Last Review Date:    03/21/2019

Description/Scope

This document addresses the use of mesenchymal stem cell (MSC) therapy for the treatment of joint and ligament disorders due to injury or degeneration, as well as autoimmune, inflammatory and degenerative diseases.

MSC therapy refers to the procurement (through autologous or cadaveric allogeneic harvest) of MSCs, processing (such as, concentration and/or expansion of cells) and subsequent infusion or implantation of the MSCs into various anatomic areas to promote healing or regeneration of damaged tissue and bone.

Notes:

Position Statement

Investigational and Not Medically Necessary:

Mesenchymal stem cell therapy is considered investigational and not medically necessary for the treatment of joint and ligament disorders caused by injury or degeneration as well as autoimmune, inflammatory and degenerative diseases.

Rationale

Mesenchymal Stem Cells

Stem cells are specialized cells that are capable of renewing themselves through cell division and differentiating into multi-lineage cells. These cells are categorized as embryonic stem cells, induced pluripotent stem cells and adult stem cells.

Mesenchymal stem cells (MSCs), also known as multipotent mesenchymal stromal cells, are adult stem cells that can be isolated from animal and human sources. Human MSCs (hMSCs) are non-hematopoietic, multipotent stem cells that can differentiate into a variety of cell types. The four major cell types are osteocytes (bone), myocytes (muscle), adipocytes (fat) and chondrocytes (cartilage). MSCs have immunomodulatory properties and secrete cytokines. MSCs remain in a quiescent (non-proliferative) state during most of their lifetime, pending stimulation by the signals triggered by tissue renewal, damage and remodeling processes. Because of their multi-lineage potential, immunomodulatory properties and ability to secrete anti-inflammatory molecules, MSCs may have the potential to treat various chronic autoimmune, inflammatory and degenerative diseases (Ullah, 2015).

MSCs have been isolated from various sites, including dermis, amniotic fluid, adipose tissue, endometrium, dental tissue, synovial fluid and umbilical cord tissue. Additionally, researchers have been able to culture hMSCs in specific media.  

The U.S. Food and Drug Administration (FDA) regulates tissues and human cells intended for implantation, infusion or transplantation via the Center for Biologics Evaluation and Research, under Code of Federal Regulation, title 21, parts 1270 and 1271.

Orthopedic Conditions

Surgical repair of tendon, ligament, cartilage and bone defects has been the standard therapy, which may be augmented by autologous grafts, cadaveric allografts or synthetic grafts. However, there have been several limitations to the use of grafts in orthopedic therapy. For instance, autologous graft sources may be hampered by comorbid conditions, limited sites suitable for harvesting, and the potential of graft failure. Alternative regenerative technologies, which could minimize or avoid these issues while regenerating damaged tissue, are being actively investigated.

Various agents and techniques to procure and expand MSCs to achieve sufficient numbers for infusion or implantation are being studied and implemented in proprietary processes for diverse orthopedic indications. The processing of cadaveric allogeneic donor MSCs typically involves proprietary techniques and a combination of MSCs with various transport mediums. In addition, it is not clear that MSCs procured from different tissue sources are functionally equivalent. There is a paucity of randomized controlled trials in humans to support the safety and efficacy of using MSC therapy for orthopedic indications, including cartilage and ligament repair and bone regeneration.

At this time, the medical evidence supporting the use of MSCs for orthopedic indications involving the cartilage or ligaments is limited to pre-clinical studies, case series and small, randomized controlled trials. The efficacy and safety of these novel therapies have not been established in well-designed, large randomized controlled trials with long-term follow-up.

Several preclinical studies have been conducted to evaluate the effectiveness of MSCs in tissue regeneration. Caudwell and colleagues (2014) conducted a systematic review of preclinical studies using MSC and scaffolds in the treatment of knee ligament regeneration. The authors concluded, based on their investigation of 21 articles, that preclinical evidence of ligamentous regeneration with MSC and scaffold use was established, but limited clinical evidence exists to support recently developed scaffolds. Furthermore, no consensus has been reached on the nature of scaffold material that is most suitable.

A systematic review of preclinical studies published by Haddad and colleagues (2013) reviewed 19 articles that had used cell-based approaches to tissue-engineered menisci; cell types used included MSCs amongst others. The authors stated that, “The diversity of studies made it impossible to adhere to full guidelines or perform a meta-analysis,” but concluded that overall superior tissue integration and favorable biochemical properties were observed in regenerated tissues when compared to acellular techniques.

In 2011, Wakitani reported long-term follow-up of 45 articular cartilage repairs utilizing autologous bone marrow-derived MSCs (BMSCs) in 41 individuals. With a mean follow-up of 75 months (5 to 137 months), the authors reported no tumors or infections observed in the individuals who were treated between 1998 and November 2008. Although considered a low risk, the authors concluded that, “The possibility that the cells transplanted in joints move and injure other parts of the body remains unresolved” (Wakitani, 2011)

A pilot study was conducted by Wakitani and colleagues (2004) using autologous bone MSC therapy to repair nine full-thickness cartilage defects in the patello-femoral joints of 3 individuals. The assessment of clinical symptoms were rated with the International Knee Documentation Committee Subjective Knee Evaluation Form (IKDC score), with 0 being the worst and 100 being the best rating. IKDC scores improved for all 3 individuals during the follow-up period ranging from 7 to 20 months after receiving mesenchymal therapy. In all 3 cases, the investigators were unable to confirm the material covering the defects was in fact hyaline cartilage resulting from mesenchymal cell therapy.

In 2012, Lee and colleagues conducted a prospective, short-term comparative study to determine if knees with symptomatic cartilage defects treated with outpatient injections of MSCs and hyaluronic acid (HA; n=35) had better outcomes than an open-air implantation of MSCs (n=35). The outcome of interest was the International Cartilage Repair Society (ICRS) Cartilage Injury Evaluation Package and MRI results 1 year post-procedure. No adverse event was reported and significant improvement was seen across several domains of the ICRS evaluation package at final follow-up (mean 24 months). Although MRI results were promising, authors acknowledge that the sensitivity of MRIs in lesion identification was only estimated at 45%. A shortcoming of this study, aside from the small sample size and short-term data, is the inability to distinguish the MSC effect on outcomes from the HA effect since the control group received neither.

In 2013, Wong and colleagues conducted a randomized controlled trial evaluating 56 participants with unicompartmental, osteoarthritic, varus knees enrolled in either the stem cell recipient group (n=28) or the control group (n=28). The treatment group received intra-articular injections of MSCs and HA 3 weeks post-surgical intervention and the control group received HA only. Participants were re-evaluated at 6-, 12- and 24-month follow-up. The treatment group showed significantly better scores than the control group in Tegner (p=0.021), Lysholm (p=0.016), and IKDC (p=0.01) scores. MRI scans at 1 year follow-up showed significantly better Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scores (p<0.001). Authors conclude that the investigated intervention demonstrated efficacy in short-term clinical and MOCART outcomes. However, data was insufficient to demonstrate clinical improvement and long-term efficacy and safety data.

Vega and colleagues (2015) conducted a small, randomized, controlled trial comparing intra-articular injections of allogeneic bone marrow MSCs and HA in individuals with knee osteoarthritis (n=30). Each participant received either one injection of MSC or HA and were followed for 1 year. Assessed outcomes included evaluations of pain, disability, quality of life and articular cartilage quality as determined by MRI. The MSC group reported a medium to large treatment effect (effect size, 0.58-1.12) while the HA group reported a small treatment effect (effect size, 0.19-0.48). While the MSC group reported improved results over the HA group, it is noted that this is the first study to demonstrate the feasibility, safety and efficacy of the use of allogeneic MSCs in treating osteoarthritis. The authors note that further research is needed on how MSCs “relieve pain, promote regeneration, and become immune evasive.”

Jo and colleagues (2017) reported the results of a 2-year follow-up study that evaluated the safety and effectiveness of intra-articular injections of adipose tissue-derived MCSs (AD-MCSs) for the treatment of osteoarthritis of the knee. A total of 18 subjects with osteoarthritis of the knee were enrolled (15 female; 3 male; mean age, 61.8 ± 6.6 years [range, 52-72 years]). Participants in the low-, medium-, and high-dose groups received an intra-articular injection of 1.0 × 107, 5.0 × 107, and 1.0 × 108 AD MSCs into the knee, respectively. Clinical and structural evaluations were conducted using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and measurements of the size and depth of the cartilage defect, signal intensity of regenerated cartilage, and cartilage volume MRI. No treatment-related adverse events were reported during the 2-year period. An intra-articular injection of autologous AD MSCs enhanced knee function, as measured with the WOMAC, Knee Society clinical rating system (KSS), and Knee injury and Osteoarthritis Outcome Score (KOOS), and decreased knee pain, as measured with the visual analog scale (VAS), for up to 2 years regardless of the cell dosage. However, statistical significance was seen primarily in the high-dose group. Clinical outcomes tended to decline after 1 year in the low- and medium-dose groups, whereas those in the high-dose group remained level until 2 years. The structural outcomes gauged with MRI also showed similar trends. The authors concluded that this study demonstrated the safety and efficacy of the intra-articular injection of AD-MSCs into the osteoarthritic knee over 2 years. The authors acknowledged that this study highlighted potential concerns about the durability of clinical and structural outcomes and encouraged larger randomized clinical trials.

Ha and colleagues (2019) conducted a systematic review assessing the efficacy of intra-articular MSCs in terms of clinical outcomes including pain and function and cartilage repair in individuals with osteoarthritis of the knee. Clinical outcomes were evaluated using clinical scores, and cartilage repair was assessed using magnetic resonance imaging and second-look arthroscopy findings. A total of 17 studies met the inclusion criteria: 6 randomized controlled trials; 8 prospective observational studies; and 3 retrospective case-control studies. Of the 17 studies, 1 used umbilical cord blood-derived MSCs, 2 used adipose tissue-derived MSCs, 6 used adipose tissue-derived stromal vascular fraction and 8 studies used bone marrow-derived MSCs. All studies except 2 reported improved clinical outcomes at final follow-up or significantly better clinical outcomes in the MSC group. With regard to cartilage repair, 9 of 11 studies reported an improvement in the state of the cartilage on magnetic resonance imaging. A total of 6 of 7 studies reported the presence of repaired tissue on second-look arthroscopy. The authors concluded that in many cases, intra-articular MSCs improve pain and function in knee osteoarthritis at short-term follow-up (< 28 months), however, the evidence of efficacy of intra-articular MSCs on both cartilage repair and clinical outcomes remains limited.

In 2014, Vangsness and colleagues performed the first randomized, double-blind controlled clinical trial investigating the efficacy and safety of MSCs in the treatment of an orthopedic indication. A total of 55 participants from seven institutions who were eligible for a partial medial meniscectomy were enrolled and randomized into one of three treatment groups: Group A (n=17) received an injection of 50x106 allogeneic MSCs; Group B (n=18), received 150x106 MSCs; and the control group (n=19) received an HA injection only. Outcomes of interest at intervals over the 2-year follow-up period included safety, meniscus regeneration, overall knee joint condition and clinical outcomes. No adverse events occurred and investigators found a significant increase in meniscal volume (p=0.022; determined by MRI) in both Groups A and B; no participants met the threshold for increased volume (15%) in the control group. Furthermore, both groups A and B reported a significant reduction in pain compared to the control group. Results of this small, Phase I/II clinical trial are promising for use of MSCs in knee-tissue regeneration. Data from larger trials are needed to confirm the early results.

In a systematic review by Longo and colleagues (2011), authors state that the use of MSC therapy for repair of tendon injuries is “At an early stage of development. Although these emerging technologies may develop into substantial clinical treatment options, their full impact needs to be critically evaluated in a scientific fashion.”

Although preclinical studies, case series, and small, randomized trials suggest that MSC therapy may improve regeneration of bone or tissue in orthopedic indications, the lack of validated, comparable scoring, robust sample sizes and long-term follow-up data, preclude definitive conclusions regarding the net health benefit of MSC therapy.  

Neurodegenerative Diseases

Alzheimer’s Disease

Kim and colleagues (2015) conducted a phase I clinical trial in individuals (n=9) with mild-to-moderate Alzheimer's disease to evaluate the safety and dose-limiting toxicity of stereotactic brain injection of human umbilical cord blood-derived MSCs (hUCB-MSCs). The low- (n=3) and high-dose (n=6) cohorts received a total of 3.0 × 106 cells/60 μL and 6.0 × 106 cells/60 μL, respectively, into the bilateral hippocampi and right precuneus. None of the study participants demonstrated serious adverse reactions during the 24-month follow-up period. During the 12-week follow-up period, the most frequent acute adverse event was wound pain from the surgical procedure (n=9), followed by headache (n=4), dizziness (n=3), and postoperative delirium (n=3). No dose-limiting toxicity was reported. The authors concluded that the administration of hUCB-MSCs into the hippocampus and precuneus by stereotactic injection was feasible, safe, and well tolerated but additional trials are warranted to determine treatment efficacy.

Amylotrophic lateral sclerosis (ALS)

Mazzini and colleagues (2003) evaluated the feasibility and safety of a method of intraspinal cord implantation of autologous MSCs in 7 participants (4 females and 3 males; range: 23–74 years, mean age 46.6 ± 16.8 years) with ALS. The group had severe functional impairment of the lower limbs and mild functional impairment of the upper limbs without signs of respiratory failure. Participants were monitored by clinical evaluation which included the Norris score, ALS-FRS scale, bulbar score, and MRC strength scale. Respiratory assessment included clinical evaluation, arterial blood gas analysis, pulmonary function tests and nocturnal cardio-respiratory monitoring. The neurophysiological assessments consisted of somatosensory evoked potentials (SEP) and EMG. The neuro-radiological assessment included MRI of the spinal cord and brain before and after gadolinium DTA infusion. A clinical psychologist conducted a psychological evaluation. None of the participants experienced severe adverse events such as death, respiratory failure or permanent post-surgical neurological deficits. Minor adverse events included intercostal pain (n=4) which was reversible after a mean period of 3 days (range: 1–6) after surgery, and leg sensory dysesthesia (n=5) which resolved after a mean period of 6 weeks (range: 1–8) following surgery. None of the participants manifested bladder and bowel dysfunction, or leg motor deficit. There were no anesthetic complications. MRI with gadolinium DTA infusion carried out at 3 and 6 months post implantation demonstrated no evidence of structural changes of the spinal cord or signs of abnormal cell proliferation when compared with the baseline. SEPs from tibial nerve stimulation demonstrated a mild delay of the central conduction time 3 days after surgery but this normalized within 1 month following transplantation. All of the participants showed a good acceptance of the procedure and no significant modifications of the quality of life or the psychological status were observed. In all of the participants, muscular strength (MRC scale) declined during the 6 months before transplantation. However, at the third month post stem cell implantation a trend towards a slowing down of the linear decline of muscular strength was evident in 4 participants in the proximal muscle groups of the lower limbs, while a mild increase in strength was observed in the same muscle groups of 2 participants. While the authors concluded that the study seemed to demonstrate MSC transplantation into the spinal cord of humans is safe and well tolerated by individuals with ALS, the authors stated that additional controlled studies are needed to evaluate the efficacy of stem cell therapy in the treatment of ALS.

Parkinson’s Disease

Research exploring the feasibility of MSC transplantation as a treatment of Parkinson’s disease is ongoing. In one study (NCT00976430), researchers investigated the safety and efficacy of autologous MSCs in treating advanced Parkinson’s disease by harvesting and processing the stem cells from bone marrow and transplanting them via stereotactic techniques into the striatum of the subject. However, the study was terminated because an adequate number of participants could not be recruited in the set timeframe. Other studies exploring the use of MSCs as a treatment of Parkinson’s disease are ongoing but not yet completed or published. Information regarding these studies is available on the clinicaltrials.gov web site.

At this time, there is insufficient evidence from well-designed clinical trials to evaluate the clinical utility of MSC therapy in individuals with neurodegenerative diseases. 

Autoimmune Diseases

Celiac Disease

Ciccocioppo and colleagues (2016) reported the results of a study that investigated the feasibility, safety, and efficacy of serial infusions of autologous bone marrow-derived MSCs in a 51-year-old woman with type II refractory celiac disease. MSCs were separated, expanded, and characterized according to standard protocols. The researchers monitored the participant’s malabsorption indexes, mucosal architecture, and percentage of aberrant intraepithelial lymphocytes during study enrollment, at each infusion, and 6 months post treatment. Mucosal expression of interleukin (IL)-15 and its receptor was also monitored. The subject underwent 4 systemic infusions of 2×106 MSCs/kg body weight 4 months apart, without adverse effects. During the treatment period, the participant experienced gradual and durable amelioration of her general condition, with normalization of stool frequency, body mass index, laboratory test results, and mucosal architecture. The expression of IL-15 and its receptor practically disappeared.  At this time, there is insufficient evidence from well-designed clinical trials to evaluate the clinical utility of MSC therapy in individuals with celiac disease. 

Multiple sclerosis

Harris and colleagues (2018) conducted a phase I open-label clinical trial investigating the safety and tolerability of autologous bone marrow MSC-derived neural progenitor cells for the treatment of progressive multiple sclerosis. Of the 20 participants in the study, 16 (80%) had secondary progressive multiple sclerosis. MSC-derived neural progenitor treatment was administered intrathecally in three separate doses of up to 1 × 107 cells per dose, spaced 3 months apart. The primary endpoint was to evaluate the safety and tolerability of the treatment. Expanded disability status scale (EDSS), timed 25-ft walk (T25FW), muscle strength, and urodynamic testing were employed to evaluate treatment response. The MSC-derived neural progenitor treatment was safe and well tolerated. The participants completed all 60 planned treatments without serious adverse effects. Approximately 85% of the participants experienced headaches and transient fever during the first 24 hours post the treatment. Post-treatment disability score analysis showed improved median EDSS scores, suggesting possible efficacy. Positive trends were identified more frequently in the subset of individuals with secondary progressive multiple sclerosis. Following treatment, 70% of the participants demonstrated improved muscle strength and 50% of the participants had improved bladder function. The disease worsened in 2 participants and the condition of 3 individuals remained the same. The results of this study are limited by its small size and the lack of a placebo or active comparator.

In a triple-blind, placebo-controlled study, Fernandez and colleagues (2018), investigated the safety and feasibility of the use of adipose-derived MSCs for the treatment of secondary-progressive multiple sclerosis. The cell samples were obtained from consenting participants by lipectomy and subsequently expanded. Study participants were randomized 1:1:1 to an intravenous infusion of placebo or one of two dose-groups (1x106 cells/kg or 4x106 cells/kg). The study was triple blinded (the treating physician, study participant and statisticians were unaware of treatment assignment). Participants were followed for 12 months. The researchers monitored safety using laboratory parameters, vital signs and spirometry. EDSS, MRI and other measures of possible treatment effects and adverse events were also recorded. A total of 34 subjects underwent lipectomy for adipose-derived MSC collection, were randomized and 30 were infused (11 placebo, 10 low-dose and 9 high-dose); 4 randomized participants were not infused due to karyotype abnormalities in the cell product. Measures of treatment effect demonstrated an inconclusive trend of efficacy. The mean EDSS score and the individual EDSS did not reflect any significant changes over the course of the study. Baseline MRI data was similar between the three groups. The researchers reported some non-statistically significant differences between the placebo and treatment groups for the evoked potentials parameters after 12 months of treatment. Tibial SEP central conduction time (N22-P39) and the motor evoked potential (MEP) central conduction time for the legs, reflected statistically significant diminishing latencies over time in placebo and the two treatment groups, but these differences were not statistically significant comparing placebo and both treatment groups. Visual evoked potential (VEP) and median nerve SEP (N13-N20) also demonstrated a trend of stabilization or amelioration of latencies over time in treatment groups, however, these differences did not reach statistical significance over the time. There were no significant changes in the cerebral spinal fluid from baseline to the 12-month follow-up. One serious adverse event was reported in the treatment arms (urinary infection, considered not related to study treatment). No other changes in safety parameters were reported. Although the results of the study did not demonstrate treatment efficacy, the authors found infusion of autologous adipose-derived MSCs safe and feasible in individuals with secondary-progressive multiple sclerosis.

Systemic Lupus Erythematosus (SLE)

Wang and colleagues (2014) conducted a multicenter clinical trial to assess the safety and efficacy of allogeneic umbilical cord MSC transplantation (MSCT) in subjects with active and refractory SLE. Researchers recruited 40 individuals with active SLE from four clinical centers. Allogeneic umbilical cord MSCs were infused intravenously on days 0 and 7. The primary endpoints were safety profiles. The secondary endpoints included major clinical response (MCR), partial clinical response (PCR) and relapse. Each participant was re-assessed at 1, 3, 6, 9 and 12 months post MSC transplantation. Evaluations performed at the follow-up visits included a physical examination, determination of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, British Isles Lupus Assessment Group (BILAG) analysis, serologic studies and evaluation of organ function. A total of 39 subjects (39/40, 97.5%) underwent umbilical cord MSC infusions twice with an interval of 1 week, and 1 participant (1/40, 2.5%) was exempted from the second MSC infusion due to uncontrolled disease progression. The overall survival rate was 92.5% (37 of 40 subjects). Umbilical cord MSCT was well tolerated, and no adverse events related to the transplantation were observed. During the 12 months of follow-up, an MCR was achieved in 13 participants (32.5%) and 11 participants (27.5%) achieved a PCR. Three individuals (12.55%) experienced disease relapse at 9 months and 4 participants (16.7%) experienced disease relapse at 9 months after a prior clinical response. The SLEDAI scores decreased significantly at 3, 6, 9 and 12 months follow-up. Total BILAG scores decreased at 3 months and continued to decrease at subsequent follow-up visits. BILAG scores for hematopoietic, renal and cutaneous systems improved. Among participants with lupus nephritis, 24-hour proteinuria diminished after transplantation, with statistically significant differences at 9 and 12 months. Serum creatinine and urea nitrogen declined to the lowest level at 6 months, but these values slightly increased at 9 and 12 months in 7 relapse cases. Additionally, serum levels of albumin and complement 3 rose after MSCT, peaked at 6 months and then slightly declined by the 9- and 12-month follow-up examinations. Serum antinuclear antibody and anti-double-stranded DNA antibody diminished after MSCT, with statistically significant differences at 3-month follow-up examinations. The authors concluded that the study results demonstrate that umbilical cord MSCT is a safe and effective treatment for individuals with SLE, but a repeated MSC infusion may be necessary after 6 months to avoid disease relapse. The authors also acknowledge that limitations of the study include its lack of a randomized controlled design and the lack of uniformity amongst the condition of the study participants.

In 2015, Wang and colleagues reported the results of a study that investigated whether double transplantations of MSCs is superior to single transplantation. Of the 58 refractory SLE subjects enrolled in the study, 30 were randomly given single MSCT, and the other 28 were given double MSCT. Participants were followed to determine rates of survival, disease remission, and relapse, as well as transplantation-related adverse events. Serologic features and changes in the SLEDAI were monitored. At more than 1 year follow-up, the results demonstrated that no remarkable differences between single and double allogeneic MSCT were found in terms of disease remission and relapse, amelioration of disease activity and serum indexes. This study demonstrated that single MSC transplantation at the dose of one million MSCs per kilogram of body weight was sufficient to induce disease remission for refractory SLE subjects. Although 95% of the participants had lupus nephritis at the time of enrollment, it is unclear whether MSC therapy can ameliorate renal pathology, aside from the improvements in renal function, because the pathological data on the participants at the time of enrollment was not available.

Crohn’s Disease

In a Phase I trial, Duijvestein and colleagues (2010) assessed the safety and feasibility of the use of autologous bone marrow-derived MSC treatment for luminal Crohn's disease refractory to steroids and immunomodulators. A total of 10 adult participants with refractory Crohn's disease underwent bone marrow aspiration under local anesthesia. Bone marrow MSCs were isolated and expanded ex-vivo. MSCs were assessed in- vitro for functionality and phenotype.  Nine participants received two doses of 1-2×106 cells/kg body weight, intravenously, 7 days apart. During follow-up, the participants were monitored for possible side effects and changes in the Crohn's disease activity index (CDAI). Colonoscopies were conducted at weeks 0 and 6, and mucosal inflammation was assessed using the Crohn's disease endoscopic index of severity. The study demonstrated a decline in CDAI by ≥ 70 from baseline in 3 participants at 6 weeks post treatment; conversely 3 participants required surgery due to worsening Crohn’s disease. None of the participants achieved remission. The subjects reported minor allergic reaction (10%), headache (30%), as well as taste and smell disturbances (90%) which were considered related to MSC infusion.

Zhang and colleagues (2018) investigated the efficacy and safety of umbilical MSCs for the treatment of Crohn’s disease. The Phase III clinical trial included 82 participants who were diagnosed with Crohn’s disease and had received steroid maintenance therapy for more than 6 months. A total of 41 participants were randomly selected to receive four peripheral intravenous infusions of 1×106 umbilical cord MSCs/kg, with one infusion per week. Participants were followed for 12 months. Assessment tools included the CDAI and Harvey-Bradshaw index (HBI). Corticosteroid dosage was also assessed. Twelve months post treatment, the CDAI, HBI, and corticosteroid dosage had decreased by 62.5 ± 23.2, 3.4 ± 1.2, and 4.2 ± 0.84 mg/day, respectively, in the umbilical cord-MSC group and by 23.6 ± 12.4, 1.2 ± 0.58, and 1.2 ± 0.35 mg/day, respectively, in the control group (p˂0.01, p˂0.05, and p˂0.05 for UC-MSC vs control, respectively). Fever after the administration of MSC infusion was reported in 4 participants. No serious adverse events were reported. The authors concluded that umbilical cord-MSCs were an effective treatment for Crohn’s disease that produced mild side effects. A limitation of this study was that it did not examine indicators of immune status or intestinal histopathology in the participants. Therefore, the mechanism by which stem cell therapy modifies Crohn’s disease remains unclear.

While small, preliminary studies investigating the use of MSC therapy as a treatment for Crohn’s disease may show promise, additional well-designed studies with larger populations and longer follow-up periods are needed before conclusions regarding the safety and efficacy of MSC therapy can be made.

Summary

MSCs isolated from bone marrow and other sites, display specific anti-inflammatory and immunomodulation properties and may be a tool for the treatment of various chronic diseases. While the results of some early trials have been promising, a number of questions remain (Goldberg, 2017; Viganò, 2016). The available data have not yet established that MSCs, when infused or transplanted, can regenerate by incorporating themselves into native tissue, survive, differentiate, and promote the preservation of injured tissue. In addition, the optimal source for MSCs has not been clearly identified. Randomized, controlled trials that are adequately powered and include long-term follow-up data are needed before conclusions regarding the safety, efficacy and clinical utility of MSC therapy for the treatment of chronic autoimmune, inflammatory, orthopedic and degenerative diseases can be made.

Background/Overview

MSCs are being investigated as a regenerative biologic agent because of their ability to differentiate into multiple tissue types and to self-renew. MSCs can be derived from a variety of sources, including adipose tissue, bone marrow, placenta, and peripheral or umbilical blood. The MSC population in red bone marrow is estimated at 1 per 105 nucleated cells. The incidence of MSCs in adults is 1 per 103 nucleated cells (Piccirilli, 2017). Counts in cord blood or peripheral blood are lower (Bonab, 2006). These tissue sources differ with respect to MSC cell density and differentiation capacity. Bone marrow-derived MSCs are considered the preferred source for bone repair and regeneration as there is better chondrogenic differentiation potential (Shao, 2015). Although other sources for MSCs have been identified, the bone marrow is currently the primary source of procurement.

MSC therapy has been proposed as a treatment option for orthopedic indications that include torn cartilage, osteoarthritis, and bone grafting. The proposed benefits of MSC therapy are improved healing and possible avoidance of surgical procedures with protracted recovery times. MSCs are used as a stand-alone therapy in the form of an injection or in combination with scaffolds (Viganò, 2016),

Optimal materials or grafts that promote bone growth and healing require the following properties (Shen, 2005):

Currently, the risks of MSC therapy for the treatment of chronic, autoimmune, inflammatory and degenerative conditions are unknown. Insufficient data have been reported to allow a proper understanding of how this technology may affect individuals either in the short or long-term. Furthermore, there are known risks related to the various methods utilized to harvest MSCs from the bone marrow, including pain and hemorrhage.

MSC therapy is being investigated as a treatment of many chronic, autoimmune, inflammatory and degenerative conditions, including but not limited to the following diseases:

Definitions

Multipotent: Possessing the ability to produce more than one type of specialized cell of the body, but not all types of cells.

Stem cells: A type of self-renewing cell from which other types of cells develop.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT

 

17999

Unlisted procedure, skin, mucous membrane and subcutaneous tissue [when specified as harvesting of MSCs]

20999

Unlisted procedure, musculoskeletal system, general [when specified as harvesting of MSCs or MSC implant]

38230

Bone marrow harvesting for transplantation; allogeneic

38232

Bone marrow harvesting for transplantation; autologous

38999

Unlisted procedure, hemic or lymphatic system [when specified as MSC implant]

64999

Unlisted procedure, nervous system [when specified as MSC implant]

 

 

ICD-10 Procedure

 

30230AZ

Transfusion of embryonic stem cells into peripheral vein, open approach

30233AZ

Transfusion of embryonic stem cells into peripheral vein, percutaneous approach

30240AZ

Transfusion of embryonic stem cells into central vein, open approach

30243AZ

Transfusion of embryonic stem cells into central vein, percutaneous approach

3E0Q0AZ

Introduction of embryonic stem cells into cranial cavity and brain, open approach

3E0Q3AZ

Introduction of embryonic stem cells into cranial cavity and brain, percutaneous approach

3E0R0AZ

Introduction of embryonic stem cells into spinal canal, open approach

3E0R3AZ

Introduction of embryonic stem cells into spinal canal, percutaneous approach

 

 

ICD-10 Diagnosis

 

 

Including, but not limited to, the following:

G12.21

Amyotrophic lateral sclerosis

G20-G21.9

Parkinson’s disease, secondary parkinsonism

G30.0-G30.9

Alzheimer’s disease

G31

Other degenerative diseases of nervous system, not elsewhere classified

G35

Multiple sclerosis

K50.00-K51.919

Crohn’s disease [regional enteritis], ulcerative colitis

K52.3

Indeterminate colitis

K90.0

Celiac disease

M04.1-M04.9

Autoinflammatory syndromes

M15.0-M19.93

Osteoarthritis

M21.00-M21.079

Valgus deformity, not elsewhere classified

M21.10-M21.179

Varus deformity, not elsewhere classified

M21.70-M21.769

Unequal limb length (acquired)

M21.80-M21.869

Other specified acquired deformities of limbs

M21.90-M21.969

Unspecified acquired deformity of limb and hand

M23.000-M23.92

Internal derangement of knee

M24.10-M24.176

Other articular cartilage disorders

M24.20-M24.28

Disorder of ligament

M24.60-M24.676

Ankylosis of joint

M24.7

Protrusio acetabuli

M24.80-M24.876

Other specific joint derangements, not elsewhere classified

M24.9

Joint derangement, unspecified

M25.50-M25.579

Pain in joint

M32.0-M32.9

Systemic lupus erythematosus (SLE)

M75.00-M75.92

Shoulder lesions

M84.30XA-M84.9

Disorder of continuity of bone

M87.00-M87.9

Osteonecrosis

M91.0-M94.9

Chondropathies

S43.401A-S43.499S

Sprain of shoulder joint

References

Peer Reviewed Publications:

 

  1. Bonab MM, Alimoghaddam K, Talebian F, et al. Aging of mesenchymal stem cell in vitro. BMC Cell Biol. 2006; 7:14.
  2. Buda R, Vannini F, Cavallo M, et al. One-step arthroscopic technique for the treatment of osteochondral lesions of the knee with bone-marrow-derived cells: three year results. Musculoskelet Surg. 2013; 97(2):145-151.
  3. Ciccocioppo R, Gallia A, Avanzini MA, et al. A refractory celiac patient successfully treated with mesenchymal stem cell infusions. Mayo Clin Proc. 2016; 91(6):812-819.
  4. Dave M, Mehta K, Luther J, et al. Mesenchymal stem cell therapy for inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis. 2015; 21(11):2696-2707.
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Government Agency, Medical Society, and Other Authoritative Publications:

  1. Jaslok Hospital and Research Centre. Autologous Mesenchymal Stem Cell Transplant for Parkinson's Disease. NLM Identifier: NCT00976430. Last updated on August 14, 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT00976430?term=NCT00976430&rank=1. Accessed on February 12, 2019.
  2. U.S. Food and Drug Administration (FDA). Regulatory considerations for human cells, tissues, and cellular and tissue-based products: minimal manipulation and homologous use guidance for industry and food and drug administration staff (Nov 2017) Available at: https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGene
    Therapy/UCM585403.pdf
    . Accessed on February 12, 2019.
Websites for Additional Information

U.S National Institute of Health. Stem Cell Information. Available at: http://stemcells.nih.gov/. Accessed on February 12, 2019.

Document History

Status

Date

Action

Reviewed

03/21/2019

Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Rationale, Background/Overview, Definitions, References and Websites for Additional Information sections. 

Revised

01/24/2019

MPTAC review. Title changed to “Mesenchymal Stem Cell Therapy for the Treatment of Joint and Ligament Disorders, Autoimmune, Inflammatory and Degenerative Diseases”. Updated the Description/Scope, Rationale, Background/Overview, Definitions, References and Websites for Additional Information sections. Deleted Index section.  Updated Coding section to include removing 20930 for spinal surgery no longer addressed.

Reviewed

09/13/2018

MPTAC review Updated Rationale and References sections.

Reviewed

11/02/2017

MPTAC review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Rationale, Background, References and Website sections.

 

03/06/2017

Revised note in Scope section to clarify that TRANS.00035 addresses bone graft products with added or exogenous MSCs and that bone graft products with endogenous MSCs are addressed in CG-SURG-45.

Reviewed

11/03/2016

MPTAC review. Removed the products Osteocel, Trinity Evolution and Elite and BIO4 from the rationale. Updated Description, Rationale, References, Website and Index sections.

Reviewed

08/04/2016

MPTAC review. Updated Description, Rationale, Background, References and Websites sections.

 

04/01/2016

Updated Coding section with corrected diagnosis code range for spondylosis; also removed ICD-9 codes.

Reviewed

08/06/2015

MPTAC review. Updated Description/Scope, Rationale, Coding, References, Websites and Index sections.

Reviewed

08/14/2014

MPTAC review. Updated Description/Scope, Rationale, References and Websites sections.

Reviewed

08/08/2013

MPTAC review. Updated Rationale, Background, References and Websites sections.

Reviewed

08/09/2012

MPTAC review. Rationale, Background, References and Websites updated.

 

01/01/2012

Updated Coding section with 01/01/2012 CPT changes.

Reviewed

08/18/2011

MPTAC review. Rationale, Background, References and Websites updated. Updated Coding section with 10/01/2011 ICD-9 changes.

Reviewed

08/19/2010

MPTAC review. Rationale, Background, References and Websites updated.

Reviewed

08/27/2009

MPTAC review. Rationale, websites and references updated.

New

08/28/2008

MPTAC review. Initial document development.