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Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: long-term follow up of a multicenter randomized controlled clinical trial (phase I/II)

Authors:
  • ITRAMED (Instituto de Traumatologia y Medicina Regenerativa Avanzada)
  • University Hospital of Salamanca

Abstract

Background: Mesenchymal stromal cells (MSCs) are a promising option to treat knee osteoarthritis (OA). Their safety and usefulness have been reported in several short-term clinical trials but less information is available on the long-term effects of MSC in patients with osteoarthritis. We have evaluated patients included in our previous randomized clinical trial (CMM-ART, NCT02123368) to determine their long-term clinical effect. MATERIALS: A phase I/II multicenter randomized clinical trial with active control was conducted between 2012 and 2014. Thirty patients diagnosed with knee OA were randomly assigned to Control group, intraarticularly administered hyaluronic acid alone, or to two treatment groups, hyaluronic acid together with 10 × 106 or 100 × 106 cultured autologous bone marrow-derived MSCs (BM-MSCs), and followed up for 12 months. After a follow up of 4 years adverse effects and clinical evolution, assessed using VAS and WOMAC scorings are reported. RESULTS: No adverse effects were reported after BM-MSCs administration or during the follow-up. BM-MSCs-administered patients improved according to VAS, median value (IQR) for Control, Low-dose and High-dose groups changed from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 7 (6, 7), 2 (2, 5) and 3 (3, 4), respectively at the end of follow up (Low-dose vs Control group, p = 0.01; High-dose vs Control group, p = 0.004). Patients receiving BM-MSCs also improved clinically according to WOMAC. Control group showed an increase median value of 4 points (- 11;10) while Low-dose and High-dose groups exhibited values of - 18 (- 28;- 9) and - 10 (- 21;- 3) points, respectively (Low-dose vs Control group p = 0.043). No clinical differences between the BM-MSCs receiving groups were found. CONCLUSIONS: Single intraarticular injection of in vitro expanded autologous BM-MSCs is a safe and feasible procedure that results in long-term clinical and functional improvement of knee OA.
Lamo‑Espinosaetal. J Transl Med (2018) 16:213
https://doi.org/10.1186/s12967‑018‑1591‑7
COMMENTARY
Intra‑articular injection oftwo
dierent doses ofautologous bone marrow
mesenchymal stem cells versushyaluronic
acid inthetreatment ofknee osteoarthritis:
long‑term follow upofa multicenter
randomized controlled clinical trial (phase I/II)
José María Lamo‑Espinosa1,2, Gonzalo Mora1, Juan F. Blanco3, Froilán Granero‑Moltó1,2,
Jorge María Núñez‑Córdoba6,7,8, Silvia López‑Elío1, Enrique Andreu2, Fermín Sánchez‑Guijo4,
José Dámaso Aquerreta5, José María Bondía5, Andrés Valentí‑Azcárate1, María del Consuelo del Cañizo4,
Eva María Villarón4, Juan Ramón Valentí‑Nin1 and Felipe Prósper2,9*
Abstract
Background: Mesenchymal stromal cells (MSCs) are a promising option to treat knee osteoarthritis (OA). Their safety
and usefulness have been reported in several short‑term clinical trials but less information is available on the long‑
term effects of MSC in patients with osteoarthritis. We have evaluated patients included in our previous randomized
clinical trial (CMM‑ART, NCT02123368) to determine their long‑term clinical effect.
Materials: A phase I/II multicenter randomized clinical trial with active control was conducted between 2012 and
2014. Thirty patients diagnosed with knee OA were randomly assigned to Control group, intraarticularly administered
hyaluronic acid alone, or to two treatment groups, hyaluronic acid together with 10 × 106 or 100 × 106 cultured autol‑
ogous bone marrow‑derived MSCs (BM‑MSCs), and followed up for 12 months. After a follow up of 4 years adverse
effects and clinical evolution, assessed using VAS and WOMAC scorings are reported.
Results: No adverse effects were reported after BM‑MSCs administration or during the follow‑up. BM‑MSCs‑adminis‑
tered patients improved according to VAS, median value (IQR) for Control, Low‑dose and High‑dose groups changed
from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 7 (6, 7), 2 (2, 5) and 3 (3, 4), respectively at the end of follow up (Low‑dose vs Control
group, p = 0.01; High‑dose vs Control group, p = 0.004). Patients receiving BM‑MSCs also improved clinically accord‑
ing to WOMAC. Control group showed an increase median value of 4 points ( 11;10) while Low‑dose and High‑
dose groups exhibited values of 18 ( 28; 9) and 10 ( 21; 3) points, respectively (Low‑dose vs Control group
p = 0.043). No clinical differences between the BM‑MSCs receiving groups were found.
Conclusions: Single intraarticular injection of in vitro expanded autologous BM‑MSCs is a safe and feasible proce‑
dure that results in long‑term clinical and functional improvement of knee OA.
Keywords: Knee osteoarthritis, Mesenchymal stem cells, Intraarticular injection
© The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
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provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
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Open Access
Journal of
Translational Medicine
*Correspondence: fprosper@unav.es
2 Cell Therapy Area, Clínica Universidad de Navarra, Pamplona, Spain
Full list of author information is available at the end of the article
Page 2 of 5
Lamo‑Espinosaetal. J Transl Med (2018) 16:213
Background
Osteoarthritis is a chronic disease involving the pro-
gressive degeneration of the articular cartilage and sub-
chondral bone, accompanied by synovitis [1]. Current
treatment options for articular cartilage injury and osteo-
arthritis are aimed to relieve inflammation and pain, but
have no effect on the natural progression of the disease
[2]. Mesenchymal stromal cells are a promising option
to treat knee osteoarthritis (OA) where, to date, knee
arthroplasty is the only therapeutic option [3]. In the
short term, the safety and usefulness of single injection
of expanded autologous MSCs have been reported with
positive results [46]. However, long-term results on
the efficacy of MSCs in patients with osteoarthritis have
been scarcely reported. Reservations about the time and
extent of the anti-inflammatory effects of MSCs are pre-
sent, questioning the real value of these therapies in the
medium and long term.
Here, we present the long-term results of a prospective
randomized clinical trial (No EudraCT: 2009-017624-
72, Clinical Trials. gov identifier: NCT02123368) of
patients with knee osteoarthritis previously reported [4].
e occurrence of complications and/or adverse effects
during the clinical study was registered. e knee OA
treatments received during these time were recorded.
In addition, the response to the intra-articular infusion
of HA with or without BM-MSCs was assessed using
VAS and WOMAC scores in the patients whom did not
underwent total knee arthroplasty.
Because the mild effect reported in MRI studies during
the initial follow-up, 12months, and because the absence
of femorotibial joint space in 50% of the patients, 0mm at
baseline (IV Kellgren-Lawrence grade), imaging studies
were not prolonged.
Demographic data
We were able to contact 27 of the 30 patients included
in the clinical trial and them have been included in
the follow up (Fig.1). Two of the patients of the Con-
trol group and one patient of the Low-dose group
received a total knee arthroplasty. Nonetheless, one
of these patients of the Control group was included
in the clinical analysis because the surgical treatment
was performed after the data collection. In addition,
two patients of the Control group underwent infiltra-
tion treatment with platelet rich plasma in the knee
included in the clinical trial. In spite of these, we have
finally included 25 patients (9, 8 and 8 patients in Con-
trol, Low-dose and High-dose group, respectively) for
the clinical analysis (Fig. 1). All the groups showed
similar baseline characteristics of age and body mass
index. Patients in the three groups showed an uneven
distribution according to the Kellgren-Lawrence scale
but without statistical significance (p = 0.585, Table 1).
e follow up was 48months (4years).
Safety
No serious adverse events or complications derived
from the procedures or treatments were noted during
the follow up. e patients who required anti-inflam-
matory treatment during the first 24h after infiltration
did not evolve with greater pain at the end of follow up.
Clinical assessment ofpain andfunction
VAS and WOMAC clinical scores were used in order to
obtain the best picture of how patients perceived their
own evolution at 4years.
e VAS scale showed a progressive improvement
during the follow up in the groups treated with BM-
MSCs (Fig.2) while the control group, patients showed
a progressive deterioration, increasing in two points the
median at the end of the follow up. Median VAS val-
ues (IQR) for Control, Low-dose and High-dose groups
changed from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 7 (6, 7),
2 (2, 5) and 3 (3, 4), respectively at the end of follow
up (Low-dose vs Control group, p = 0.01; High-dose vs
Control group, p = 0.004).
Similarly, the results of the WOMAC score showed
an improvement at the end of the follow up in both
groups treated with BM-MSCs. Median WOMAC val-
ues (IQR) for Control, Low-dose and High-dose groups
changed from 27 (19, 32), 37 (30, 46) and 29 (22, 35.5)
to 27 (17, 30), 17 (13, 25.5) and 16.5 (8, 23), respectively
at the end of follow up (Low-dose vs Control group,
p = 0.04). Furthermore, although patients receiving
only HA initially perceived some improvement for pain
and physical function subscores, this perception was
not sustained after long-term follow up. Intraarticu-
lar delivery of BM-MSCs, especially when used at low
dose, enabled patients to perceive an improvement in
their perception of pain in their daily activity (Fig.3).
A statistically significant improvement in WOMAC
value (calculated as the value at baseline versus end
of follow up) was observed in patients receiving BM-
MSCs, but not in the group treated with HA alone [4
( 11, 10), 18 ( 27.5, 8.5), and 10 ( 21.5, 3),
median (IQR), for Control, Low-dose and High-dose
BM-MSCs groups, respectively]. us, only the patients
Page 3 of 5
Lamo‑Espinosaetal. J Transl Med (2018) 16:213
Fig. 1 Study flow diagram. We have included 27 patients of the 30 patients that participate in the clinical trial
Page 4 of 5
Lamo‑Espinosaetal. J Transl Med (2018) 16:213
who had been treated with BM-MSCs met criteria to be
considered WOMAC responders after 4years of follow
up [7].
Conclusions
Our study shows that the single intraarticular injection
of invitro expanded autologous BM-MSCs together with
HA is a safe and feasible procedure that results in a clini-
cal and functional improvement of knee OA after a fol-
low up of 4years. ere are some questions that would
need further analysis, especially if a high dose of cells
is needed and if the repeated intraaticular injection of
BM-MSC may increase clinical results. In any case these
results support the development of future phase III clini-
cal trial.
Abbreviations
BM‑MSCs: bone marrow mesenchymal stromal cells; GMP: good manufacture
practices; HA: hyaluronic acid; K‑L: Kellgren and Lawrence scale; MRI: magnetic
resonance imaging; MSCs: mesenchymal stromal cells; OA: osteoarthritis; VAS:
visual analogue scale; WOMAC: Western Ontario and McMaster Universities
Osteoarthritis Index.
Authors’ contributions
Study design: JML‑E, GM, JM‑NC, MCC, FP. Provision of study materials or
patients: JML‑E, GM, JFB, AV‑A, EMV, GS‑G, JRV‑N, EA, FP. Data collection and
assembly: JML‑E, GM, EA, JFB, SLE, JMN‑C, FG‑M, CS‑E, JMB, JD‑A. Obtaining of
funding: FG‑M, MCC and FP. Drafting manuscript: JML‑E, FG‑M, FP. Approv‑
ing final version: JML‑E, GM, JFB, FG‑M, JMN‑C, CS‑E, SLE, JMB, JD‑A, EJA, EO,
EMV, AV‑A, FS_G, MCC, JRVN, FP. JML‑E, FG‑M, JMN‑C, FP take responsibility
for the integrity of the data analysis. All authors read and approved the final
manuscript.
Author details
1 Department of Orthopaedic Surgery and Traumatology, Clínica Universi‑
dad de Navarra, Pamplona, Spain. 2 Cell Therapy Area, Clínica Universidad
de Navarra, Pamplona, Spain. 3 Department of Traumatology, Complejo
Hospitalario de Salamanca, Salamanca, Spain. 4 Department of Hematol‑
ogy, Complejo Hospitalario de Salamanca, Salamanca, Spain. 5 Department
of Radiology, Clínica Universidad de Navarra, Pamplona, Spain. 6 Division
of Biostatistics, Research Support Service, Central Clinical Trials Unit, University
of Navarra Clinic, Pamplona, Spain. 7 Department of Preventive Medicine
and Public Health, Medical School, University of Navarra, Pamplona, Spain.
Table 1 Demographic data
Data are presented as median [interquartile range (IQR)]. OA osteoarthritis *K‑L:
Kellgren and Lawrence grading scale of severity of knee osteoarthritis at the
beginning of the clinical trial
Control BM-MSCs
Low-dose High-dose
N 9 8 8
Age (years) 60.6 (58.9, 61.1) 65.9 (58.3, 69.5) 57.8 (54.4, 63.0)
Males, n (%) 7 (77.8) 4 (50) 6 (75)
BMI (kg/m2) 29.4 (26.2, 30.8) 26.6 (23.6, 32) 28.6 (24.9, 31.8)
K‑L* 2, n (%) 4 (44.4) 1 (12.5) 2 (25)
K‑L* 3, n (%) 2 (22.2) 2 (25) 3 (37.5)
K‑L* 4, n (%) 3 (33.3) 5 (62.5) 4 (37.5)
Fig. 2 VAS scores along the study. The median values of VAS in the
three groups before administration of treatments and 3, 6, 12 months
and 4 years afterwards are presented. At 4 years: Low‑dose vs Control
group, p = 0.01 and High‑dose vs Control group, p = 0.004
Fig. 3 WOMAC scores along the study. The median values of
WOMAC in the three groups before administration of treatments
and 3, 6, 12 months and 4 years afterwards are presented. At 4 years:
Low‑dose vs Control group, p = 0.01 and High‑dose vs Control group,
ns
Page 5 of 5
Lamo‑Espinosaetal. J Transl Med (2018) 16:213
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8 Epidemiology and Public Health Area, Navarra Institute for Health Research
(IdiSNA), Pamplona, Spain. 9 Department of Hematology, Clínica Universidad
de Navarra, Pamplona, Spain.
Acknowledgements
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from
the corresponding author on reasonable request.
Consent for publication
Not applicable.
Ethics approval and consent to participate
All the procedures were approved by the Institutional Review Board of Navarra
and the Spanish Agency of Medicines and Medical Devices.
Funding
Clinical Trial has been partially supported by grants PI17/00163 (MINECO
through Instituto de Salud Carlos III to FG‑M) and RD12/0019/0017
and RD12/0019/0031 from Instituto de Salud Carlos III (Red TerCel)
and RD16/0011/0005 to FP. EMV is supported by Centro en Red de Medicina
Regenerativa y Terapia Celular de Castilla y León, Consejería de Sanidad, Junta
de Castilla y León.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations.
Received: 13 June 2018 Accepted: 25 July 2018
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... There were no severe adverse events; however, 4 individuals experienced transient knee joint pain and swelling after local administration. In a longterm follow-up of a multicenter randomized controlled clinical trial by Espinosa et al. [120], 30 OA patients were administered the intra-articular infusion of two diverse doses of autologous BMSCs cells (10 × 10 6 or 10 × 10 7 ) versus hyaluronic acid in the treatment of OA. No adverse effects occurred after MSCT or during the 4-year follow-up. ...
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... Stem cell therapy was very well-tolerated, and none of the dogs in the study developed adverse events that were likely to be related to UMSC treatment. Our findings are similar to studies in animals and humans reporting no adverse effects following intra-articular MSC treatment (5,7,24). The lack of side effects of MSC is attractive, because other intra-articular treatments for OA such as corticosteroids have reported risks associated with cytotoxicity, anaphylactic reactions or septic arthritis (25)(26)(27). ...
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