Table 2A

Clinical trials of mesenchymal stromal cells in MS, RA and SLE

Diseases and clinical trials	Number of patients, source of cells, dose and route of administration	Outcomes	Comments
Multiple sclerosis, MS
1. Karussis et al (2010)67 Phase I/II uncontrolled feasibility study of patients with MS and ALS	34 patients (15 with MS, 19 with ALS) received autologous BM-derived MSCs intrathecally (n=34) at a mean dose of 63.2×10⁶ in 2mls of saline and intravenously (n=14) at a mean dose of 23.4×10⁶ cells in 2mls of saline.	No major AEs. EDSS score improved over 6 months. Proportion of CD4⁺CD25⁺ Tregs increased, and expression of CD40, CD83, CD86 and HLA-DR on myeloid dendritic cells decreased 24 hours post-administration. MRI of MSC labelled with superparamagnetic particles showed MSCs in meninges, subarachnoid space, and spinal cord.	No comparison between intravenous and Intrathecal routes as regards homing of MSCs to the CNS. Cryopreserved cells were used.
2. Bonab et al (2012)68 Phase II uncontrolled study of patients with SPMS	22 patients received Intrathecal, autologous BM-derived MSCs at a mean dose of 29.5×10⁶ cells in 10mls of normal saline.	AEs were low-grade: transient fever, headache, nausea/vomiting (related to lumbar puncture). Disease progression stabilised in the short-term evidenced by MRI and EDSS score.	After initial improvement some patients reported worsening EDSS, and about 25% showed worsening lesions on MRI, after 12 months. Cryopreservation was not discussed.
3. Connick et al (2012)69 Phase IIa feasibility/ proof-of-concept study in patients with SPMS	10 patients received autologous bone marrow (BM)-derived MSCs intravenously at a mean dose of 1.6×10⁶ cells/kg.	Mild AEs such as transient post-transfusion rash and self-limiting bacterial infections. Improvement in visual acuity, visual evoked potentials, optic nerve area and EDSS. No change in post-treatment T cell subset counts.	Cryopreserved cells were used.
4. Li et al (2014)70 Randomised Controlled Phase II study in patients with RRMS and SPMS	13 patients received 3 cycles of intravenous, allogeneic umbilical cord (UC)-derived MSCs, 2 weeks apart, at a dose of 4×10⁶ cells/kg body weight in 100mls of saline. Conventional treatment (anti-inflammatory and immunosuppressants) was continued; 10 patients received only conventional treatment.	Reduced frequency of recurrence in the treatment group, who also had a more steady disease course. No significant adverse event. Transient improvement in immunomodulatory cytokines was recorded	Randomised controlled study but not blinded. Cryopreservation was not discussed
Rheumatoid arthritis
5. Wang et al (2013)72 Phase II non-randomised, controlled study	172 patients with active RA. 136 received 4×10⁷ allogeneic UC-derived MSCs in 40mls of intravenous saline while 36 received only saline. All patients continued their DMARDS.	No serious adverse events. TNF-alpha and IL-6 decreased while FoxP3⁺ Tregs increased in the treatment group after infusion. Better clinical outcomes (ACR responses, HAQ and DAS28) after 3 months in the treatment group	Non-randomised study. Treatment group and control group were recruited in different time frames. Cryopreserved cells were used
6. Alvaro-Gracia et al (2017)73 Dose-escalation, randomised, single-blind (double-blind for efficacy), phase Ib/IIa study	53 patients with refractory RA (failed two biologics) received three intravenous infusions at different doses (1×10⁶, 2×10⁶ and 4×10⁶ cells/kg) of allogeneic, adipose-derived MSCs or placebo	Generally well-tolerated. Mild adverse events. Dose-dependent response especially DAS28-ESR at 1 month and 3 months post-infusion. Distribution of T cell populations was not significantly modified.	First placebo-controlled study of MSCs in RA. 19% of patients generated mesenchymal stromal cell-specific anti-HLA1 antibodies without apparent clinical consequences. Cryopreserved cells were used
SLE
7. Sun et al (2009)74 Safety of MSC in Patients with refractory SLE	Four patients with refractory SLE received intravenous, allogeneic BM-derived MSCs at a dose of 1×10⁶ cells/kg.	Safe and well-tolerated. Stable course of SLE disease activity by 12–18 months post-treatment, with improvement in SLEDAI and serological markers.	First study in SLE. Provided evidence for further studies in SLE. Cryopreservation was not discussed.
8. Liang et al (2010)75 Early phase safety/efficacy study in refractory SLE	15 patients with refractory SLE were treated with one intravenous infusion of 1×10⁶ cells/kg allogeneic BM-MSC. Mean follow-up period of 17.2 months	No serious adverse events. All patients clinically improved with decrease in SLEDAI, proteinuria, and anti-dsDNA.	Improvement in some patients allowed reduction in doses of steroids and immunosuppressants. Cryopreservation was not discussed.
9. Sun et al (2010)76 Early phase I/II study	16 patients with active and refractory SLE on different treatment regimens received 1×10⁶ cells/kg intravenous of UC-derived MSC.	Significant improvement in SLEDAI score, autoantibodies, complement C3 and renal function accompanied by increased Tregs.	Patients clinically improved despite reducing doses of maintenance steroids and immunosuppressants. Cryopreservation was not discussed.
10. Wang et al (2012)77 Early phase I/II study. Compared the efficacy of single and double infusions	58 patients with refractory and active SLE. 30 received one intravenous dose of 1×10⁶ cells/kg allogeneic BM-MSCs or UC-MSCs, while 28 received two infusions of 1×10⁶ cells/kg 1 week apart.	No remarkable difference in SLEDAI and serological marker changes between the two groups.	Non-significance of difference in clinical improvement between single and double dose cohorts may be related to sample size. Cryopreservation was not discussed.
11. Li et al (2013)78 Early phase I/II study in patients with SLE with refractory cytopaenia	35 patients with SLE with refractory cytopaenia received 1×10⁶ cells/kg of either allogeneic BM-derived or allogeneic UC-derived MSCs and followed up for an average of 21 months.	Well-tolerated. Significant improvement in blood cell counts after MSC treatment. Clinical improvement was also associated with increased Tregs and decreased Th17.	Focused on haematological parameters in SLE. Cryopreservation was not discussed.
12. Wang et al (2013)79 Early phase I/II 4 year single-centre study	87 patients with SLE . Allogeneic BM-MSC or UC-MSC infused intravenously at 1×10⁶ cells/kg. Some patients were treated with cyclophosphamide to inhibit active lymphocyte response. 18 patients received repeat doses of MSC for relapses	Generally safe and well-tolerated. SLEDAI score, renal function and blood counts significantly improved for up to 4 years. All patients underwent tapering of steroids and immunosuppressants according to clinical status.	No differences in outcomes between those pretreated with cyclophosphamide and those that were not. No differences with regard to source of cells (UC and BM). Cryopreservation was not discussed.
13. Wang et al (2014)80 Multicentre phase I/II study	40 patients with active and refractory SLE received two intravenous doses of 1×10⁶ cells/kg allogeneic UC-derived MSCs while still maintaining baseline immunosuppressants+/-steroids.	Well-tolerated. 60% achieved major clinical response or partial clinical response as determined by BILAG scores. SLEDAI, renal function and serological indices also improved allowing tapering of steroid and immunosuppressant doses.	12.5% and 16.7% relapse rate at 9 and 12 months, respectively. Cryopreservation was not discussed.

ACR, American College of Rheumatology; AE: adverse events; ALS, amyotrophic lateral sclerosis; BM, bone marrow; BILAG, British Isles Lupus Activity Group; DAS28, Disease Activity Score-28 joint count; EDSS, Expanded Disability Status Score; HAQ, Health Assessment Questionnaires; RA, rheumatoid arthritis; RRMS, relapsing remitting multiple sclerosis; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; SPMS,secondarily progressive multiple sclerosis; UC, umbilical cord.