*Clinical Use of Mesenchymal Stem Cells in Treatment of Systemic Lupus Erythematosus DOI: http://dx.doi.org/10.5772/intechopen.97261*

*Lupus - Need to Know*

**142**

**Reference** 

**Study type/**

**Number** 

**MSC** 

**Type and** 

**Prior treatment**

**Outcome criteria**

**Improvement** 

**Improvement** 

**(%) in 12 m** 

**and above**

**(%) in 6 months**

**amount** 

**(dose)**

**source\***

**of patients** 

**studied, Age** 

**range**

3(40–45 years)

BM-MSC

Allogenic

Patients were pretreated with

The 24-h

100% of patients

Follow up

stopped after

9 months

showed decreased

level of proteinuria

SLEDAI scores

revealed early,

durable, and

substantial

remissions

proteinuria

level, glomerular

hematuria,

leukocyturia,

serum creatinine,

and the glomerular

filtration rate was

measured just

before treatment

(0), and at 1, 3, 6,

and 9 months after

treatment.

To study the

Number of

peripheral

tolerogenic

CD1c+ dendritic

cells and levels

of serum FLT3L

are significantly

decreased in SLE

patients esp. with

lupus nephritis

compared with

healthy controls.

Following

transplant,

significant

upregulation of

peripheral blood

CD1c+ dendritic

cells and serum

FLT3L was seen.

mechanisms of

immunoregulatory

mechanism in SLE

patients.

variety of chemotherapy

before enrollment to the study

1.5 × 106/kg

**SLE, organ** 

**involvement**

**(First** 

**author,** 

**date)**

J Barbado

Active SLE with

proteinuria

(1,000 mg in

24 h) and class

IV proliferative

nephritis

Yuan X et

SLE refractory

21

UC-MSCT

Allogenic

1 × 106/kg

to conventional

therapies

al. (2019)

[88]

et al.

(2018)

[87]

approach to MSC treatment took hematopoietic stem cell replacement therapies (HSCT) as examples, and protocols that mimicked HSCT were investigated. One similarity was to use autologous cells rather than allogeneic stem cells and the other similarity was to use myeloablation therapies with chemotherapy agents before the MSC treatment.

While autologous MSC treatment trials showed efficacy in increasing the amount of immune regulatory cells that play an important role in SLE, the clinical disease activity scores were not changed [79]. Same center that published the failure in 2 patients treated with autologous MSCs also performed a study using allogeneic MSCs in 15 patients and showed efficacy [78]. Because sources of allogeneic MSCs are more available and carry less concern of being defective due to disease state or genetic background [90], the following SLE clinical trials used mostly allogeneic MSC sources from variable tissues.

Initial reports of allogeneic MSC trials came from a group of investigators from China. Sun et al. reported a study performed between April 2007 to July 2009 on 16 patients with active SLE nephritis who were enrolled and underwent allogeneic umbilical cord (UC) driven MSC treatment. Study showed efficacy of allogeneic UC MSCs in SLE and suggested that clinical remission was correlating to the increase in peripheral Treg cells and an improved balance between Th1- and Th2- cytokines [77]. Cellular significance was correlating with the decreased amount of proteinuria and decreased SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) scores. Patients in this trial received IV cyclophosphamide treatment for 2–4 days prior to UC MSC treatment.

Same group continued to treat resistant SLE patients and enrolled eighty-seven patients with persistently active SLE who were refractory to standard treatment or had severe organ involvement. While some patients received allogeneic bone marrow some received umbilical cord derived MSCs intravenously (1 × 106 cells/ kg of body weight). Three of them were given a second UC-MSC treatment (8, 3, 4 months after the first BM MSC treatment and one was given UC-MSCT additional three times (11, 19, 20 months after the first BM MSC treatment). During the 4-year follow-up the overall rate of survival was 94% (82/87). Complete clinical remission rate was 28% at 1 year (23/83). The overall rate of relapse was 23% (20/87). Only five patients (6%) died after MSC treatment from non-treatmentrelated events in the 4-year follow-up. Allogeneic MSC were suggested to result in the induction of clinical remission and improvement in organ dysfunction in drug resistant severe SLE patients [83].

Debate of allogeneic versus autologous stem cell treatment continued while initial phase I and II trials were ongoing with MSCs. Sui et al. [91] compared the research of autologous or allogeneic HSC/MSC in SLE. They analyzed the data of Wang et al. [83] i.e. allogeneic group and that of Jayne et al. [74] and Burt et al. [75], i.e. autologous group. In conclusion, they found that the rate of complete clinical remission was similar in these clinical trials (approximately 50%). However, there was higher overall survival rate, lower overall rate of relapse and no transplantation-related mortality in the allogeneic group. Because these 3 studies were not randomized, and it was not possible to compare them with each other exactly due to the heterogeneous disease manifestation at baseline. Authors suggested the importance of randomized clinical trials consisting of a large sample and long term follow up of these patients to further investigate the efficacy and safety of autologous/ allogeneic stem cell transplantation [91].

**X Li et al.** [82, 92] further assessed the roles of allogeneic (BM and UC) MSC treatment with in SLE patients with refractory cytopenia. Thirty-five SLE patients with refractory cytopenia were enrolled and hematological changes of pre- and post-transplantation were evaluated. Significant improvements in blood cell count

**145**

*Clinical Use of Mesenchymal Stem Cells in Treatment of Systemic Lupus Erythematosus*

were found after MSC treatment for most patients, in parallel with the decline of disease activity. Clinical remission was again correlating with increased Treg cells and decreased Th17 cells. Results suggested that MSCs are successful in correcting refractory cytopenia in SLE patients which might be associated with reconstitution

Use of chemotherapy together or before MSC treatment for induction was also assessed by variety of small clinical trials. Wang et al. [71] found no differences between the patient groups that received pretreatment with cyclophosphamide and untreated with cyclophosphamide. There was no difference in the rate of clinical remission after MSC treatments [71]. In addition there were significant number of patients that developed relapse in 6 months and additional MSC treatments were

**Fei Gu et al.** [72] assessed the role of allogeneic MSC treatment to induce renal remission in patients with active and refractory lupus nephritis (LN). They conducted an open-label and single-center clinical trial conducted from 2007 to 2010 in which 81 Chinese patients with active and refractory LN were enrolled. Allogeneic bone marrow- or umbilical cord-derived mesenchymal stem cells (MSCs) were administered intravenously at the dose of 1 million cells per kilogram of bodyweight. During the 12-month follow-up, the overall rate of survival was 95% (77/81). Totally, 60.5% (49/81) patients achieved renal remission during 12-month visit by MSCT. Eleven of 49 (22.4%) patients experienced renal flare by the end of 12 months after a previous remission. Renal activity evaluated by BILAG (British Isles Lupus Assessment Group) scores significantly declined after MSC treatment, in parallel with the obvious amelioration of renal function. Glomerular filtration rate (GFR) improved significantly 12 months after. Total disease activity evaluated by SLEDAI scores also decreased after treatment. Additionally, the doses of concomitant prednisone and immunosuppressive drugs were tapered. No transplantation-related adverse event was observed. They concluded that allogeneic MSC treatment resulted in renal remission for active LN patients within 12-month

visit, confirming its use as a potential therapy for refractory LN.

**Woodworth et al.** [93] examined whether collective data from Wang et al. [71] provided sufficient evidence for the feasibility, safety, dose rationale, and potential efficacy of UC-MSCs to conduct a randomized controlled trial in treatment-refractory SLE nephritis. They observed that results, though confounded by variable baseline prednisone and immuno-suppressive treatment, appear to indicate near term response rates of approximately 50%, which are comparable to those seen with hematopoietic stem cell transplantation but with less morbidity and mortality. They also noticed that apparently, conditioning pre-MSC dosing is not required, although this aspect of the treatment had not been studied in a controlled manner [93]. Another group performed an interesting combination therapy with HSCs and MSCs for life threatening organ involvement involving SLE patient refractory to cyclophosphamide. After being pretreated with CYC, Fudarabine and antithymocyte globulin, the patient was transplanted with autologous CD34+ HSCs and MSCs by intravenous infusion. Hematopoietic regeneration was observed on day 12 thereafter. After HSC and MSC transplantation, the patient's clinical symptoms caused by SLE were remitted, and the SLEDAI score decreased. One more time CD4 + CD25 + FoxP3+ Treg cells were found to be increased in peripheral blood mononuclear cells (PBMCs) after transplantation. This study was important to show that combined transplantation of HSCs and MSCs may reset the adaptive immune system to re-establish self-tolerance in SLE. A 36-month follow-up showed

that the clinical symptoms remained in remission for the index patient [94]. A randomized double blind placebo control trial was reported by **Deng et al.** [84] that assessed the efficacy of human umbilical cord-derived mesenchymal

*DOI: http://dx.doi.org/10.5772/intechopen.97261*

given to those patients with relapse.

of Treg and Th17.

#### *Clinical Use of Mesenchymal Stem Cells in Treatment of Systemic Lupus Erythematosus DOI: http://dx.doi.org/10.5772/intechopen.97261*

were found after MSC treatment for most patients, in parallel with the decline of disease activity. Clinical remission was again correlating with increased Treg cells and decreased Th17 cells. Results suggested that MSCs are successful in correcting refractory cytopenia in SLE patients which might be associated with reconstitution of Treg and Th17.

Use of chemotherapy together or before MSC treatment for induction was also assessed by variety of small clinical trials. Wang et al. [71] found no differences between the patient groups that received pretreatment with cyclophosphamide and untreated with cyclophosphamide. There was no difference in the rate of clinical remission after MSC treatments [71]. In addition there were significant number of patients that developed relapse in 6 months and additional MSC treatments were given to those patients with relapse.

**Fei Gu et al.** [72] assessed the role of allogeneic MSC treatment to induce renal remission in patients with active and refractory lupus nephritis (LN). They conducted an open-label and single-center clinical trial conducted from 2007 to 2010 in which 81 Chinese patients with active and refractory LN were enrolled. Allogeneic bone marrow- or umbilical cord-derived mesenchymal stem cells (MSCs) were administered intravenously at the dose of 1 million cells per kilogram of bodyweight. During the 12-month follow-up, the overall rate of survival was 95% (77/81). Totally, 60.5% (49/81) patients achieved renal remission during 12-month visit by MSCT. Eleven of 49 (22.4%) patients experienced renal flare by the end of 12 months after a previous remission. Renal activity evaluated by BILAG (British Isles Lupus Assessment Group) scores significantly declined after MSC treatment, in parallel with the obvious amelioration of renal function. Glomerular filtration rate (GFR) improved significantly 12 months after. Total disease activity evaluated by SLEDAI scores also decreased after treatment. Additionally, the doses of concomitant prednisone and immunosuppressive drugs were tapered. No transplantation-related adverse event was observed. They concluded that allogeneic MSC treatment resulted in renal remission for active LN patients within 12-month visit, confirming its use as a potential therapy for refractory LN.

**Woodworth et al.** [93] examined whether collective data from Wang et al. [71] provided sufficient evidence for the feasibility, safety, dose rationale, and potential efficacy of UC-MSCs to conduct a randomized controlled trial in treatment-refractory SLE nephritis. They observed that results, though confounded by variable baseline prednisone and immuno-suppressive treatment, appear to indicate near term response rates of approximately 50%, which are comparable to those seen with hematopoietic stem cell transplantation but with less morbidity and mortality. They also noticed that apparently, conditioning pre-MSC dosing is not required, although this aspect of the treatment had not been studied in a controlled manner [93].

Another group performed an interesting combination therapy with HSCs and MSCs for life threatening organ involvement involving SLE patient refractory to cyclophosphamide. After being pretreated with CYC, Fudarabine and antithymocyte globulin, the patient was transplanted with autologous CD34+ HSCs and MSCs by intravenous infusion. Hematopoietic regeneration was observed on day 12 thereafter. After HSC and MSC transplantation, the patient's clinical symptoms caused by SLE were remitted, and the SLEDAI score decreased. One more time CD4 + CD25 + FoxP3+ Treg cells were found to be increased in peripheral blood mononuclear cells (PBMCs) after transplantation. This study was important to show that combined transplantation of HSCs and MSCs may reset the adaptive immune system to re-establish self-tolerance in SLE. A 36-month follow-up showed that the clinical symptoms remained in remission for the index patient [94].

A randomized double blind placebo control trial was reported by **Deng et al.** [84] that assessed the efficacy of human umbilical cord-derived mesenchymal

*Lupus - Need to Know*

MSC treatment.

MSC sources from variable tissues.

prior to UC MSC treatment.

resistant severe SLE patients [83].

allogeneic stem cell transplantation [91].

approach to MSC treatment took hematopoietic stem cell replacement therapies (HSCT) as examples, and protocols that mimicked HSCT were investigated. One similarity was to use autologous cells rather than allogeneic stem cells and the other similarity was to use myeloablation therapies with chemotherapy agents before the

While autologous MSC treatment trials showed efficacy in increasing the amount of immune regulatory cells that play an important role in SLE, the clinical disease activity scores were not changed [79]. Same center that published the failure in 2 patients treated with autologous MSCs also performed a study using allogeneic MSCs in 15 patients and showed efficacy [78]. Because sources of allogeneic MSCs are more available and carry less concern of being defective due to disease state or genetic background [90], the following SLE clinical trials used mostly allogeneic

Initial reports of allogeneic MSC trials came from a group of investigators from China. Sun et al. reported a study performed between April 2007 to July 2009 on 16 patients with active SLE nephritis who were enrolled and underwent allogeneic umbilical cord (UC) driven MSC treatment. Study showed efficacy of allogeneic UC MSCs in SLE and suggested that clinical remission was correlating to the increase in peripheral Treg cells and an improved balance between Th1- and Th2- cytokines [77]. Cellular significance was correlating with the decreased amount of proteinuria and decreased SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) scores. Patients in this trial received IV cyclophosphamide treatment for 2–4 days

Same group continued to treat resistant SLE patients and enrolled eighty-seven patients with persistently active SLE who were refractory to standard treatment or had severe organ involvement. While some patients received allogeneic bone marrow some received umbilical cord derived MSCs intravenously (1 × 106

kg of body weight). Three of them were given a second UC-MSC treatment (8, 3, 4 months after the first BM MSC treatment and one was given UC-MSCT additional three times (11, 19, 20 months after the first BM MSC treatment). During the 4-year follow-up the overall rate of survival was 94% (82/87). Complete clinical remission rate was 28% at 1 year (23/83). The overall rate of relapse was 23% (20/87). Only five patients (6%) died after MSC treatment from non-treatmentrelated events in the 4-year follow-up. Allogeneic MSC were suggested to result in the induction of clinical remission and improvement in organ dysfunction in drug

Debate of allogeneic versus autologous stem cell treatment continued while initial phase I and II trials were ongoing with MSCs. Sui et al. [91] compared the research of autologous or allogeneic HSC/MSC in SLE. They analyzed the data of Wang et al. [83] i.e. allogeneic group and that of Jayne et al. [74] and Burt et al. [75], i.e. autologous group. In conclusion, they found that the rate of complete clinical remission was similar in these clinical trials (approximately 50%). However, there was higher overall survival rate, lower overall rate of relapse and no transplantation-related mortality in the allogeneic group. Because these 3 studies were not randomized, and it was not possible to compare them with each other exactly due to the heterogeneous disease manifestation at baseline. Authors suggested the importance of randomized clinical trials consisting of a large sample and long term follow up of these patients to further investigate the efficacy and safety of autologous/

**X Li et al.** [82, 92] further assessed the roles of allogeneic (BM and UC) MSC treatment with in SLE patients with refractory cytopenia. Thirty-five SLE patients with refractory cytopenia were enrolled and hematological changes of pre- and post-transplantation were evaluated. Significant improvements in blood cell count

cells/

**144**

stem cell (hUC-MSC) for the treatment of lupus nephritis (LN) among 18 patients with WHO class III or IV LN. Patients were randomly assigned to hUC-MSC (dose 2 × 108 cells) or placebo. All patients received standard immunosuppressive treatment, which consisted of intravenous methylprednisolone and cyclophosphamide, followed by maintenance oral prednisolone and mycophenolate mofetil. Initial 11 patients enrolled to the study received hUC-MSC concurrently with the intravenous methylprednisolone and CYP induction therapy, and for the 12th to 18th patients enrolled, the hUC-MSC were administered together with the intravenous methylprednisolone only and intravenous CYP was delayed to 4 weeks later. In result, similar proportion of patients on hUC-MSC and placebo achieved complete remission. Improvements in serum albumin, complement, renal function, SLEDAI and BILAG scores were similar in both groups. The trial was abandoned after 18 patients were enrolled when it had become obvious it would not demonstrate a positive treatment effect. They concluded that hUC-MSC has no apparent additional effect over and above standard immunosuppression [84].

A pilot study investigated the effect of MSCs on soluble human leukocyte antigen G (s HLA-G) levels 24 hours and 30 days after MSC injection (UC) and reported a negative correlation between the HLA-G levels and clinical SLE activity scores [85]. The levels of s HLA-G were lower in patients with renal involvement than without it.

An open label phase II trial the following year reported safety and long-term efficacy of UC MSCs in severe SLE. Wang et al. [86] reported a long-term followup study of allogeneic bone marrow and/or umbilical cord MSC transplantation (MSCT) in severe and drug-refractory systemic lupus erythematosus (SLE) patients. Eighty-one patients were enrolled, and the 5-year overall survival rate was 84% (68/81) after MSCT. At 5-year follow-up, 27% of patients (22/81) were in complete clinical remission and another 7% (6/81) were in partial clinical remission, with a 5-year disease remission rate of 34% (28/81). In total, 37 patients had achieved clinical remission and then 9 patients subsequently relapsed, with 5-year overall rate of relapse of 24% (9/37). SLEDAI scores, serum albumin, complement C3, peripheral white blood cell, and platelet numbers, as well as proteinuria levels, continued to improve during the follow-up. Their results demonstrated that allogeneic MSC treatment is safe and resulted in long-term clinical remission in SLE patients.

Barbado et al. [87] infused three SLE patients with MSCs who were diagnosed with class IV nephritis by kidney biopsies. MSCs were allogeneic MSCs from healthy donors. Total of ninety million cells were infused intravenously into each patient during high and very high activity disease. Patient 1 was treated with cyclophosphamide, azathioprine, methotrexate, mycophenolate and cyclosporine, patient 2 was treated with cyclophosphamide, mycophenolate, rituximab and patient 3 was treated with cyclophosphamide and mycophenolate before MSC treatment. Then, follow-up was performed after 9 months. Proteinuria levels improved significantly during the 1st month and then continued to be sustained in normal levels. Clinical outcome scores such as SLEDAI was perfect for 2 patients while the third SLE patient only had a partial response and the patient could reduce the dose of her current therapies down to 50–60%. Follow up stopped after 9 months SLEDAI scores revealed early, durable, and substantial remissions that were complete for two patients and partial for the third patient and that permitted medication doses to be reduced 50–90%.

In 2019 using slightly older patient population with severe SLE (SLEDAI score > =8), Wen et al. [88] also reported efficacy of allogeneic bone marrow and umbilical cord MSC treatment over one year of follow up in those patients that did not have any baseline arthritis or use of cyclophosphamide of hydroxychloroquine

**147**

*Clinical Use of Mesenchymal Stem Cells in Treatment of Systemic Lupus Erythematosus*

in 2019. Same year Yuan et al. [95] attempted to explore the immunoregulatory mechanism of MSC treatments in SLE patients. They showed that number of

cantly decreased in severely affected SLE patients especially with lupus nephritis. UC-MSC treatment however tapered the FLT3L and inhibited the apoptosis of tolerogenic CD1c + DCs. It is suggested that MSCs carry FLT3L that binds the FLT3 on CD1c + DCs and enhance their ability to proliferate and stops them from being apoptotic [95]. CD1c + DCs in human peripheral blood and in lymphoid and non-lymphoid tissues. CD1c + DCs have been previously reported to play important immune regulatory work such as secreting cytokines when exposed to (poly I:C), LPS or others and regulate the activity of many immune cells such as T regulatory cells and interferon secreting cells [96, 97]. Interferon gamma-FLT3L-FLT3 axis is one of many mechanisms that MSCs are regulating and its implications in treatment of SLE has been recently recognized. Tregs were shown to respond well to allogeneic MSC treatment in several studies. Furthermore, Chen et al. previously have shown that serum HLA-G levels correlated with the levels of Tregs after treatment with

Latest report when this chapter was being prepared was by Zhou et al. Zhou et al. [81] did a meta-analysis aiming at assessing whether MSCs can become a new treatment for SLE with good efficacy and safety. Ten studies fulfilled the inclusion criteria and were eligible for this meta-analysis, which comprised 8 prospective or retrospective case series and four randomized controlled trails (RCTs) studies. In the RCT, the results indicated that the MSC group had lower proteinuria than the control group at 3 months and 6 months and the MSC group displayed a lower SLEDAI than the control group at 2 months and 6 months. Furthermore, the MSC group showed a lower rate of adverse events than the control group (OR = 0:26, 95% CI: 0.07, 0.89, P = 0:03). In the case series trials, the results indicated that the MSC group had lower proteinuria at 1 month, 2 months, 3 months, 4 months, 6 months, and 12 months. They concluded that MSCs might be a promising therapeutic agent for patients with SLE. However, they suggested that more studies with longer-term end points and larger sample sizes should be designed and conducted to identify

additional and robust patient-centered outcomes in the future [81].

ment in SLE or due to their genetic predisposition [79].

tory lupus nephritis. Allogeneic MSCs, at 1 x 106

The clinical outcome parameters and the kind and amount of MSCs used in the clinical trials we reviewed in this chapter are variable. Most important difference of MSCs used in the clinical trials is whether they are autologous, extracted from the patient's own tissue or allogeneic extracted from health donors. When we reviewed the clinical trials using autologous MSCs trials treating SLE we observed that autologous MSCs did not show much efficacy while allogeneic MSCs regardless of their origins seem to be showing consistently better efficacy in most trials (**Table 1**). The reason for lack of efficacy in autologous use of MSCs is most probably due to their intrinsic abnormalities, and their inability to function at their best capacity. Autologous MSCs may not be functioning due their previous exposure the inflammatory micro environ-

Allogeneic mesenchymal stem cell treatment has been shown to be efficacious in the treatment of various systemic lupus erythematosus activity, mainly in refrac-

results are not as homogeneous as expected from clinical trials and FDA approval for MSCs use in rheumatologic diseases have been challenging. Heterogeneous results could be due to the heterogenous disease manifestations among patients

/kg seems to be efficacious but the

dendritic cells and levels of serum FLT3L are signifi-

*DOI: http://dx.doi.org/10.5772/intechopen.97261*

allogeneic umbilical cell derived MSCs [85].

**6. Summary/conclusions**

peripheral tolerogenic CD1c<sup>+</sup>

#### *Clinical Use of Mesenchymal Stem Cells in Treatment of Systemic Lupus Erythematosus DOI: http://dx.doi.org/10.5772/intechopen.97261*

in 2019. Same year Yuan et al. [95] attempted to explore the immunoregulatory mechanism of MSC treatments in SLE patients. They showed that number of peripheral tolerogenic CD1c<sup>+</sup> dendritic cells and levels of serum FLT3L are significantly decreased in severely affected SLE patients especially with lupus nephritis. UC-MSC treatment however tapered the FLT3L and inhibited the apoptosis of tolerogenic CD1c + DCs. It is suggested that MSCs carry FLT3L that binds the FLT3 on CD1c + DCs and enhance their ability to proliferate and stops them from being apoptotic [95]. CD1c + DCs in human peripheral blood and in lymphoid and non-lymphoid tissues. CD1c + DCs have been previously reported to play important immune regulatory work such as secreting cytokines when exposed to (poly I:C), LPS or others and regulate the activity of many immune cells such as T regulatory cells and interferon secreting cells [96, 97]. Interferon gamma-FLT3L-FLT3 axis is one of many mechanisms that MSCs are regulating and its implications in treatment of SLE has been recently recognized. Tregs were shown to respond well to allogeneic MSC treatment in several studies. Furthermore, Chen et al. previously have shown that serum HLA-G levels correlated with the levels of Tregs after treatment with allogeneic umbilical cell derived MSCs [85].

Latest report when this chapter was being prepared was by Zhou et al. Zhou et al. [81] did a meta-analysis aiming at assessing whether MSCs can become a new treatment for SLE with good efficacy and safety. Ten studies fulfilled the inclusion criteria and were eligible for this meta-analysis, which comprised 8 prospective or retrospective case series and four randomized controlled trails (RCTs) studies. In the RCT, the results indicated that the MSC group had lower proteinuria than the control group at 3 months and 6 months and the MSC group displayed a lower SLEDAI than the control group at 2 months and 6 months. Furthermore, the MSC group showed a lower rate of adverse events than the control group (OR = 0:26, 95% CI: 0.07, 0.89, P = 0:03). In the case series trials, the results indicated that the MSC group had lower proteinuria at 1 month, 2 months, 3 months, 4 months, 6 months, and 12 months. They concluded that MSCs might be a promising therapeutic agent for patients with SLE. However, they suggested that more studies with longer-term end points and larger sample sizes should be designed and conducted to identify additional and robust patient-centered outcomes in the future [81].
