**5. Recent SLE clinical trials using stem cells**

Stem cell treatment to those SLE patients who have been refractory to all known therapies have been the last resort. Although the results of studies reported in early 2000 suggested that autologous stem cells treatment (ASCT) suggested the efficacy for remission induction of refractory SLE, mortality among those patients with longer disease duration was particularly high and mostly due to immune suppressive procedure (12%). Almost 30 percent patients relapsed after therapy and longer duration of immune suppressive therapies post ASCT was suggested [73, 74]. It was clearly shown that severe myeloablative therapies prior to ASCT's to SLE patients who already have immune compromised status the success rate has been poor. Therefore, other groups assessed the safety of intense immunosuppression and autologous hematopoietic stem cell support in patients with severe and treatment refractory SLE [75, 76]. Overall 5-year survival of those SLE patients was 84%, and probability of disease-free survival at 5 years following HSCT was 50% (**Table 1**).

While the initial stem cell clinical trials were being performed for treatment of SLE, first report of successful MSC treatment in a child with acute graft-versushost disease (GvHD) using allogeneic MSCs was published in 2004 [89]. After two infusions of bone-marrow-derived MSCs obtained from his mother this child responded very well to the infusion treatment. Following the success of this pediatric case with GVHD, multiple preclinical animal studies and other human clinical trials for treatment of other autoimmune diseases started to take place. The initial

**137**

**Study type/ SLE, organ involvement**

**Reference (First author, date)**

Jayne et al. (2004) [74]

Retrospective registry. SLE or nephritis

53, (9–52 yo)

Peripheral blood (n = 44), bone marrow (n = 8), from both (n = 1)

Autologous stem cell treatment (ASCT)

Cyclophosphamide (84%), anti-thymocyte globulin (76%) and lymphoid irradiation (22%)

SLEDAI, brain MR scan, pulmonary function tests, echocardiogram, serum creatinine, ANA, anti-

dsDNA, other anti-nuclear autoantibodies and C3, C4

Burt et al. (2006)

Single arm trial.

50, Mean age

Peripheral

Autologous

IV Cyc, 50 mg/kg daily, before

Primary, survival,

2/50 patients died

after mobilization

48 patients

underwent HSCT.

Treatment-related

mortality was

2% (1/50). By

intention to treat,

treatment-related

mortality was

4% (2/50). Renal

function stabilized

and improved

SLEDAI, ANA,

anti-ds DNA,

complement, and

carbon monoxide

diffusion lung

capacity adjusted

for hemoglobin.

disease-free.

Secondary end

points included

(SLEDAI), ANA

and anti– (ds)

DNA, C3 and

C4, and changes

in renal and

pulmonary organ

function assessed

before treatment

and at 6 months,

12 months, and

then yearly for

5 years.

transplantation (total dose

200 mg/kg) and intravenous

equine ATG, 30 mg/kg daily,

before transplantation (total

dose 90 mg/kg).

stem cell

treatment

(ASCT)

blood

(SD) 30(10.9)

years

Severe fractory

SLE

[75]

**Number of patients studied, Age range**

**MSC source\***

**Type and amount (dose)**

**Prior treatment**

**Outcome criteria**

**Improvement (%) in 6 months**

**Improvement (%) in 12 m and above**

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

5-year survival

was 84% and

probability of

disease-free

survival at

5 years following

HSCT was 50%.

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

Mortality 12% at one year

Remission rate (based on a reduction of the SLEDAI to <3) in 66%, one-third of whom later relapsed to some degree.


*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*

response to tissue injury [66–69].

for the current standard of care.

SLE to date.

6–12 months [71, 72].

number of passages.

**5. Recent SLE clinical trials using stem cells**

their immune-modulatory phenotype could become activated by IFN-γ, TNF-α and IL-1β in the microenvironment [65]. Furthermore, it has been shown that MSCs are chemotactically drawn toward a variety of wound healing cytokines in vitro, including IL-1 and TNF-α. These data suggest that MSCs or endogenous cells resembling MSCs, such as pericytes, are likely to migrate to and participate in the

When MSCs are exposed to the microenvironment of diseased tissue, they control/suppress inflammation inducing regeneration [56]. With their potent immune regulatory and regenerative effects in response to their microenvironment, and as no adverse reactions in clinical trials have been reported, MSCs are an attractive treatment in SLE. By increasing the potency of MSCs in SLE, it is anticipated that primed MSCs will lower the overall cost of care for SLE patients that are refractory

Effects of human MSCs on interferon regulated mediators, and the connections of these mediators with clinical outcomes in SLE have been suggested, but MSC treatments have not been efficacious across heterogeneous organ involvement of

MSCs have been used as therapeutics in hundreds of clinical trials, as of July 2020, there were a total of 1,138 registered clinical trials to clinicaltrials.gov including SLE. In the 18 published clinical trials with outcomes there were no serious adverse events reported [70]. However, MSCs have not been FDA approved for any disease indication yet, mostly due to challenges in potency. MSC treatment has been shown to be successful for a short time and there were relapses in SLE patients in

MSC sources used in clinical trials have different donor pools and are isolated from different tissues with variable immune regulatory function. Furthermore, large-scale MSC-based cell therapy remains restricted due to the cells' ability to expand, and then efficiently respond to inflammatory environment after several

Stem cell treatment to those SLE patients who have been refractory to all known therapies have been the last resort. Although the results of studies reported in early 2000 suggested that autologous stem cells treatment (ASCT) suggested the efficacy for remission induction of refractory SLE, mortality among those patients with longer disease duration was particularly high and mostly due to immune suppressive procedure (12%). Almost 30 percent patients relapsed after therapy and longer duration of immune suppressive therapies post ASCT was suggested [73, 74]. It was clearly shown that severe myeloablative therapies prior to ASCT's to SLE patients who already have immune compromised status the success rate has been poor. Therefore, other groups assessed the safety of intense immunosuppression and autologous hematopoietic stem cell support in patients with severe and treatment refractory SLE [75, 76]. Overall 5-year survival of those SLE patients was 84%, and probability of disease-free survival at 5 years following HSCT was 50% (**Table 1**). While the initial stem cell clinical trials were being performed for treatment of SLE, first report of successful MSC treatment in a child with acute graft-versushost disease (GvHD) using allogeneic MSCs was published in 2004 [89]. After two infusions of bone-marrow-derived MSCs obtained from his mother this child responded very well to the infusion treatment. Following the success of this pediatric case with GVHD, multiple preclinical animal studies and other human clinical trials for treatment of other autoimmune diseases started to take place. The initial

**136**


**139**

**Study type/ SLE, organ involvement**

**Reference (First author, date)**

Wang et al. (2012) [81] X Li et al. (2013) [82]

Wang

Severe and

87(12–

BM/

Allogenic

Pretreatment 59% Cyc 10 mg/

Primary: Survival,

Complete clinical

Complete

clinical

remission rate

was 31% at

2 years (12/39),

42% at 3 years

(5/12), and 50%

at 4 years (3/6).

4-year follow-up

overall rate of

survival was

94% (82/87).

One-time

treatment

remission 28%

at 1 year Relapse

rates 12% at 1 year.

disease remission

and relapse,

transplantationrelated adverse events. Secondary:

SLEDAI and

serology

kg/day IV on day −4, −3, −2.

36% No treatment

1 × 106/kg

UC-MSC

56 years)

refractory SLE

et al.

(2013)

[83]

SLE refractory cytopenia

35(16– 62 years)

BM/UC MSC.

Allogenic 1 × 106/kg

1 = Pretreatment group: (15/35) Cyc 0.4–1.8 gm IV for 2–4 days 2 = No Cyc Pretreatment (20/35)

CBC's Hb and Platelet, Th17, Treg, SLEDAI

57% patients with leukopenia and 68% patients with thrombocytopenia showed hematological improvement.

Unblinded, randomized, 2-arm/12 months

58

BM/UC MSC single vs. 2× every 7 days

CYC 10 mg/kg per day, day 4, 3, and 2

**Number of patients studied, Age range**

**MSC source\***

**Type and amount (dose)**

**Prior treatment**

**Outcome criteria**

**Improvement (%) in 6 months**

**Improvement (%) in 12 m and above**

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

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

75% of SLE remained stable after 12 months

Complete remission 1× 53% 2× 29%


#### *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*

Decreased

SLEDAI and

proteinuria in

all patients in

28 months

Decreased

SLEDAI and

proteinuria in all

patients

**138**

**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**

16

UC MSC

Allogeneic

Cyclophosphamide iv for

Percent Tregs

improved in

3 months

Percentage of Treg

cells increased

at 1 week and 3

and 6 months

(P < 0.05)

Disease activity

indexes and

immunological

parameters

were assessed at

baseline, 1, 2, 7

and 14 weeks

2–4 days

**SLE, organ** 

**involvement**

**(First** 

**author,** 

**date)**

Sun et al.

Single arm SLE

nephritis

(2010)

[77]

Liang

Single arm SLE

15

nephritis

et al.

(2010)

[78]

Carrion

SLE

2 (19 yr.,

BM-derived

Autologous,

1 × 106/kg

MSCs,

25 yr)

F et al.

(2010)

[79]

Shi D

SLE associated

4

UC-MSCT

Allogenic

1 × 106/kg

hemoglobin,

Clinical changes

before and after

transplantation

platelet level,

oxygen saturation,

and serological

factors. Highresolution CT (HRCT) scans

of the chest

were performed

to evaluate

pulmonary

manifestation

(32 ± 15 years)

diffuse alveolar

hemorrhage.

et al.

(2012)

[80]


**141**

**Reference (First author, date)**

Deng et al. (2017) [84]

Randomized, double blind, placebo controlled SLE nephritis

18 patients Randomized. 12 patients h UC-MSC group and 6 patients placebo group. Mean age in both groups 29 years.

20 × 106

patient one

time

Chen C et

Active SLE

10

UC-MSCT

1 × 106/kg

Soluble human

Negative

correlation

between s HLA-G

levels and SLEDAI

score.

5-year overall

survival rate was

84%.

leukocyte antigen

G was measured

24 h and 1 mo after

infusion

5-year overall

survival. Complete

and partial clinical

remission.

refractory to

conventional

treatment

al. (2017)

[85]

Wang et

Open-label phase

81(12–

BM or

Allogeneic

39/81 received IV Cyc (10 mg/

kg/day) in days −4, −3, −2;

42/81- no IV Cyc.

1 × 106/kg

(Multiple

infusions of

MSCs were

permitted)

Patients receiving repeat

MSCT, no IV Cyc used.

UC-MSC

62 years)

II Severe and

drug refractory

SLE

al. (2018)

[86]

/

**Number of patients studied, Age range**

**MSC source\*** UC-MSC

Allogenic

11/18 pts. received methylprednisolone and CYP induction therapy, and the 12th to 18th patients enrolled received IV. methylprednisolone only and intravenous CYP

24 h urine protein, serum albumin, serum creatinine, SLEDAI and BILAG scores, C3, C4, anti-dsDNA and ANA

Remission occurred in 75% in the hUC-MSC group and 83% in the placebo group.

Stopped in less than 12 months due to lack of efficacy

**Type and amount (dose)**

**Prior treatment**

**Outcome criteria**

**Improvement (%) in 6 months**

**Improvement (%) in 12 m and above**

**Study type/ SLE, organ involvement**

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

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


#### *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*

**140**

**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**

81(12–

BM or

Allogenic

No IV Cyc pretreatment.

Primary outcome:

The mean

For 24 SLE

patients with

anemia,

normalized

remained stable

at 12- and

24-month visits

leukocyte counts

still stayed normal

for 5 patients

completing

24-month

follow-up

Renal remission

(complete/

partial) as well

as renal flares.

The secondary

outcome included

renal activity score

Safety, Major

Disease relapse at

Survival rate

was 92.5% in

12 months.

9 months 12.5%, at

12 months 16.7%

of follow-up.

clinical response

(MCR), Partial

clinical response

(PCR) and

relapse. SLEDAI,

BILAG and renal

functional indices

1 × 106/kg

at 0 and

7 days

32.5% achieved

MCR and 27.5%

achieved PCR,

during 12 months.

vs. Pretransplant

medication: Pred/

Cyclophosphamide(monthly)/

MMF

1 × 106/kg

UC-derived

MSC

55 years)

**SLE, organ** 

**involvement**

**(First** 

**author,** 

**date)**

Fei Gu

Open Label and

single center

Active and

refractory Lupus

Nephritis

et al.

(2014)

[72]

Wang

Severe and

40,

UC-MSC

Allogenic

No IV Cyc pretreatment. 26/40

pts. received Cyc as a basal

treatment.

(17–54 years)

refractory SLE

et al.

(2014)

[71]


**143**

**Study type/ SLE, organ involvement**

**Reference (First author, date)**

Wen L et al. (2019) [88]

Retrospective cohort study SLE pts. with active disease (SLEDAI score > =8

**Number of patients studied, Age range**

69

BM-/ UC-MSCs

Allogenic 1 × 106/kg

**MSC source\***

**Type and amount (dose)**

**Prior treatment**

**Outcome criteria**

**Improvement (%) in 6 months**

**Improvement (%) in 12 m and above**

Severe SLE

pts. undergo

sustained clinical

remission with

reduced disease

maintained over

a 1 year follow

up. Older age,

no arthralgia/

arthritis at

baseline, and

no prior CYC or

HCQ treatment

had better first

year outcomes

after allogenic

BM-UC-MSC

transplantation.

*\*UC, umbilical cord; bone marrow (BM) or adipogenic (AD) tissue derived MSCs; CYC, cyclophosphamide; HCQ, Hydroxychloroquine.*

*Human clinical trials that used mesenchymal stem cells (MSCs) for treatment of systemic lupus erythematosus.*

**Table 1.**

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

UC MSC treatment

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

SLE symptoms and SLEDAI scores were assessed at baseline and during follow up to determine low disease activity and clinical remission at 1, 3, 6 and 12 months. To identify predictors of clinical response to allogenic BM or



*Human clinical trials that used mesenchymal stem cells (MSCs) for treatment of systemic lupus erythematosus.*
