Research

Systemic Lupus Erythematosus

Clinical Efficacy and Safety of Mesenchymal Stem Cells for Systemic Lupus Erythematosus (Zhou, T et al 2020)

This meta-analysis published in 2020 aimed to assess the safety and efficacy of mesenchymal stem cell therapy (MSC) in the treatment of systemic lupus erythematosus (SLE). Ten studies including 8 prospective or retrospective case series involving 231 patients and four randomized controlled trials (RCTs) involving 84 were included in this meta-analysis.

Efficacy was assessed using various clinical markers including proteinuria, creatinine, BUN, albumin, C3, and C4 and the commonly used systemic lupus erythematosus disease activity index (SLEDAI) questionnaire.

Only two RCTs were analyzed for safety in this meta-analysis. Overall, the results indicate that MSC treatment was safe and patients treated with MSC therapy experienced lower rates of adverse events than control groups.

Results from the RCTs demonstrate that the MSC group had lower proteinuria at 3 and 6 months compared to control group indicating improvement in kidney function. The MSC group also had lower SLEDAI scores at 2 and 6 months compared to control group indicating reduced disease activity. In the case series studies, sustained lower proteinuria was observed up to 12 months.

Results for most clinical markers including creatinine, BUN, albumin, and C4 were observed to have a general positive trend in both RCTs and case series studies even though some data did not reach statistical significance.

Similar results were demonstrated in a 2018 meta-analysis by Liu et al which showed significant decreases in SLEDAI scores and proteinuria in patients with SLE. This analysis included 8 studies, 3 of which were RCTs involving 213 patients.

Liu S, Guo YL, Yang JY, Wang W, Xu J. [Efficacy of mesenchymal stem cells on systemic lupus erythematosus:a meta-analysis]. Beijing Da Xue Xue Bao Yi Xue Ban. 2018 Dec 18;50(6):1014-1021. Chinese. PMID: 30562774. https://pubmed.ncbi.nlm.nih.gov/30562774/

Overall this recent meta-analysis demonstrated that MSC therapy in SLE is safe and leads to improvements in proteinuria and disease activity. The authors conclude that “MSCs might be a promising therapeutic agent for patients with SLE.”

CITE: Zhou T, Li HY, Liao C, Lin W, Lin S. Clinical Efficacy and Safety of Mesenchymal Stem Cells for Systemic Lupus Erythematosus. Stem Cells Int. 2020;2020. doi:10.1155/2020/6518508. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157802/

A Long-Term Follow-Up Study of Allogeneic Mesenchymal Stem/Stromal Cell Transplantation in Patients with Drug-Resistant Systemic Lupus Erythematosus (Wang, D et al 2018)

This 2018 study reported the long term results of mesenchymal stem cell (MSC) therapy in patients with severe and drug-resistant systemic lupus erythematosus (SLE). Eighty-one patients were initially enrolled and 66 were studied for up to 5 years to assess long term safety and efficacy of bone marrow derived MSCs (BM-MSCs) and umbilical cord derived MSCs (UC-MSCs). Of the original 81 patients, 22 received allogeneic BM-MSCs and 59 received allogeneic UC-MSCs.

MSC therapy was deemed safe with few adverse effects and no treatment related deaths. Five years after therapy the overall survival rate was 84% with 27% patients in complete remission and 7% in partial remission. The 5 year remission rate was 34% compared to the 24% five year overall rate of relapse.

Disease activity of SLE, kidney function and clinical markers were also assessed and significant improvements were observed. The systemic lupus erythematosus disease activity index (SLEDAI) scores were significantly decreased and remained significantly lower 5 years after MSC therapy indicating sustained long term reduction in disease activity. At baseline, all patients had high levels of proteinuria. At yearly follow ups for 5 years, 24 hour proteinuria was significantly decreased in all analyzed patients. Albumin and complement 3 were also observed to be significantly increased after MSC therapy.
Overall, this study demonstrated the long term safety and efficacy of BM-MSC and UC-MSC in the treatment of patients with severe and drug resistant SLE. The authors of this study conclude that “this long-term follow-up study provides evidence that allogeneic MSCT had at least comparable if not better clinical efficacy than HSCT, but with fewer adverse events and significantly lower cost in treating drug-refractory active SLE patients.”

CITE: Wang D, Zhang H, Liang J, et al. A Long-Term Follow-Up Study of Allogeneic Mesenchymal Stem/Stromal Cell Transplantation in Patients with Drug-Resistant Systemic Lupus Erythematosus. Stem Cell Reports. 2018. doi:10.1016/j.stemcr.2018.01.029

Prognostic Factors for Clinical Response in Systemic Lupus Erythematosus Patients Treated by Allogeneic Mesenchymal Stem Cells. (Wen, L et al 2019)

This retrospective cohort study published in 2019 aimed to identify predictors of clinical response and evaluate efficacy of bone marrow derived MSCs (BM-MSCs) and umbilical cord derived MSCs (UC-MSCs) in the treatment of systemic lupus erythematosus (SLE).

All 69 patients had severe, drug-resistant SLE and had an initial systemic lupus erythematosus disease activity index (SLEDAI) score above 8. In addition, all of the patients had received a one year follow up visit after 1 or 2 intravenous infusions of MSCs at a dose of 1 million cells /kg.

Symptoms of SLE and the SLEDAI score before and after treatment were used to identify changes in disease activity and clinical remission. Data was collected at multiple intervals during the 12 month follow up period. Among the 69 patients 58%had improved SLEDAI scores achieving a low disease activity (LDA) status and 23% achieved clinical remission over the course this study.

LDA was associated with older age and the absence of joint pain/arthritis at baseline. Patients achieving clinical remission were also of older age, had no joint pain/arthritis at baseline and had no prior use of cyclophosphamide or hydroxychloroquine.

The authors of this study concluded “allogeneic BM-/UC-MSCs may be efficacious in treating patients with active disease who are refractory to standard treatments, with our results projecting potential rates of LDA around 58% and CR around 23% in the year following transplantation.”

CITE: Wen L, Labopin M, Badoglio M, Wang D, Sun L, Farge-Bancel D. Prognostic Factors for Clinical Response in Systemic Lupus Erythematosus Patients Treated by Allogeneic Mesenchymal Stem Cells. Stem Cells Int. 2019;2019:7061408. Published 2019 May 2. doi:10.1155/2019/7061408 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525791/

A randomised double-blind, placebo-controlled trial of allogeneic umbilical cord-derived mesenchymal stem cell for lupus nephritis. (Deng, D 2017)

A small, randomized, controlled trial published in the Annals of the Rheumatic Diseases was conducted to evaluate the efficacy of human umbilical cord derived mesenchymal stem cells (UC-MSCs) in the treatment of lupus nephritis (LN). Eighteen patients were enrolled and randomly assigned to receive UC-MSC therapy or placebo. All patients continued to receive conventional therapy.

Results show that there were similar remission rates and improvements in biochemical markers between the two groups. Remission occurred in 9 of 12 patients treated with MSC therapy and 5 of 6 patients in the placebo group. Number of patients who achieved complete remission was similar between groups. Improvement in albumin, renal function and the systemic lupus erythematosus disease activity index (SLEDAI) scores were also similar between the MSC therapy and placebo group.

The authors concluded that “hUC-MSC has no apparent additional effect over and above standard immunosuppression.”

CITE: A randomised double-blind, placebo-controlled trial of allogeneic umbilical cord-derived mesenchymal stem cell for lupus nephritis. Deng, D., Zhang, P., Guo, Y., & Lim, T. O. (2017). Annals of the Rheumatic Diseases, 76(8), 1436–1439. https://doi.org/10.1136/annrheumdis-2017-211073

Three years follow-up of refractory systemic lupus erythematosus patients with transplantation treating of umbilical cord mesenchymal stem cells. (Ru Bai et al 2017)

This 3 year follow up case series study conducted in China evaluated the clinical effects of umbilical cord derived mesenchymal stem cells (UC-MSCs) in patients with systemic lupus erythematosus (SLE). Kidney function, immunological indexes, and cytokine expression were also assessed.

Ten patients were treated with intravenous UC-MSCs and standard therapy including glucocorticoid and immunosuppressive treatment over the course of the study.

The therapy was deemed safe as no complications related to treatment were observed and no serious adverse events were reported in any of the cases.

The results show that 24 hour proteinuria and disease activity (the systemic lupus erythematosus disease activity index (SLEDAI) were decreased compared to baseline. Complement C3 and C4 along with albumin were shown to increase after therapy. In addition, cyotkines such as IL-15 and IL-2 had decreased. Other markers involved with the immunopathogenesis of SLE including CD86, Il-17c, TGF-B2 and others, were not significantly changed over the follow up period.

The authors of this study concluded “UC-MSC can regulate the expression of cytokines of participate in the immune response in the patients with SLE. Treatment of SLE by UC-MSC can elevate serum albumin and C3 and C4 level ,reduce the 24 hours urinary protein quantity, relife kidney damage, improve clinical symptoms”

CITE: 3 years follow-up of refractory systemic lupus erythematosus patients with transplantation treating of umbilical cord mesenchymal stem cells. Ru Bai et al. Chinese Journal of Immunology. 2017;33(6):905-909. http://wprim.whocc.org.cn/admin/article/articleDetail?WPRIMID=617436&articleId=617436

In addition to these aforementioned studies, there are many others demonstrating the safety and efficacy of stem cell therapy in SLE. Selected clinical studies published before 2015 are listed below.

• Allogeneic mesenchymal stem cell transplantation for lupus nephritis patients refractory to conventional therapy. Gu, F., Wang, D., Zhang, H., Feng, X., Gilkeson, G. S., Shi, S., & Sun, L. (2014). Clinical Rheumatology, 33(11), 1611–1619. https://doi.org/10.1007/s10067-014-2754-4
• Allogeneic mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus: 4 years of experience. Wang, D., Zhang, H., Liang, J., Li, X., Feng, X., Wang, H., … Sun, L. (2013). Cell Transplantation, 22(12), 2267–2277. https://doi.org/10.3727/096368911X582769
• Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus . Sun, L., Wang, D., Liang, J., Zhang, H., Feng, X., Wang, H., … Shi, S. (2010). Arthritis and Rheumatism, 62(8), 2467–2475. https://doi.org/10.1002/art.27548
• Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: A pilot clinical study . Liang, J., Zhang, H., Hua, B., Wang, H., Lu, L., Shi, S., … Sun, L. (2010). Annals of the Rheumatic Diseases, 69(8), 1423–1429. https://doi.org/10.1136/ard.2009.123463
• Mesenchymal stem cell transplantation for diffuse alveolar hemorrhage in SLE. Liang, J., Gu, F., Wang, H., Hua, B., Hou, Y., Shi, S., … Sun, L. (2010). Nature Reviews Rheumatology, 6(8), 486–489. https://doi.org/10.1038/nrrheum.2010.80
• Yang GX, Pan LP, Zhou QY, Song W, Chen ZQ, Wang CX, Wu YB, Wang X, Chen Q. [Therapeutic effects of umbilical cord mesenchymal stem cells transplantation on systemic lupus erythematosus]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2014 Mar;45(2):338-41, 350. Chinese. PMID: 24749369. https://pubmed.ncbi.nlm.nih.gov/24749369/
• Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: A multicenter clinical study. Wang, D., Li, J., Zhang, Y., Zhang, M., Chen, J., Li, X., … Sun, L. (2014). Arthritis Research and Therapy, 16(2), R79. https://doi.org/10.1186/ar4520