Action Points

• Umbilical cord mesenchymal stem cell transplantation in a series of patients with active and refractory systemic lupus erythematosus appeared to be safe and produce clinical responses in most patients during a year of follow-up.
• There were relapses in some responders, necessitating repeat infusions.

Mesenchymal stem cell transplantation is showing promise as a treatment for refractory systemic lupus erythematosus, researchers have reported.

 

In a multicenter study conducted in China that included 40 patients who had persistent disease despite aggressive treatment with cyclophosphamide, mycophenolate mofetil, leflunomide, and/or high-dose steroids, 60% of those given umbilical cord mesenchymal stem cells had a major or partial clinical response during a year of follow-up, according to Lingyun Sun, MD, of Nanjing University Medical School, and colleagues.

 

In addition, at 1 year, the survival rate was 92.5%, the researchers reported online in Arthritis Research & Therapy.

 

 

What the Cells Can Do

 

"Mesenchymal stem cells are multipotent, nonhematopoietic progenitor cells that are being explored as a promising new treatment for tissue regeneration. Although their immunomodulatory properties are not yet completely understood, their low immunogenic potential, together with their effects on immune responses, make them a promising therapeutic tool for severe and refractory autoimmune diseases," Sun and colleagues stated.

 

Various lines of research have demonstrated that mesenchymal stem cells can differentiate into bone and cartilage, and have immunomodulatory effects on T-cells and B-cells. They also are capable of eluding detection by the immune system because they lack co-stimulatory molecules.

 

Following administration, at least some of the cells are recruited to areas where inflammatory processes are occurring, and are activated by the local pro-inflammatory cytokine milieu.

 

"There are a number of immune effects of these cells that would be predicted to be beneficial in lupus," Gary Gilkeson, MD, of the Medical University of South Carolina in Charleston, said in an interview.

But uncertainty remains about many of the precise mechanisms by which the cells affect the immune system.

 

"We don't really know how the cells are working and whether they need to reach areas of inflammation for them to work. We do know that sometimes after the infusion the cells get hung up in the lung, but they still seem to be effective. So they could be working by secreting other chemicals or by direct cell-to-cell contact," Gilkeson said. "We're trying to work that out now."

 

"Up to this point, the treatment also appears to be very safe," added Gilkeson, who wasn't involved in this study.

 

 

The Multicenter Study

 

In an earlier study led by Sun, 16 patients with refractory or life-threatening lupus underwent the procedure, and the treatment had a "profound therapeutic effect," with short-term improvements in disease activity, renal function, and antibody levels.

 

Sun's group then went on to explore these effects in a larger group and over a longer period, enrolling patients between 2009 and 2011 for a multicenter trial.

 

The stem cells were obtained from fresh umbilical cords, and the dose used for intravenous infusion was 1 million cells/kg body weight, given on days zero and seven.

 

Disease activity was evaluated on the British Isles Lupus Assessment Group (BILAG) index, which rates clinical features in eight body systems. A score of "A" represents severe disease for each individual system, while B is moderate and C is mild disease.

 

A major clinical response was defined as scores of C for all body systems with no severe flares at 6 months, and maintaining the response throughout the 12-month study period.

 

A partial clinical response was defined as BILAG scores of C or better and no new A or B scores in the first 3 months, or having no more than one BILAG B score at 6 months and no more than one new BILAG A or B score through 12 months.

 

Among the 40 study participants, 38 were women. They ranged in age from 17 to 54, and mean disease duration was about 7.5 years.

 

During the 12-month follow-up, 32.5% of patients had a major clinical response and 27.5% had a partial clinical response.

 

Among responders, three relapsed at 9 months and four relapsed at 12 months. This suggested that repeat transfusions of the stem cells may be needed, perhaps at 6 months, according to the researchers.

 

"Some patients have had long-term remissions by getting these cells, but others have had to be treated again," said Gilkeson, who worked with the Chinese researchers in their earlier pilot trials.

"But even if you have to be treated again, it's usually not more than once every 6 months or even longer than that, which is certainly less than a lot of therapeutic infusions we use," he told MedPage Today.

 

Serologic changes included normalization of serum albumin, improvements in serum complement 3, and decreases in anti-dsDNA antibodies and serum antinuclear antibodies.

 

Active lupus nephritis was present in 38 of the patients at baseline, with mean 24-hour proteinuria levels of 2.24 g. By 6 months, proteinuria levels had fallen to 1.65 g and then to 1.41 g at 12 months.

During the yearlong trial, 81% of patients were able to taper their steroids, while 54% reduced their immunosuppressant drugs.

 

The researchers noted that mesenchymal stem cells can be obtained from many types of tissue, such as bone marrow, adipose tissue, and umbilical cords or umbilical cord blood -- or even dental pulp.

But obtaining the cells from bone marrow is much more difficult than umbilical sources, and the cells can be contaminated. Umbilical cord-derived cells also have advantages over umbilical cord blood cells, in that they "have a higher rate of gene expression related to cell adhesion, morphogenesis, angiogenesis, and neurogenesis," the researchers explained.

 

A limitation of the study was its uncontrolled, nonrandomized design.

 

"Thus far there haven't been reports of significant issues with the infusions, but we're still only about 4 to 5 years into human use, so whether something is going to happen in 15 years we don't know," Gilkeson cautioned.

 

 

Previous Efforts

 

The earliest case reports of hematopoietic bone marrow transplants in patients with lupus and other autoimmune diseases were in patients who had been given autologous or allogeneic transplants as cancer treatment and experienced remission from the autoimmune disease. However, the procedure was associated with high mortality rates and serious side effects.

 

To improve safety, investigators began using bone marrow stem cell transplants with nonmyeloablative conditioning and autologous stem cells among refractory lupus patients. About half of patients experienced 5-year relapse-free survival.

 

In one study of 50 patients with severe, refractory lupus treated using this approach, treatment-associated mortality was 2%. After a mean follow-up of 29 months, 5-year survival was 84% and likelihood of disease-free survival was estimated to be 50%.

 

With this type of transplant, the effects of treatment aren't directly from the stem cells, but from the conditioning regimen, which usually included cyclophosphamide and anti-thymocyte globulin, which "resets" the bone marrow.

 

"Eliminating autoreactive lymphocytes with reconstitution of the immune system with naive cells allows the immune system to start over," Gilkeson wrote in Clinical Immunology.

 

However, this approach still was associated with mortality and can't be used for patients with major organ damage, who are unlikely to survive the procedure; a National Institutes of Health-sponsored trial was unable to enroll an adequate number of patients.

 

 

Looking Ahead

 

The Chinese researchers are considering undertaking a randomized controlled trial in patients with lupus nephritis in which mesenchymal stem cell treatment plus steroids will be compared with traditional immunosuppressive therapy, such as with cyclophosphamide plus steroids.

 

In addition, the Stromal Cell Group of the European League Against Rheumatism is planning a double-blind trial in renal lupus.

 

"Controlled trials need to be done to definitely prove that these cells work. But the current human and animal data out there do suggest promise," Gilkeson concluded.

 

 

http://www.medpagetoday.com/Rheumatology/Lupus/45205

 

 

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