Stem Cell Transplants Successful in Stiff Person Syndrome

Pauline Anderson

August 29, 2014

An intensive approach to autologous stem cells transplantation has allowed a return to normal function for patients with stiff person syndrome (SPS).

Researchers at the Ottawa Blood and Marrow Transplant Program have so far performed transplants on 3 women with SPS. They describe the first 2 cases, both involving relatively young women, in a case series published online August 25 in JAMA Neurology.

Both women were in clinical remission following the transplant and both have returned to their normal functioning.

SPS is a rare neurologic disorder that affects proximal muscles in the upper and lower extremities as well as trunk muscles. Being unable to bend their arms and legs properly, some patients develop a stiff gait. The disorder is about twice as common in women as men.

Although SPS is believed to be an autoimmune condition, it's not clear what changes to the immune system lead to decreased neuromuscular function. It could involve some combination of genetic susceptibility and environmental exposure, said study author Christopher Bredeson, MD, head, Malignant Hematology and Stem Cell Transplantation, Ottawa Hospital, and senior scientist, Ottawa Hospital Research Institute, Ontario, Canada.

Dr. Christopher Bredeson

About 60% to 80% of those affected have autoantibodies against glutamic acid decarboxylase (GAD).

That the immune system of patients with SPS is at the root of the problem is the rationale for testing autologous hematopoietic stem cell transplants (auto-HCT) in this group.

"If we can wipe out their immune system and have it start over again from bone marrow stem cells or hematopoietic stem cells, and if we're lucky, maybe it won't happen again," Dr. Bredeson told Medscape Medical News. "At worst, it will just set the disease course back by knocking out most of the cells that are causing the problem."

Tin Soldier Gait

The first patient in the case series was diagnosed with SPS in August 2005 at age 48 years. She presented with progressive leg stiffness, hyperreflexia, and falls, and she walked with an abnormal "tin soldier" gait. MRI findings were normal. Anti-GAD antibodies were present at a very high titer (127 U/mL). Over the next few years, her symptoms worsened.

The second case was a woman with episodic leg muscle stiffening, with normal neurologic exams between attacks. The patient had a low titer of anti-GAD antibody. She was diagnosed with SPS in 2008 at age 30 years.

GAD is considered one of the strongest candidate autoantigens involved in triggering β-cell-specific autoimmunity.

The intense protocol used by the research team begins with a thorough consultation involving a discussion of the risks and benefits of the transplant. During the first part of the procedure, patients are hooked up to a machine that retrieves the cells of interest, those that can regrow the bone marrow, said Dr. Bredeson.

These hematopoietic stem cells (CD34-selected auto-HSCT) are put into a preservative and stored in liquid nitrogen.

Patients are then given a conditioning regimen that includes chemotherapy and antilymphocyte antibodies to try to kill the immune system.

The cells are then thawed and re-infused into the patient. "When you re-infuse them, the patient is really redeveloping their immune system from scratch; it's like they're a baby," said Dr. Bredeson.

The transplanted patients have to be revaccinated starting about 6 months after transplant.

Challenging Infections

Since one of the challenges is dealing with unusual viral or fungal or mold-type infections, patients take medications in an effort to prevent these adverse effects, said Dr. Bredeson.

The patients' blood counts recover within a few weeks, but their immune recovery can take from 3 to 6 months, said Dr. Bredeson. "Patients don't get better immediately, but once they're better, it's really quite amazing to see them."

A month following her transplant, the first woman's symptoms had resolved. After 2 months, her GAD antibody titer was 87 U/mL. Despite continued circulating anti-GAD antibodies, at 6 months, she was fully mobile, had returned to work, and was enjoying skiing and biking. She remains asymptomatic 4 years and 8 months following the transplant.

"While anti-GAD antibodies may serve as a biomarker for the illness, it is unlikely that they are involved in the pathogenesis of disease activity," noted the authors.

The second woman experienced 2 episodes of severe muscle spasms in the first 2.5 months after the transplant, followed by a third and then a fourth, but the last 2 episodes were less severe and of shorter duration. She also has returned to work and not had symptoms related to SPS in more than a year.

Neither women had unexpected treatment-related toxic effects. And neither needs ongoing immunomodulatory or immunosuppressant medication.

The research team has already transplanted a third woman who "is recovering and her symptoms are going away," Dr. Bredeson reported.

While the results so far are "favorable," the treatment approach involves a mortality risk on the order of about 5%, the recovery period is long, and it's unclear if the effects are permanent, said Dr. Bredeson. "It's hard to know if it will last 1 more day or 20 more years."

However, he added, "in select patients who have sort of exhausted other things, it proves the principle and we are encouraged to continue and try to develop the approach."

Although other researchers are using autologous transplants in autoimmune diseases, including multiple sclerosis, said Dr. Bredeson, this approach uses a much more intensive chemotherapy and much stronger conditioning regimen.

This high-dose approach may be needed to minimize the likelihood of relapse, which has occurred with less intense approaches, he added.

While the results to date are promising, the challenge is that patients with SPS are so heterogeneous, said Dr. Bredeson.

"The ideal would be to do a randomized trial of the transplant approach versus something else, but that 'something else' keeps changing because new drugs keep coming along."

And referred patients who meet eligibility criteria would be likely be interested in the transplant alone and not that "something else," he added.

Underlying Nature

Commenting on this research for Medscape Medical News, Alberto Espay, MD, associate professor, Neurology, University of Cincinnati, said it's "definitely a unique intervention" that appears to address the underlying nature of the abnormality involved in SPS and to have an impact beyond just symptom improvement.

"The beauty of this approach is that it's targeting the mechanism to some extent, and that's something we haven't done very well in the past necessarily," he said.

Typical treatments for SPS, for example intravenous immunoglobulin, which aim to modulate antibody levels, haven't been tremendously successful, said Dr. Espay. The reason for that, he believes, is that GAD levels in general don't bear much of a relationship with the severity of the disease.

"Someone with a terrible disease may have antibodies that are not so high, and conversely, someone else with relatively mild SPS may have really high antibodies."

But while the research is "very important and a great observation," it's still early in the development of this new approach, Dr. Espay cautioned. "Obviously, the question will become, if we are to test this in a larger group of people, will the same magnitude of benefit be confirmed?"

Dr. Bredeson has disclosed no relevant financial relationships.

JAMA Neurol. Published online August 25, 2014. Abstract

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