乌鸦传媒

PHILADELPHIA -- Treatment outcomes in stiff person syndrome are often suboptimal but, in the absence of a single standard of care, clinicians continue to try novel approaches to a disorder that appears more varied than it once seemed, suggested several studies presented here at the American Academy of Neurology's annual meeting.

Among them: favorable reports on rituximab (Rituxan) and, intriguingly, bortezomib (Velcade), as well as one large health system's experience with stiff person syndrome over the past decade.

Although much about the disease (formerly "stiff man" syndrome, even though most patients are women) remains unclear, it's now understood to be an . Autoantibodies against glutamic acid decarboxylase (GAD), necessary for GABAergic neurotransmission, are believed to be responsible for most cases. The result is spasmodic muscle rigidity, which may come and go without warning; patients are thus at risk of falling -- and those falls may be extra injurious since self-protective reflexes are impaired.

Yet despite the understanding of an autoimmune mechanism, treatments still vary widely with no standard. Patients may receive therapies directed at the immune system (intravenous immunoglobulin [IVIG], plasmapheresis), others targeting nervous system activity (e.g., benzodiazepines, anticonvulsants, and gabapentin).

This was made plain here by the review from the University of Utah researchers, led by Jonathan Galli, MD, of their institution's experience since 2010. Reviewing charts of 31 patients (24 of them women), they found nine different treatments administered. Diazepam (25 patients), IVIG (20), and baclofen (14) were most common. Diazepam and baclofen were judged effective in most of those cases, although IVIG -- which is endorsed by the National Institute of Neurological Diseases and Stroke -- was markedly less so, the researchers said.

Other immunotherapies including plasmapheresis, rituximab, steroids, cyclophosphamide, mycophenolate mofetil (MMF), and even autologous marrow stem cell transplant -- a treatment increasingly in vogue for a variety of autoimmune disorders -- were tried in smaller numbers of patients. The Utah group's results with plasmapheresis, rituximab, and steroids were disappointing (most patients showing no benefit) although the other immunotherapies performed better. Both patients undergoing marrow transplant responded, but these procedures were performed relatively recently and the researchers suggested more follow-up is needed to fully judge its potential. Galli was nevertheless enthusiastic about it, although he noted that persuading the patients' insurers to pay for it was an arduous process.

Part of the problem is that while the autoimmune target is reasonably well understood, there is clearly substantial heterogeneity in both the clinical presentation as well as the responses to treatment.

For example, the 31 patients in the Utah study showed a variety of symptoms in addition to stiffness, ranging from seizures and respiratory difficulty to pain and visual abnormalities.

Galli told 乌鸦传媒 that GAD is not the only autoimmune target in stiff person syndrome; disruption of the glycine receptor also appears to be involved in some patients. The ultimate mechanism "is the million dollar question," he said.

Presentations by a group at Johns Hopkins University in Baltimore elaborated on the heterogeneity. One poster summarized history and laboratory findings in 125 stiff person syndrome patients seen there. Among the findings: 80% showed significant titers of at least one other autoantibody besides anti-GAD, and other autoimmune diseases were common as well. These included type 1 diabetes, vitiligo, ulcerative colitis, lupus, and others.

One member of the Hopkins team, Salman Aljarallah, MD, told 乌鸦传媒 that the burden of these other autoimmunities appears to be a factor in the variable treatment response. Aljarallah was presenting a separate study on Hopkins's experience with rituximab in stiff person syndrome patients, which stood in stark contrast to those from Galli's group in Utah.

As an antibody-mediated disorder, many in the field had thought rituximab -- which depletes antibody-producing B cells -- had an excellent chance to be highly effective in stiff person syndrome. Those hopes took a hit, however, when a showed no benefit, with response rates of 33% both with rituximab and with placebo.

While those results were mirrored in the Utah experience reported by Galli and colleagues, Aljarallah reported a response rate of 69.5% among 23 patients at Hopkins. (Galli had lamented the lack of a standardized measure of treatment response in the disorder.) The Hopkins group noted that the 2017 trial was marred by short follow-up and, perhaps more importantly, treatment consisted of just two infusions. At Hopkins, rituximab treatment was open-ended and some patients received it for years.

Still, Aljarallah and colleagues noted, a substantial minority did not find relief with rituximab and there wasn't much to distinguish responders from nonresponders. Mainly, those who benefited tended to be younger with shorter disease duration, Aljarallah said. Both he and Galli suggested that the disorder becomes too firmly established to respond to therapy as currently conceived.

Meanwhile, a group at the University of Texas Southwestern Medical Center in Dallas hit on another immunological approach to stiff person syndrome to treat such a refractory case.

Bortezomib, approved for multiple myeloma but also sometimes used off-label for lupus, targets plasma cells in a way that also leads to reduced antibody production, according to Khalil Husari, MD, and colleagues. When confronted by a patient whose stiff person symptoms did not respond to a series of other treatments -- immunotherapies including IVIG, plasmapheresis, MMF, and rituximab, as well as diazepam, baclofen, tizanidine, and methocarbamol -- they decided to try bortezomib.

The drug was given in 3-week cycles, at 1.3 mg/m² on days 1, 4, 8, and 11, for a total of four cycles. The final cycle was delayed for 2 weeks when the patient, a 58-year-old woman, developed mild neutropenia.

There was no miracle cure, but the woman reported fewer spasms, improved walking ability, and less need for some of the drugs that had been continued, including diazepam and methocarbamol.

"Randomized controlled trials are needed," Husari and colleagues concluded.