Rituximab Promising in New-Onset Myasthenia Gravis

Batya Swift Yasgur, MA, LSW

May 11, 2020

Patients with myasthenia gravis (MG) who are treated early with the monoclonal antibody rituximab (multiple brands) achieve remission sooner than those treated later in the disease process, new research suggests.

Investigators compared patients with generalized MG who received rituximab within the first year of disease onset to those who received rituximab more than 1 year after disease onset and to a control group who received immunotherapy.

Results showed that time to median remission in the early-treatment group was 7 months, compared to 11 months in the conventional immunotherapy group and 16 months in the group with refractory disease.

"While these results have to be regarded as preliminary, they indicate that rituximab might be a promising therapy in MG," senior author Fredrik Piehl, MD, PhD, professor of neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden, told Medscape Medical News.

"In particular, we think the finding that it performs better among those newly diagnosed with MG is important, since most prior evidence is on rituximab for those that did not respond to regular therapies," Piehl added.

The findings were published online May 4 in JAMA Neurology.

Hard to Beat

Mainstay MG treatments include corticosteroids and oral immunosuppressants. However, the investigators note that most of the conventional treatments for MG are mainly based on empirical evidence, not randomized clinical trials.

In 2017, the US Food and Drug Administration (FDA) approved eculizumab for MG. However, its prohibitive cost of approximately $500,000 per year puts it out of reach for many patients.

In light of the "heterogeneity of MG, it is likely that additional biologic agents, some of which may already be approved for other conditions, can be effective," the authors write.

One potential candidate is rituximab, which targets the CD20 antigen found on the surface of B cells. It has been approved by the FDA for treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and several other conditions.

In addition, rituximab is under investigation for the treatment of multiple sclerosis (MS) as well as neuromyelitis optica, and it is sometimes used off label to treat these illnesses.

In previous research, rituximab showed promise in treating patients with refractory MG.

"Having worked clinically in parallel with MG and MS for a long time, it was hard not to notice the difference in availability of new drugs and trial opportunities for my patients. So far, only one biologic is approved for MG, eculizumab, which, due to pricing, is out of reach for the vast majority of patients," said Piehl.

He added that his group began using rituximab almost 10 years ago for patients with MG and "quite quickly changed to using this as our preferred first-line choice."

He added that safety was an important consideration and that the "record of exposure data for rituximab is hard to beat."

The current study was designed to assess response to rituximab between patients with new-onset, vs refractory, MG and to compare it conventional immunotherapy.

The study included 72 patients (57% men; mean age at initiation of treatment, 60 years). Subgroups included the following:

  • Patients with new-onset disease for whom rituximab treatment was initiated less than 12 months after disease onset (n = 24; mean disease duration at rituximab initiation, 5 months)

  • Patients with refractory disease for whom rituximab treatment was initiated 12 months or more after disease onset and after treatment with at least 1 conventional immunosuppressant (n = 34; mean time to rituximab initiation, 122 months)

  • Patients who received their first rituximab treatment 12 months or longer after disease onset but who had not previously undergone immunotherapy (mean time to rituximab treatment, 14 months)

Baseline characteristics of these groups, including disease severity, were comparable.

A control group included 26 MG patients (mean age at treatment start, 68 years) who were receiving conventional immunosuppressants.

Conventional immunotherapy included prednisolone, azathioprine, cyclosporine, tacrolimus, methotrexate, and mycophenolate mofetil.

Patients treated with rituximab received a low dose consisting of a single 500-mg infusion every 6 months.

Early Treatment, Faster Remission

Results showed that 76% of rituximab-treated patients achieved clinical remission.

After adjusting for age, sex, and disease severity, as measured by Quantitative Myasthenia Gravis score, a significantly shorter median time to remission was shown for new-onset patients compared with patients with refractory disease, at 7 vs 16 months (hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.26 – 5.07; P = .009).

Adjusted time to remission was also shorter for rituximab-treated patients (7 months) than for those treated with conventional immunosuppressants (11 months; HR, 2.97; 95% CI, 1.43 – 6.18; P = .004).

In addition, adjusted analyses revealed that patients who received rituximab needed fewer rescue therapies during the first 24 months of observation compared with those who received conventional immunosuppressants (mean, 0.38 vs 1.31; P < .001); and a larger proportion of the group had minimal need or no need of additional immunotherapies (70% vs 35%; P = .02).

A post hoc analysis showed that the proportion of patients in clinical remission at 12 and 24 months was larger with rituximab than with conventional immunotherapies (87% vs 58%; P = .01).

The safety profile of rituximab was also superior. Fewer patients who received the drug discontinued treatment because of adverse events compared with those who received conventional therapies (3% vs 46%; P < .001).

"For the practicing clinician, I think our data improve the evidence base for using rituximab," Piehl said. However, he noted the importance of the fact that it is not an approved treatment.

"Still, rituximab is a drug with a known safety record, and many of us probably have used it in other contexts, for example, in neuromyelitis optica or MS.

"I also think it is valuable to know that the effects we saw came with a low-dose protocol, one single 500-mg infusion, compared with the most frequently used protocol in patients with MG, which is 4 weekly infusions of 500 mg over a month," Piehl said.

The lower-dose protocol "certainly reduces costs but potentially also improves safety," he added.

Important Findings

Commenting on the findings for Medscape Medical News, Rafi Topakian, MD, head of the Department of Neurology, Klinikum Wels-Grieskirchen, Wels, Austria, said the study is "very important for the MG community."

In particular, he said, the efficacy of the low-dose rituximab is reassuring "since higher doses could be followed by very prolonged B-cell depletion, with serious issues regarding the timing of much-needed vaccinations and immunosuppression-related infections," said Topakian, who was not involved with the research.

"With COVID-19 and other ugly threats around, you do not want your patients in B-cell depletion forever," he added.

Piehl noted that his group plans to corroborate these findings in a placebo-controlled nationwide trial in Sweden that "recently became fully recruited, with topline results expected next spring."

The study was supported by Stockholm County, with additional grants from the Swedish Brain Foundation, the Hans and Loo Osterman Foundation, and the Åke Wiberg Foundation. Piehl has received grants from Stockholm County, the Swedish Medical Research Council, Genzyme, Novartis, and Merck KGaA and personal fees from Parexel. The other study authors and Topakian have disclosed no relevant financial relationships.

JAMA Neurol. Published online May 4, 2020. Abstract

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