Azathioprine, MMF effective, but more studies needed: PROMISE-MG

Study included adults with MG who hadn't had immunosuppressants

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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No significant differences in clinical outcomes or quality of life were observed between myasthenia gravis (MG) patients treated with azathioprine or mycophenolate mofetil (MMF), results from the PROMISE-MG observational study show.

While “more comparative effectiveness studies are required,” the findings “provide important information for the clinical management of patients, as the algorithm of myasthenia gravis treatment evolves,” the researchers wrote in “Comparative effectiveness of azathioprine and mycophenolate mofetil for myasthenia gravis (PROMISE-MG): a prospective cohort study,” which was published in The Lancet Neurology.

Different immunosuppressant medications may be used to treat MG, an autoimmune disease where the immune system attacks proteins involved in nerve-muscle communication. Azathioprine, sold as Imuran, among others, and MMF, sold as CellCept, are two of the most common nonsteroidal immunosuppressants and work to slow the growth of the immune cells that produce MG-causing antibodies. They’re intended to be steroid-sparing, meaning patients taking them can stop using steroids such as prednisone or take a lower dose.

Despite their widespread use, clinical studies that evaluated and compared their effectiveness in MG are lacking.

PROMISE-MG (NCT03490539) sought to better understand the real-world treatment effects across 19 centers in North America. It enrolled adults with MG who hadn’t been treated with nonsteroidal immunosuppressants. Physicians at each center determined a treatment course based on patients’ individual needs. As its main goal was to compare MMF and azathioprine, the analysis included only the 78 out of 167 participants who received MMF (47) or azathioprine (31). The patients were followed from the start of treatment (baseline) for a median of 20-25 months, or about 1.5 to two years.

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Comparing immunosuppressants

One of the study’s main goals was to evaluate changes in patient-reported quality of life, assessed by scores on the MG-Quality of Life 15-revised (MGQOL-15r), where a lower score reflects better life quality. Changes in MGQOL-15r scores were assessed from the start of treatment to the follow-up visit where they reached their lowest value.

Scores dropped by a mean of 10.4 points for patients on MMF and 6.8 points for those on azathioprine, but the difference between the groups wasn’t statistically significant.

More patients on MMF (81%) achieved a clinically meaningful MGQOL-15r score reduction — a drop of at least 5 points — than the azathioprine group (57%), but again without significance.

The second main outcome was to evaluate the proportion of participants who achieved a composite indicator of clinician-reported improvement during that same time.

To achieve this, a patient had to reach a clinical status of minimal disease manifestations or better on the MG Foundation of America Post-Intervention Status (MGFA-PIS), meaning no symptoms or functional limitations, but still some degree of muscle weakness, and a low adverse event burden, meaning only mild side effects.

The clinical composite outcome was achieved in nearly half (47.7%) of those on MMF and just over a quarter (28.1%) of those on azathioprine, again with no significant difference between the groups.

Other secondary efficacy outcomes, including other clinical scales of disease severity, didn’t differ significantly between the groups, with more than 70% of patients achieving clinically meaningful responses.

“More than half of patients treated with azathioprine and mycophenolate mofetil felt their quality of life improved; no difference in clinical outcomes was noted between the two drugs,” the researchers wrote.

Around two-thirds of MMF-treated patients were given a dose similar to what is typically recommended in clinical practice. But about three-quarters of azathioprine-treated patients received doses lower than recommended for immunosuppression.

Still, the scientists didn’t identify any substantial differences in those patients compared with the analysis of the whole study population, suggesting these lower doses “could be effective and could reduce dose-dependent side effects.”

The most common side effects were gastrointestinal disturbances in the MMF group and liver toxicity with azathioprine. The frequency or severity of side effects didn’t differ between the groups.

The side effects related to azathioprine “were potentially more serious,” wrote the researchers, who noted the data may favor MMF for clinical practice, but the small number of patients limited their interpretation and there are factors that may influence treatment choice. MMF can cause fetal harm and isn’t safe to use during pregnancy, for instance.

“Therefore, considerations beyond effectiveness, such as sex, childbearing potential, and [coexisting conditions] are essential when choosing treatments for myasthenia gravis, and the choice is influenced by physician and patient preferences,” wrote the researchers, who said, given the study’s small and observational nature, more research is needed to determine how these medications fare in clinical practice and their place in the evolving MG treatment landscape.

The study was funded by the MG Foundation of America and the Patient-Centered Outcomes Research Institute.