Rituximab Shows Fast-Acting High Efficacy in Myasthenia Gravis

Raffi Topakian, MD, a professor in the Department of Neurology at Klinikum Wels-Grieskirchen

Raffi Topakian, MD

A recent study of the anti-CD20 antibody rituximab in myasthenia gravis (MG) revealed that it was both safe and effective in treating the condition, as well as fast-acting.

At the final follow-up at an average of 20 months, 42.9% of the 56 patients were in remission, and an additional 25% were in a state of minimal manifestations or better, as measured by the Myasthenia Gravis Foundation of America-Postintervention Status.¹ The study, led by Raffi Topakian, MD, a professor in the Department of Neurology at Klinikum Wels-Grieskirchen, in Wels, Austria, was the largest retrospective assessment of rituximab to date.

To find out more about the promising therapy and the results of the trial, NeurologyLive reached out to Topakian. He explained some of the compound’s history and what is still needed to advance it further down the pipeline.

NeurologyLive: What prompted this research?

Raffi Topakian, MD: Most patients with MG require long-term steroid and immunosuppressive therapy, but conventional drugs may have intolerable side effects, take too long to achieve disease control or fail altogether. In recent years, rituximab has emerged as a promising off-label treatment for MG, but efficacy and safety data are still sparse and expert opinions on its use are controversial. We conducted a nationwide retrospective study in Austria to further elucidate the current role of rituximab for MG.

What has been the controversy regarding rituximab’s use in MG?

Rituximab is a relatively new drug for neurologists, while oncologists and rheumatologists have been using it for many years. Rituximab induces long-term B cell depletion, so there is the risk of opportunistic infections, including progressive multifocal leukoencephalopathy caused by the JC virus.

Oral immunosuppressive medication such as azathioprine or cyclosporine can be stopped, and then immunosuppression fades away. Rituximab is an infusion—if it´s in the patient, it´s in the patient, so following rituximab, it can take months, in some patients even years, for B cells to reappear. This can pose problems with regard to much-needed immunizations, treatment of infections, et cetera.

Most importantly, there are no randomized placebo-controlled trials supporting the use of rituximab in MG. On the other hand, most drugs used in MG have no randomized clinical trial-supported evidence and it is very difficult to conduct randomized clinical trials in MG due to some variability of MG symptoms in some patients even from day to day, the lack of an ideal end point measure, and confounding factors like steroid co-medication.

What’s the main takeaway for the clinician community in this study?

Rituximab was found to be well tolerated, safe and efficacious. Benefit from rituximab was greatest in patients with MG with antibodies against muscle-specific tyrosine kinase antibodies, while none of the patients with early onset MG (age <50 years, generalized symptoms, and antibodies against acetylcholine receptors) achieved pharmacological remission. At last follow-up, two-thirds of the cohort had achieved the post-intervention status of minimal manifestations or better. Following rituximab, concomitant steroid medication and high-cost therapies such as immunoglobulins and plasma exchange could be tapered and stopped in a substantial proportion of patients.

Are these findings reason enough for further exploration of rituximab in MG to make a case for FDA approval, or is much more data needed?

We urgently need randomized clinical trial-based evidence supporting rituximab in MG. Retrospective studies have flaws inherent to the retrospective study design.

The still unpublished, in a journal, randomized clinical trial, the BeatMG study, from Yale was negative, but the study design was somewhat artificial, and steroids were given in high doses. However, there was a positive signal: subgroup analysis showed that compared to patients who received placebo, patients with rituximab had lower rates of relapse with a need for rescue treatment such as immunoglobulins or plasma exchange.

Hopes are high that a currently recruiting study (NCT02950155) from the Karolinska Institutet, in Stockholm, Sweden, will show positive results. I like the study design and the low dose of rituximab (only once at 500 mg) used in that study.

Were there any surprising or unexpected findings in your group’s study?

Rituximab appeared fast-acting, even when given at lower doses. The majority of patients received an induction therapy consisting of only two rituximab infusions (500-1000mg each) within two weeks. Despite the high proportion of severely affected patients, three months after induction therapy pharmacological remission was already observed in every fourth patient (26.4%).

Was the reason for its fast-acting nature apparent, or is this not understood?

B cell depletion by rituximab has been shown before to be fast acting in other conditions. Following rituximab, B cells are at 0% in peripheral blood for many months, and antibody production, including antibodies against AchR and MuSK, comes to a halt in a very short time.

MG experts are used to the fact that conventional immunosuppressive medication takes time.

One of the most brilliant MG experts, Prof David Hilton-Jones, from Oxford, once wrote: "Azathioprine is very slow to act and should be considered to have little or no effect for at least 12 months, with maximum benefit within 24 months. A fair trial should, therefore, last at least 18 months before considering it ineffective and trying another drug.”² Well, you probably can do that in the UK, but sure enough, not in Upper Austria.

Because patients need fast-acting therapies, it is not only about quality of life. A high dose of steroids over 1-2 years will do a lot of irreversible, and mostly non-neurological damage to multiple organs despite careful prophylaxis of complications.

Transcript edited for clarity.

REFERENCES

1. Topakian R, Zimprich F, Iglseder S, et al. High efficacy of rituximab for myasthenia gravis: a comprehensive nationwide study in Austria. J Neurol. Published online January 16, 2019. doi: 10.1007/s00415-019-09191-6.

2. Hilton-Jones D. When the patient fails to respond to treatment: myasthenia gravis. Pract Neurol. 2007;7:405-411. doi: 10.1136/jnnp.2007.134130.