Rituximab Highly Efficacious in Myasthenia Gravis, Especially in MuSK Positive Patients

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

Raffi Topakian, MD

In the largest retrospective study of rituximab in the treatment of myasthenia gravis (MG) to date, the anti-CD20 monoclonal antibody was shown to be safe, efficacious, and importantly, fast acting.¹

The study, led by Raffi Topakian, MD, a professor in the Department of Neurology at Klinikum Wels-Grieskirchen, ultimately found that at the final follow-up at an average of 20 months, remission was present in 42.9% of patients, and an additional 25% had minimal manifestations.

“Correspondingly, the need for high-cost therapies such as [intravenous immunoglobulins, plasma exchange, or immunoadsorption] had decreased substantially at last follow-up, and in the large subgroup of 39 patients with steroid treatment at the time of [rituximab], steroids could be stopped or the dose tapered to less than half of starting dose in 5 of every 6 patients,” the investigators wrote.

In totality, the assessment explored 56 patients with MG, with an average age at diagnosis and mean age of rituximab initiation of 41.5 years (interquartile range [IQR], 24.3 to 65.8) and 47.5 years (IQR, 33 to 71), respectively. Antibodies against the acetylcholine receptor (AchR) and muscle-specific tyrosine kinase (MuSK) were present in 69.6% and 25% of patients, respectively (seronegative, 5.4%).

"Most patients with MG require long-term steroid and immunosuppressive therapy, but conventional drugs may have intolerable [adverse] effects, take too long to achieve disease control or fail altogether," Topakian told NeurologyLive. "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."

At 3 months post-treatment initiation, 26.4% of patients already reached remission, with an additional 18.9% showing minimal manifestations or better as measured by the Myasthenia Gravis Foundation of America-Postintervention Status (MGFA-PiS). At the final follow-up, remission was achieved in 71.4% (n = 10) of the 14 patients who were MuSK+, and 35.9% (n = 14) of the 39 patients who were AchR+ (P = .022).

Additionally, an outcome of minimal manifestations or better was achieved in 85.7% (n = 12) of the MuSK+ patients and 64.1% (n = 25) of AchR+ patients, respectively. Of the 3 patients with seronegative MG, a single patient achieved minimal manifestations and 2 patients showed some improvement. “Interestingly, none of the 13 patients with [early onset MG] had reached remission at last follow-up,” Topakian and colleagues noted.

At last follow-up, high-cost therapies— intravenous immunoglobulins, plasma exchange, immunoadsorption, or eculizumab—were given to 23.2% (n = 13) of patients. In total, 11 patients were treated with immunoglobulins (10 intravenous, 1 subcutaneous), and 2 patients were receiving immunoadsorption on a non-regular basis. Additionally, 84.6% (n = 33) of 39 patients who were still taking steroids at the initiation of rituximab therapy had either stopped steroid treatment altogether (n = 23; 59%) or the dose had been tapered to ≤50% (n = 10; 25.6%).

“We compared baseline and follow-up characteristics in patients who had achieved remission at last follow-up vs. patients without remission,” Topakian and colleagues wrote. They noted that in the remission group (n = 24), the median age at diagnosis of MG and at start of rituximab were significantly higher, at 58 years (IQR, 33 to 71) compared to 29.5 years (IQR, 20 to 57.5; P = .01) in the non-remission group (n = 32), and 67 years (IQR, 40 to 72) compared to 40.5 years (IQR, 31 to 64.3; P = .029), respectively.

Additionally, the investigators reported a trend towards a shorter duration of disease before the start of rituximab (2.5 years [IQR, 1 to 6.8] vs. 6 years [IQR, 2 to 12]; P = .09) in the remission group compared to the non-remission group. In the remission group, MuSK+ MG was significantly more prevalent, being present in 41.7% of patients compared to 12.5% of the non-remission group (P = .013). “The mean number of steroid-sparing therapies [being utilized] before start of [rituximab] was lower, and the use of high-cost therapies was less frequent compared to patients without remission,” the authors acknowledged.

As for safety, the reported adverse events (AEs) potentially related to the study drug included infusion reactions (n = 3), respiratory tract infections (n = 3), chronic pain syndromes (n = 2), enteritis (n = 2), herpes zoster (n = 1), erysipelas (n = 1), cholecystitis (n = 1), unspecified mental disorder (n = 1), and alopecia areata (n = 1). A single death occurred during follow-up. The patient was a 59-year-old man with highly refractory late onset MG, who died 4.5 months post-treatment initiation with rituximab due to a cardiac issue.

“This study found that [rituximab] is a well-tolerated, safe, efficacious, and relatively fast-acting treatment for patients with MG. Benefit from [rituximab] was greatest in [MuSK+] MG. Placebo-controlled, randomized trials are needed to further clarify the role of [rituximab] in MG,” Topakian and colleagues concluded.

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.