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Cyclophosphamide for myasthenia gravis: a comeback?
  1. Carolina Barnett-Tapia,
  2. Hans D Katzberg
  1. Neurology, Toronto Genreal Hospital, Toronto, Ontario, Canada
  1. Correspondence to Dr Carolina Barnett-Tapia, Division of Neurology, Department of Medicine, Toronto General Hospital, Toronto, Canada; c.barnetttapia{at}

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Myasthenia gravis (MG) treatment’s landscape has dramatically changed with the approval of novel therapeutics that can provide rapid improvement, including in patients typically considered refractory. These treatments are a welcome addition in MG, since a proportion of patients traditionally considered ‘responders’ to standard treatments, live with unacceptable disease burden, side effects and reduced quality of life.1

There are some limitations to newly approved treatments. Neonatal Fc receptor blockers and complement inhibitors do not reduce the production of pathogenic antibodies: they inhibit Ig recycling and complement-mediated damage, respectively. Therefore, in the absence of other treatments working further upstream or affecting the immune system more broadly, it is unlikely these interventions will induce remission, requiring continuous use. Another limitation is their costs, and health economic assessments often conclude that these are not cost-effective without significant discounts.2 As a consequence, these treatments are available but not accessible in some countries. Therefore, there is a need for effective interventions that are more accessible, especially in lower-income settings.

The JNNP paper by Chan et al is a retrospective cohort of 31 individuals with MG, some refractory and some considered ‘high-risk’, such as with contraindications to other treatments like steroids.3 Patients received cyclophosphamide every 4 weeks (0.75 g/m2) for six cycles. The overall safety profile was good; there were three grade three adverse events, and one death secondary to P. jirovecii pneumonia, 7 years after cyclophosphamide, considered unrelated. Most patients had marked and fast improvement in their MG symptoms, with a reduction or complete withdrawal of prednisone.

Some limitations include the lack of a control group and blinding. While all patients were receiving prednisone when starting cyclophosphamide, ~50% had not received a non-steroidal immunosuppressive agent. Although this may reflect country-specific practices, other factors could play a role. A large proportion of patients started mycophenolate after cyclophosphamide, suggesting cyclophosphamide treatment occurred earlier in the disease course. Disease duration before treatment is not described, and it is possible that patients treated more aggressively earlier may respond better to lower doses of medications. An example is the RINOMAX trial,4 where AChRAb positive individuals received 500 mg of rituximab within 12 months of onset, with excellent response. This was in contrast with a previous negative randomised controlled trial of rituximab in AChRAb positive MG, where mean duration was 5.5 years at randomisation.5 More clarity on the IST profile would be helpful to clinicians considering the proposed cyclophosphamide treatment strategy, to gauge the potential infection risk in individual patients.

Despite these limitations, this study shows that lower doses of cyclophosphamide can be effective and safe in people with MG, including older age. Clinicians may consider low-dose cyclophosphamide as a safe and cost-effective intervention in carefully selected patients, especially when novel treatments are inaccessible. Further studies are needed to understand the effect of timing of cyclophosphamide, as well as efficacy in other MG subtypes (eg, MuSK). This study also shows that the ongoing research and approvals of novel therapeutics in MG should not deter researchers from looking at older interventions, as these still play an important role in the treatment of MG.

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  • X @crampologist

  • Contributors CBT conceptualised draft and approved final manuscript. HDK reviewed manuscript for critical content and approved final version.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests CBT has served as a member of the advisory board for argenx, Alexion, UCB and Janssen. She has been a consultant for argenx, Janssen and UCB. She has received research support from US Department of Defense, Muscular Dystrophy Canada and MGNet. Grifols and Octapharma. She is the primary developer of the MGII and may receive royalties. HDK: Consultancy or Research Support: Grifols, CSL Behring, Octapharma, Takaeda, Pfizer, Biogen, Akcea, Alexion, Terumo, UCB, Roche, Argenx, Dyne, Merz, Syneos.

  • Provenance and peer review Commissioned; internally peer reviewed.

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