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Myasthenia gravis (MG) is a disease of the neuromuscular junction, usually caused by an autoimmune process associated with antibodies against the acetylcholine receptor (AChR) or muscle-specific kinase (MuSK). Rituximab (RTX), a monoclonal antibody targeting CD20, has emerged as a potential treatment in the management of MG, in particular for MuSK positive patients.1 2 Most (80%) patients received 375 mg/m2 of RTX per week for 4 weeks, with lower doses being infrequently reported.
We previously reported on our experience with low-dose RTX in the treatment of MG3 and now report our long-term experience from an enlarged cohort.
We identified retrospectively all patients with MG treated with RTX between May 2006 and July 2017 in South East Queensland, Australia. Cases were identified via review of pharmacy and hospital records as well as by direct contact with the treating neurologists.
The clinical states of patients were scored using the Myasthenia Gravis Association of America (MGFA) Clinical Research Standards. Disease severity and concurrent therapies were documented through review of medical records (Timepoints: Diagnosis, RTX treatment, 3-monthly for the first year, annually thereafter). Wilcoxon ranked test was used to assess difference in steroid doses.
A total of 38 patients were treated (AChR: 28 patients (74%, female:male (F:M)=18:10), MuSK: six patients (16%, F:M=4:2), antibody negative four patients (10%, all female)). The mean age at initial treatment was 51.5 (range 22–87 years) with mean disease duration prior to initial therapy of 11.3 (range 2–52 years). Illness severity at the time of initial RTX administration and at last follow-up is outlined in figure 1 (additional data in online supplementary appendix 1).
Reasons for RTX administration included: refractory disease (26 patients, 68%), side effects with standard immunosuppression (nine patients, 24%), contraindications to standard immunosuppression (three patients, 8%).
Corticosteroids were used in 22 patients, with doses ranging from 5 mg to 75 mg daily. Twenty-seven patients (71%) were using concurrent steroid-sparing agents, including azathioprine, methotrexate, ciclosporin, cyclophosphamide, tacrolimus and mycophenolate mofetil. One patient received cisplatin-based chemotherapy for recurrent thymoma. Intravenous immunoglobulin (IVIg) infusions were used in 24 (63 %) patients and plasma exchange (PLEX) was used in three patients.
In total, 80 cycles of RTX were administered (64 cycles: 1000 mg, 13 cycles 500 mg, three cycles 2000 mg). Most patients were treated with one (12 patients, 31%) or two (12 patients, 31%) cycles of RTX. Other patients (14 patients, 36%) needed repeated cycles (up to nine), with further cycles being given at the treating physician’s discretion. Cumulative doses of RTX ranged from 500 mg to 9500 mg, with most patients receiving between 1000 mg RTX (10 patients, 26%) and 2000 mg RTX (10 patients, 26%).
Patients were followed up for a mean of 55 months (range 1–131 months, median 49 months). Mean time from last RTX administration to last assessment was 45 months (range 10–101 months, median 43.5 months).
Of the 38 patients, 28 patients experienced clinical improvement (10 patients clinical remission, seven patients minimal manifestations and 11 patients improvement). Five patients were unchanged or worse. At the point of last follow-up, five patients had moderately severe disease (one MGFA 3b, four MGFA 3a), 18 patients had mild disease (two MGFA 2b, six MGFA 2a, 10 MGFA 1) with 10 patients being asymptomatic (MGFA 0) (see figure 1). No patient had severe disease (MGFA 4 or 5). Five patients were deceased.
Change to immunosuppressive medications
The mean dose of prednisolone declined from 17.5 mg to 3.2 mg at the time of last follow-up (81.8% reduction, p<0.001). Other immunosuppressants were ceased in 19 patients. Four patients had complete cessation of all therapy. Six patients had an unchanged therapeutic regime after RTX therapy. Three patients required change in immunosuppressive agents.
Of 24 patients receiving IVIg, five patients had therapy ceased and six patients’ dose reduced, one patient was commenced on IVIg. PLEX was ceased for two of three patients.
Five patients died days to 3 years after RTX. Cause of death was glioblastoma multiforme several years after initial RTX administration, known metastatic thymoma, pneumonia and gastroenteritis, aspiration pneumonia and asystole days after the initial RTX administration. Deceased patients were of older age (mean age 68 years at time of death) than the overall cohort (mean age 57 at time of last follow-up).
Several case series, reviews and single case studies have outlined the use of RTX in MG.1 2 4 A phase 2 trial of RTX in AChR MG has been preliminarily reported as negative (https://clinicaltrials.gov/ct2/show/results/NCT02110706?sect=X301256), but differed from our series in a number of factors, including ancillary therapies. While most reports use doses adapted from the use of RTX in lymphoma patients (375 mg/m2×4 infusions), low-dose RTX has been used for non-neurological autoimmune diseases, such as idiopathic thrombocytopenic purpura.5
In our series, most patients received 1–2 g of RTX with substantial long-term improvement of symptoms, while often substantially reducing doses of other immunosuppressive therapy, such as steroids, steroid-sparing agents and IVIg. Prior studies have reported MuSK MG to respond better to RTX than AChR MG.2 In our series, MuSK patients had less severe disease at last follow-up, but were also more mildly affected initially. Timing of retreatments was at the discretion of the treating neurologists and frequency of redosing varied widely between patients.
Five patients died during the follow-up period due to malignancy, infection and asystole. This might partially be explained by the use of RTX as a treatment of last resort in severely unwell patients. A causative link to RTX therapy could not be established for any of the five deaths, but cannot be excluded.
Our report is limited by the retrospective nature of data collection, ongoing other immune therapies and heterogeneity of treatment protocols used in different patients. Timing of initial RTX therapy was likely influenced by the poor clinical status of patients at the time, which might influence the perceived relative treatment effect.
In summary, low-dose RTX in treatment of MG appears to lower disease severity and allows reduction of other immunosuppressive therapies in some patients.
Contributors FC and AS performed data collection and wrote the initial drafts of the manuscript. DG, MW, RDH, PAM and RCW were involved in patient care and revision of manuscript. SB was involved in patient care and writing of the manuscript.
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 None declared.
Patient consent Obtained.
Ethics approval Human Research Ethics Committee, Metro South Health, Queensland Australia.
Provenance and peer review Not commissioned; externally peer reviewed.
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