Rituximab in the management of refractory myasthenia gravis.
ABSTRACT Myasthenia gravis (MG) is an immune-mediated disorder with a variable response to treatment. In this study, patients with refractory MG who were treated with rituximab were identified. A review of patients referred to the Yale Neuromuscular Clinic was performed. Patients with refractory MG who were treated with rituximab were reviewed for response to treatment. Patients who had muscle-specific kinase (MuSK(+)) or acetylcholine receptor (AChR(+)) antibodies were included. Six patients were identified who met the criteria described. All patients tolerated rituximab without side effects and had a reduced need for immunosuppressants and/or improvement in clinical function. Patients with refractory MG appeared to respond to rituximab in this small, retrospective study. This result suggests that a larger, prospective trial is indicated.
- SourceAvailable from: sonepsyn.cl[show abstract] [hide abstract]
ABSTRACT: In chronic autoimmune conditions such as myasthenia gravis (MG), immunosuppression--usually long-term--is often necessary. The mechanisms of action of immunosuppressant drugs in MG fall into three main categories: inhibition of the cell cycle (azathioprine, cyclophosphamide, methotrexate and mycophenolate mofetil), immunosuppression of T cells (steroids, ciclosporin and tacrolimus), and B-cell depletion (rituximab). Data on immunosuppressant drugs in MG derive mainly from clinical experience, observational studies and expert opinion. The main drawbacks of the randomized evidence are the small size of most drug trials, variations in study design, and a lack of head-to-head studies. It is therefore difficult to determine the relative efficacy of each immunosuppressant. Oral prednisolone, usually started at a low dose on an alternate-day regimen, and gradually increased, is the recommended first-choice short-term immunosuppressant. Long-term immunosuppression regimens vary between different countries and physicians. Azathioprine is often the first-choice drug for long-term immunosuppression, and it is usually started together with steroids to allow tapering of steroids to the lowest dose possible. Methotrexate, mycophenolate mofetil or tacrolimus should be considered in patients who are intolerant of or unresponsive to azathioprine. Ciclosporin and cyclophosphamide should only be considered as a last resort, as these drugs can cause serious adverse events. Data on rituximab use in MG are sparse, but the initial results are promising.Nature Clinical Practice Neurology 07/2008; 4(6):317-27. · 7.64 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The chimeric anti-CD20 monoclonal antibody rituximab has become part of the standard therapy for patients with non-Hodgkin's lymphoma (NHL). To date, more than 300 000 patients have been treated with rituximab worldwide, including patients with indolent and aggressive NHL, Hodgkin's disease and other B-cell malignancies. Combination of rituximab with cytotoxic agents or cytokines has been explored in a number of different studies. Rituximab is now also approved for patients with diffuse large B-cell lymphoma when combined with standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone). The monoclonal antibody is generally well tolerated. Most adverse events are infusion-associated, including chills, fever and rigor related to the release of cytokines.Annals of Oncology 05/2003; 14(4):520-35. · 7.38 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Myasthenia gravis is a B-cell-mediated autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles. The underlying defect is an autoantibody-mediated attack on the acetylcholine receptors (AchRs) at the neuromuscular junction. Rituximab is a genetically engineered chimeric murine/human monoclonal antibody indicated for treatment of patients with low-grade or follicular, CD20-positive, B-cell non-Hodgkin lymphoma. Based on its potential for elimination of auto-reactive B-cell clones, rituximab may have a role in the management of some autoimmune disorders. We report a patient with B-cell, follicular non-Hodgkin lymphoma and a long-standing history of myasthenia gravis and the favorable impact of rituximab on both disorders.American Journal of Hematology 11/2004; 77(2):196-7. · 4.00 Impact Factor
RITUXIMAB IN THE MANAGEMENT OF REFRACTORY MYASTHENIA
NAZLEE ZEBARDAST, MS, HUNED S. PATWA, MD, STEVEN P. NOVELLA, MD, and JONATHAN M. GOLDSTEIN, MD
Department of Neurology, Yale University School of Medicine, 40 Temple Street,
Suite 6C, New Haven, Connecticut 06510, USA
Accepted 22 July 2009
disorder with a variable response to treatment. In this study,
patients with refractory MG who were treated with rituximab
were identified. A review of patients referred to the Yale Neuro-
muscular Clinic was performed. Patients with refractory MG
who were treated with rituximab were reviewed for response to
treatment. Patients who had muscle-specific kinase (MuSKþ) or
acetylcholine receptor (AChRþ) antibodies were included. Six
patients were identified who met the criteria described. All
patients tolerated rituximab without side effects and had a
reduced need for immunosuppressants and/or improvement in
clinical function. Patients with refractory MG appeared to
respond to rituximab in this small, retrospective study. This
result suggests that a larger, prospective trial is indicated.
Myasthenia gravis (MG) is an immune-mediated
Muscle Nerve 41:375–378, 2010
Myasthenia gravis (MG) is the prototypical auto-
immune disorder and is characterized by fatigable
oculobulbar and limb weakness. Treatment of MG
consists of symptomatic therapy with acetylcholin-
esterase inhibitors and immunotherapy such as
corticosteroids, azathioprine, cyclosporine, plas-
(IVIg).1Despite these therapies there are patients
who remain refractory to treatment. Medication
side effects are common, and therefore new ther-
apy options are desirable.
Autoreactive B-cells play an important role in
the immunopathogenesis of MG.2Rituximab is a
chimeric monoclonal antibody that targets the
CD20 antigen found on B-lymphocytes and modu-
lates B-cell activation. Rituximab has been used as
part of the standard therapy for non-Hodgkin’s
lymphoma (NHL) as well as a number of autoim-
mune diseases.3In 2004, Gajra et al. reported a
patient with both NHL and MG who responded
favorably to rituximab.4Since then there have
been several case reports and case series that dem-
onstrated the benefits of rituximab in acetylcholine
receptor antibody (AChR-Abþand AChR-Ab?) and
We treated 6 patients with refractory MG with
rituximab therapy and report on the clinical and
Patients referred to the Yale Neuromuscular Clinic
from 2003 to 2007 who received rituximab for re-
fractory MG were reviewed for clinical and serolog-
ical response to treatment. Patients were defined
as refractory when they could not lower their
immunotherapy without clinical relapse, were not
clinically controlled on their immunotherapy regi-
men, or had severe side effects from immunosup-
pressive therapy. All patients were examined by
one of the neurologists (J.M.G.). AChR-Ab testing
was performed at Mayo Medical Laboratories,
Rochester, Minnesota (normal 0.00–0.02 nmol/li-
ter). MuSK antibody testing was performed at
Athena Diagnostics (Four Biotech Park, Worcester,
Representative Case Report: MuSK1MG.
old woman presented in July 2003 with dysarthria,
dysphagia, and weakness. She was evaluated by her
dentist who referred her to an otolaryngologist
who did not make a diagnosis. The patient then
visited a local neurologist in August 2003. She had
negative findings for AChR-Ab, magnetic reso-
nance imaging (MRI) of the brain, serum creatine
kinase (CK), thyroid function test, and computed
tomography (CT) of the chest. The patient then
had a positive MuSK antibody test. She was started
on pyridostigmine, but it was soon discontinued
due to lack of efficacy. Prednisone was started at
the same time at 30 mg/day and was titrated to
60 mg/day by 1 month, with an incomplete effect.
The patient was referred to the Yale Neuromus-
cular Clinic in November 2003 for a second opin-
ion. Neurological examination was notable for di-
plopia, dysphagia, and upper and lower extremity
weakness. She was started on azathioprine at a
dose of 50 mg/day, but it was discontinued shortly
thereafter due to elevated liver function tests. She
was also given five doses of IVIg from December
28, 2003 to January 1, 2004 with no effect. On
February 2004, the patient was started on plasma-
pheresis, receiving two treatments every 2 weeks.
Although improved, she remained symptomatic.
Abbreviations: AChR-Ab, acetylcholine receptor antibody; CK, creatine
kinase; CBC, complete blood count; CT, computed tomography; FDA,
Food and Drug Administration; IVIg, intravenous immunoglobulin; MRI,
magnetic resonance imaging; NHL, non-Hodgkin’s lymphoma; PML,
MuSK, muscle-specific kinase; NHL, non-Hodgkin’s lymphoma; SLE,
systemic lupus; erythematosus
Key words: immunosuppression; myasthenia gravis; refractory; rituximab;
Correspondence to: J.M. Goldstein; e-mail: email@example.com
interscience.wiley.com). DOI 10.1002/mus.21521
C 2009 Wiley Periodicals, Inc.
Rituximab in MGMUSCLE & NERVEMarch 2010 375
Therefore, in May 2004, she was started on cyclo-
sporine at 200 mg/day.
By 6 months, all symptoms had resolved except
for diplopia and facial weakness. She was able to
undergo prednisone tapering to 20 mg/day by this
time. However, in October 2005, she again began
to experience diplopia, dysarthria, and facial upper
extremity weakness. Plasmapheresis was increased
to two treatments every 10 days.
The patient was started on rituximab in August
2006 (Fig. 1C) and received six intravenous infu-
sions weekly at a dose of 375 mg/m2. One month
later she was able to extend the interval between
plasmapheresis to two treatments every 20–30 days
and reduce prednisone to 20 mg and 10 mg on
alternating days. She continued to experience di-
plopia, dysarthria, and facial and upper and lower
extremity weakness. In October 2006, prednisone
was reduced to 10 mg/day, and 1 month later it
was further reduced to 10 mg every other day. As
of December 2006, her symptoms had markedly
improved and she experienced only mild facial
and proximal upper extremity weakness and mild
dysarthria. She was taking a reduced dose of cyclo-
sporine, 100 mg/day, at this time. Prednisone was
reduced to 5 mg/day in April 2007.
The patient was given a second course of rituxi-
mab in April 2007. She received five infusions
weekly at a dose of 375 mg/m2. One month later,
physical examination was notable only for neck
weakness. She discontinued cyclosporine at this
time and reduced prednisone to 5 mg every other
day. Plasmapheresis was discontinued in July 2007.
The patient was given a third course of four weekly
infusions of rituximab at the same dose in Novem-
ber 2007. At this time, she was able to discontinue
prednisone, because she was asymptomatic. She
received a fourth course of rituximab in November
2008 and continues to remain symptom-free.
Representative Case Report: AChR-Ab1MG.
year-old woman presented in July 2004 with left
ptosis, diplopia, and generalized weakness. She was
evaluated in a local emergency room and sent to a
neurologist for further testing. The patient was
found to have AChR-Abs and she was diagnosed
with generalized MG. She was started on pyridos-
tigmine, but her symptoms quickly worsened to
include ptosis, diplopia, dysphagia, and upper and
lower extremity weakness.
She was admitted to a local hospital for MG cri-
sis and was treated with prednisone, azathioprine,
and IVIg. Due to an incomplete response, the
patient was started on plasmapheresis and varying
doses of prednisone and azathioprine up to
250 mg/day. Pyridostigmine was discontinued at
The patient sought a second opinion at the
Yale Neuromuscular Clinic in January 2007 due to
60-lb. weight gain and continued symptoms despite
immunosuppressive therapy. Neurological exami-
nation was notable for left ptosis, diplopia, and
proximal arm and leg weakness. Laboratory testing
revealed an AChR-Ab titer of 0.78 nmol/liter (Fig.
2A), normal thyroid function test, and normal CK.
She was maintained on 150 mg/day of azathio-
prine and 30 mg/day of prednisone, and under-
went thymectomy in June 2007. Pathology showed
involuted thymic tissue. In spite of this she
remained symptomatic and showed no major
change in AChR-Ab titer (0.81 nmol/liter).
Multiple attempts were made to taper predni-
sone; however, the patient experienced increased
symptoms, including weakness, dysphagia, dysarth-
ria, diplopia, and weight gain. At this time, her
AChR-Ab titer was markedly increased to 1.61
The patient was admitted to Yale–New Haven
Hospital in November 2007 for MG crisis. She was
treated with four rounds of plasmapheresis and
5 days. She was was discharged on 60 mg/day
prednisone, which resulted in a 60-lb. weight gain.
Azathioprine was discontinued due to lack of effect.
The patient was started on rituximab in January
2008 (Fig. 2A) and received four intravenous infu-
sions per week at a dose of 375 mg/m2. By
2 months, she reported improvement in diplopia,
ptosis, and upper and lower extremity strength.
Her AChR-Ab titer was reduced to 0.47 nmol/liter
by this time. She was able to have prednisone
tapered to 40 mg/day by 3 months post-rituximab
with a dose that continued to decrease by 5 mg/
month. In June 2008, the patient was on 25 mg/
motor exam and a reduced AChR-Ab titer of 0.39
nmol/liter. In July 2008, she received a second
course of rituximab using the same protocol as
with the first infusion. She was able to undergo
prednisone taper to 20 mg/day by this time, but
diplopia continued. Three months later, however,
she was asymptomatic and on 10 mg/day of pred-
nisone, with a reduced AChR-Ab titer of 0.27
nmol/liter. She received a third course of rituxi-
mab in January 2009. Since then she has been able
to undergo reduced prednisone to 5 mg/day, with
a continued reduction in AChR-Ab titer (0.19
nmol/liter), and has remained symptom-free.
All patients with refractory MG who were treated
with rituximab had a decreased need for immuno-
suppressive therapy, improved clinical function, or
both (Table 1 and Figs. 1 and 2). No side effects
376Rituximab in MG MUSCLE & NERVE March 2010
were reported or observed. AChR-Abþpatients had
a decrease in antibody titers (Fig. 2). Six patients
were included, of whom 4 were MuSKþand 2 were
AChR-Abþ. All but 2 patients were asymptomatic
after rituximab treatment.
Our results support the hypothesis that rituximab
can be helpful in managing refractory MG. This is in
agreement with previous reports of its efficacy.5–7,9
The need for treatments for patients who do
not respond to traditional therapy has led to a
search for new options. Rituximab is an appealing
treatment choice due to its mechanism of action
targeting CD20þB-cells that are involved with anti-
body production,10and other mechanisms that are
not completely understood. There is also prece-
dent for using rituximab in the treatment of anti-
We used a fixed rituximab dosing regimen of
four to six intravenous infusions weekly at the
recommended dose for non-Hodgkin’s lymphoma
of 375 mg/m2.12Similar pilot studies have used the
same dose in either four cycles13or six cycles.14
Reduction of AChR-Ab titers and the decreased
need for immunotherapy medications combined
with clinical improvement suggest that rituximab
can be very effective in these patients. Understand-
ing of this drug in MG is still incomplete, as a vari-
FIGURE 1. MuSK-antibody-positive patients. Treatment course for patient 1 (A), patient 2 (B), patient 3 (C), and patient 4 (D).
FIGURE 2. AChR-Ab-positive patients. Treatment course for patient 5 (A) and patient 6 (B).
Rituximab in MGMUSCLE & NERVEMarch 2010377
ably number of treatments with rituximabe may be
required to obtain clinical response in patients
with refractory disease.
We looked at patients with both MuSKþas well
as AChR-AbþMG. Although these two groups of
patients likely have differences in their immunol-
ogy, both are antibody-mediated. At present, there
is no commercial assay available for measuring
MuSK antibody titers. Therefore, it is unknown
whether there is a similar decline in MuSK anti-
body titers as seen with AChR-Abþpatients. How-
ever, both groups share a marked reduction in the
need for multiple- and/or high-dose immunother-
apy with clinical improvement that is sometimes
Although rituximab has been in use since 1997
in oncology patients, we do not yet have long-term
data on patients with immune-mediated disease
such as MG. Two cases of progressive multifocal
leukoencephalopathy (PML) in patients who were
treated with rituximab for systemic lupus erythema-
tosus (SLE) have been reported by the U.S. Food
and Drug Administration (FDA).15As of December
2006, the FDA had received 23 reports of PML in
patients taking rituximab for hematological malig-
nancies. This is of concern, as several other drugs
in the monoclonal antibody class have been associ-
ated with PML.16This must be weighed with great
care in deciding when to treat patients with refrac-
tory MG with drugs such as rituximab.
The most common side effect or rituximab is
infusion reaction, including fevers, chills, rigors,
nausea, and other symptoms. Reactivation of hepa-
titis B and other viral infections have been
adverse effects, such as tumor lysis syndrome and
renal toxicity, are specific to patients with hemato-
Our study subjects were
monitored with a complete blood count (CBC) at
baseline and after each infusion.
The marked effect of rituximab in our patients
with refractory MG and among those in previous
studies suggests that further investigation of this
drug be undertaken in a large, prospective trial,
where efficacy and safety data can be more care-
The authors thank Jenny Chan for assistance in preparation of the
1. Sathasivam S. Steroids and immunosuppressant drugs in myasthenia
gravis. Nat Clin Pract Neurol 2008;4:317–327.
2. Dalakas MC. Inhibition of B cell functions: implications for neurol-
ogy. Neurology 2008;70:2252–2260.
3. Boye J, Elter T, Engert A. An overview of the current clinical use of
the anti-CD20 monoclonal antibody rituximab. Ann Oncol 2003;14:
4. Gajra A, Vajpayee N, Grethlein SJ. Response of myasthenia gravis to
rituximab in a patient with non-Hodgkin lymphoma. Am J Hematol
5. Baek WS, Bashey A, Sheean GL. Complete remission induced by rit-
uximab in refractory, seronegative, muscle-specific, kinase-positive
myasthenia gravis. J Neurol Neurosurg Psychiatry 2007;78:77.
6. Hain B, Jordan K, Deschauer M, Zierz S. Successful treatment of
MuSK antibody-positive myasthenia gravis with rituximab. Muscle
7. Thakre M, Inshasi J, Marashi M. Rituximab in refractory MuSK anti-
body myasthenia gravis. J Neurol 2007;254:968–969.
8. Lebrun C, Bourg V, Tieulie N, Thomas P. Successful treatment of re-
fractory generalized myasthenia gravis with rituximab. Eur J Neurol
9. Illa I, Diaz-Manera J, Rojas-Garcia R, Pradas J, Rey A, Blesa R, et al.
Sustained response to rituximab in anti-AChR and anti-MuSK posi-
tive myasthenia gravis patients. J Neuroimmunol 2008;201–202.
10. Shiratori S, Kondo T, Kubota K, Wakasa K, Ibata M, Shono Y, et al.
Loss of CD20 expression following rituximab-combined chemother-
apy in CD20-positive and CyclinD1-positive multiple myeloma. Rin-
sho Ketsueki 2008;49:1536–1540.
11. Dalakas MC, Rakocevic G, Salajegheh M, Dambrosia JM, Hahn AF,
Raju R, et al. Placebo-controlled trial of rituximab in IgM anti-mye-
lin-associated glycoprotein antibody demyelinating neuropathy. Ann
12. RXList. http://www.rxlist.com/rituxan-drug.htm#
13. Tandan R, Potter C, Bradshaw DY. Pilot trial of rituximab in myas-
thenia gravis. Neurology 2008;70(suppl 1):A301.
14. Illa I, Diaz-Manera J, Rojas-Garcia R, Pradas J, Rey A, Blesa R, et al.
Rituximab in refractory myasthenia gravis: a follow-up study of
patients with anti-AChR or anti-MuSK antibodies. Neurology 2008;
15. FDA public health advisory. Life-threatening brain infection in
patients with systemic lupus erythematosus after Rituxan (rituximab)
Dec 18, 2008.
16. Aksamit AJ. Review of progressive multifocal leukoencephalopathy
and natalizumab. Neurologist 2006;12:293–298.
17. McDonald V, Leandro M. Rituximab in non-haematological disor-
ders of adults and its mode of action. Br J Haematol 2009;146:
Table 1. Patient characteristics and response to rituximab treatment.
T, Py, MM, P, PPx
Py, P, PPX, IVIg
Py, P, Aza, CsA, PPx
T, Py, P, PPx
T, Py, P, Aza, PPx
T, Py, P, Aza, PPx
Di, Pt, lw
Dya, Dyp, lw
Di, Dya, Dyp, lw
Di, Pt, Dya, Dyp, lw
NA, not available; Aza, azathioprine; CsA, cyclosporine; MM, mycophenolate mofetil; P, prednisone, Py, pyridostigmine; PPx, plasma exchange; T, thymec-
tomy; Di, diplopia; Pt, ptosis; Dya, dysarthria; Dyp, dysphagia; lw, limb weakness.
*Exam prior to first rituximab treatment and following last rituximab treatment
378Rituximab in MGMUSCLE & NERVEMarch 2010