Abstract
Objective: We aimed to determine the effectiveness of IV immunoglobulin (IVIG) in the treatment of patients with myasthenia gravis (MG) and worsening weakness in a randomized, placebo-controlled, masked study.
Methods: Fifty-one patients with worsening weakness due to MG were randomized to infusion with 2 g/kg of IVIG or an equivalent volume of IV dextrose 5% in water. The Quantitative Myasthenia Gravis (QMG) Score for Disease Severity, a validated clinical composite scale, was calculated by a masked observer at baseline and days 14 and 28.
Results: In IVIG-treated patients, a clinically meaningful improvement in QMG Score for Disease Severity was observed at day 14 and persisted at day 28. The greatest improvement occurred in patients with more severe disease as defined by a QMG Score for Disease Severity greater than 10.5.
Conclusion: This study provides level 1 evidence for the effectiveness of IV immunoglobulin in patients with worsening weakness due to myasthenia gravis.
Acquired myasthenia gravis (MG) is mediated by two autoantibodies: acetylcholine receptor antibodies (AChRAb) and antibodies to muscle-specific tyrosine kinase (MuSK).1,2 AChRAb lead to clinical weakness by blocking and accelerating degradation of acetylcholine receptors, thus impairing neuromuscular transmission,1,3 but it is unknown if MuSK behave in the same fashion. Successful treatment of MG requires attenuation or elimination of the aberrant immune process using immunosuppressive medications and immunomodulation therapy.4–8 IV immunoglobulin (IVIG) is an immunomodulatory treatment commonly used in patients with MG with a clinical exacerbation requiring a rapid improvement in strength, who are intolerant of or fail immunosuppressive therapy or who live in centers lacking plasma exchange facilities,7,9,10 but the efficacy of IVIG in these patients is controversial.7,9–11 The most recent Cochrane Review concluded that there is insufficient evidence from randomized, controlled trials to determine if IVIG treatment improves functional outcome in patients with chronic MG.12 Therefore, we sought to determine the effectiveness of IVIG vs placebo in patients with MG in an appropriately powered, double-masked, randomized, controlled clinical trial.
Methods.
The study was performed at the University Health Network (UHN) Neuromuscular Clinic from March 2004 to May 2005. Both the UHN Research Ethics Board and the Health Products and Food Branch of Health Canada (Biologics and Genetic Therapies Directorate) approved the study. This study was registered with the US NIH.
Patient population.
Patients age 18 or older with a diagnosis of MG and worsening weakness were enrolled in the study after providing written informed consent. Patients were excluded from the study if they had respiratory distress requiring intensive care unit admission, a vital capacity less than 1 L, severe swallowing difficulties with a high risk of aspiration, a change in corticosteroid dosage in the 2 weeks prior to screening, other disorders causing weakness or fatigue, known IgA deficiency, active renal or hepatic insufficiency, clinically significant cardiac disease, known hyperviscosity or hypercoaguable state, or if they were pregnant or breast-feeding. Patients with worsening weakness secondary to concurrent infections or medications (e.g., aminoglycosides) were excluded. No changes in cholinesterase inhibitors or other immunodulators were made from study initiation to the primary outcome measure on day 14. After day 14, only initiation or changes to cholinesterase medications were allowed. Patients with clinical worsening requiring initiation of plasma exchange or steroids during the 28 days of the study were considered treatment failures and withdrawn from the study.
The diagnosis of MG was based on the clinical evaluation performed by a neuromuscular expert, abnormal electrodiagnostic studies on single-fiber electromyography (SFEMG) testing, and previous response to treatment. Abnormal repetitive nerve stimulation (RNS) testing supported the diagnosis, and abnormal AChRAb or MuSK levels confirmed the diagnosis, when present. Worsening weakness was defined as increasing diplopia, ptosis, blurred vision, dysarthria, dysphagia, difficulty chewing, or limb weakness severe enough as judged by both the patient and the physician to warrant a change in therapy.
Study procedures.
Clinical evaluation.
Patients with MG attending the UHN Neuromuscular Clinic and who provided informed consent were screened for the study by a neurologist who remained masked throughout the study. Patients had clinical assessments at baseline and 2 and 4 weeks after treatment by the same masked neurologist. The clinical assessments included the Quantitative Myasthenia Gravis (QMG) Score for Disease Severity and the Post-Intervention Status classification.13–15 The QMG score for Disease Severity is a validated clinical measure of sentinel muscle groups developed by the Myasthenia Gravis Foundation of America and the current clinical gold standard recommended for all prospective studies in MG.14,16 A change of 3.5 U on the QMG score for Disease Severity is considered clinically meaningful17 and was the effect size used to determine the sample size for this study. A value of greater or less than 10.5 was used to separate mild from more severe disease.11 The Post-Intervention Status rates the patient's clinical status on a five-step scale as improved, unchanged, worse, exacerbation, and died from MG. Adverse events that occurred during the study were assessed by an unmasked neurologist. Cholinesterase inhibitors were held for a minimum of 12 hours prior to all clinical assessments.
Electrodiagnostic investigations.
Standardized electrodiagnostic testing (SFEMG and RNS) was performed in all subjects at baseline and at the end of the study by a masked observer and a masked certified technologist. In patients with ocular and bulbar symptoms, the frontalis muscle was used preferentially for SFEMG testing. In patients with limb weakness without ocular or bulbar findings, the extensor digitorum communis muscle was tested. Jitter in at least 20 muscle fiber pairs was measured, and abnormal SFEMG was defined as increased mean jitter for a given muscle, elevated mean consecutive differences value in more than 10% of pairs for a given muscle, or the presence of blocking.18 RNS was performed by stimulating the facial nerve at a rate of 3 Hz and recording the compound muscle action potential (CMAP) over the frontalis muscle in most patients. Some patients had testing of the musculocutaneous nerve with recordings over the biceps muscle, depending on the clinical presentation. RNS was considered abnormal if the decrement from the first to fifth CMAP was greater than 10%. Cholinesterase inhibitors were held for a minimum of 12 hours prior to testing.
Laboratory investigations.
All patients had AChRAb levels checked at baseline. If abnormal, then AChRAb titers were rechecked on day 28. In those with normal AChRAb levels, MuSK antibodies were assayed during the study. No other laboratory tests were performed routinely.
Intervention.
The subjects were randomized in blocks of four to receive either 2 G/kg IVIG (Gamunex; Talecris Biotherapeutics, Toronto, Canada) or the equivalent volume of IV dextrose 5% in water (D5W) divided over 2 days and administered in the Medical Day Unit (MDU). The hospital pharmacist prepared the solutions in opaque bottles indistinguishable to the nursing staff, patients, and treating physicians. All study patients received the MDU standard treatment protocol for IVIG infusions with the preinfusion administration of acetominophen tablets and dimenhydramine 50 mg orally.
Efficacy measures.
The primary outcome measure was the change in the QMG Score for Disease Severity from baseline to day 14. The secondary outcome measures included the changes in the QMG Score for Disease Severity from day 1 to day 28 and from day 14 to day 28, changes in SFEMG and RNS results from baseline to day 14, and the Post-Intervention Status on days 14 and 28.
Statistical analyses.
Homogeneity of baseline characteristics between treatment groups was assessed by the Student t test for the continuous variables age, baseline QMG Score for Disease Severity, disease duration, percentage decrement on RNS, and SFEMG jitter and by the χ2 or Fisher exact test for categorical variables gender, type of MG, baseline disease severity, thymectomy history, thymoma, medications, and presence of AChRAb. Patients with thymoma had either undergone resection or were prethymectomy at the time of the study. An analysis of covariance (ANCOVA) was performed for the primary outcome measure and ANCOVA, χ2, or Fisher exact test was performed for secondary outcome measures. p values of <0.05 were considered significant. An exploratory analysis of the IVIG treatment effect was performed stratifying patients by baseline severity of disease using an ANCOVA model. Disease severity was dichotomized using a QMG Score for Disease Severity greater or less than 10.5 as performed in a previous study.11 Subsequently, the ANCOVA model was extended to assess the effects of baseline covariates of age, gender, duration of MG, baseline QMG Score, thymoma, presence of AChRAb, SFEMG jitter, and percentage decrement on RNS for the primary outcome measure. For jitter and percentage decrement, the change from baseline to day 14 was used in the model. A change of 3.5 U on the QMG Score for Disease Severity has been demonstrated to be clinically significant in a previous study and requires a sample size of 22 patients per treatment arm.13,17 We enrolled 52 patients to allow for study withdrawals.
Results.
Fifty-two patients were recruited for the study. One patient withdrew consent prior to study initiation and was not included in the analysis. The demographic profile for the 51 remaining patients enrolled in the study is shown in table 1. The baseline characteristics were balanced between the IVIG and placebo groups. Cases classified as “ocular” MG by routine clinical history and examination had a mean QMG Score of 10.9 ± 4.9 (range: 5 to 23, 10% at ≤6) compared with the mean of 13.0 ± 5.1 for those with “generalized” MG. The maximum QMG Score due to ocular findings alone is 6. At screening, medications included cholinesterase inhibitors in 57%, corticosteroids in 24%, azathioprine in 18%, and cyclophosphamide in 4%. Therapy with cholinesterase inhibitors and immunotherapies was balanced between the treatment groups as shown in table 1. In this MG cohort, 24 patients (47%) were AChRAb positive, and these patients were balanced between treatment groups. In those lacking AChRAb, 14 had elevation of anti-MuSK antibodies, or 52% of those who were AChRAb negative.
Table 1 Baseline characteristics
Table 2 displays the change in QMG Scores for Disease Severity 14 and 28 days after treatment. A small and significant improvement in QMG Score for Disease Severity was observed for patients treated with IVIG compared with those receiving placebo after 14 days. Treatment with IVIG reduces the QMG Score for Disease Severity by 2.5 U at day 14 (an additional 1.6 U compared with placebo; figure 1). The treatment effect was maintained at 28 days with a 3-U reduction in the QMG score, although it just failed to reach significance (p = 0.055).
Table 2 Mean change in QMG Score for Disease Severity at days 14 and 28
Figure 1. The mean change in Quantitative Myasthenia Gravis (QMG) Score for Disease Severity in all patients treated with IV immunoglobulin (IVIG) and placebo. There is a small decrease in the QMG Score for Disease Severity with IVIG treatment observed at day 14 (2.5 U; p < 0.047).
The Post-Intervention Status measure on day 14 demonstrated that 25% of patients on IVIG improved compared with 6% on placebo (p < 0.004, χ2 test). None of the patients on IVIG worsened compared with 4% worsening on placebo. Of those on placebo, 42% remained unchanged vs 23% on IVIG (p < 0.004, χ2 test). No patients required plasma exchange or initiation of steroids during the study. Those patients who had undergone thymectomy had a meaningful improvement in QMG Score at day 14 (−2.8 3 ± 1.1 on IVIG compared with 1.1 ± 0.9 on placebo; p = 0.0168) in contrast to patients who had not had thymectomy.
When stratifying patients by baseline MG disease severity (QMG Score for Disease Severity greater or less than 10.5), a significant IVIG treatment effect was observed only in patients with more severe disease (table 3). Patients with moderate to severe MG who were treated with IVIG had a 4.1-U reduction in the QMG score at day 14 (an additional 3.4 U of improvement compared with placebo-treated patients; figure 2). The Post-Intervention Status on day 14 was three times more likely to have improved with IVIG compared with placebo (23% improved with IVIG compared with 8% with placebo; χ2, p < 0.015). None of the patients on IVIG worsened, although 6% on placebo worsened. Patients with milder disease (QMG Score for Disease Severity less than 10.5) did not respond to IVIG treatment (p = 0.914). Additional ANCOVA analyses of QMG Score for Disease Severity change from baseline to day 28 and change from day 14 to 28 showed persistence of the IVIG treatment effect, but no additional improvement. None of the electrophysiologic measures showed a significant improvement with IVIG. When various factors that might influence response to therapy were added to the ANCOVA model, the presence of thymoma predicted a greater response to IVIG.
Table 3 Mean change in QMG Score for Disease Severity on day 14 in patients with mild and moderate to severe MG
Figure 2. The mean change in Quantitative Myasthenia Gravis (QMG) Score for Disease Severity in patients with moderate to severe disease, as defined by a baseline QMG Score for Disease Severity greater than 10.5, treated with IV immunoglobulin (IVIG) and placebo. There is a clinically significant decrease in the QMG Score for Disease Severity with IVIG treatment on day 14 (4.1 U; p < 0.010).
In this study, no serious adverse events occurred, and headache was the most frequent side effect. In the IVIG group, 18 patients (75%) had headache for a mean duration of 6.9 ± 6.2 days (range: 1 to 25 days) compared with 5 patients on placebo (19%; p < 0.001, χ2 test). None of the patients required hospitalization and the symptoms resolved with standard nonprescription analgesic therapy.
Discussion.
This randomized, double-blind, appropriately powered study provides the first reliable evidence for the effectiveness of IVIG in patients with MG and worsening weakness. A significant benefit of IVIG compared with placebo therapy was demonstrated 14 days after treatment (primary outcome measure), and the treatment effect was maintained 28 days after the infusion. It is of interest that the response to IVIG was rapid compared with the typical response observed with immunosuppressive medications for MG. Therefore, IVIG treatment can be a useful adjunctive therapeutic strategy in symptomatic patients awaiting the characteristically long latent response to immunosuppressive medications.
Despite the significant change, the improvement in motor scores with IVIG vs placebo was relatively small for the entire treatment cohort. Importantly, when subjects were stratified by disease severity, patients with moderate to severe disease demonstrated both a highly statistical and a clinically meaningful improvement with a corresponding improvement in the Post-Intervention Status. It appears that patients with more severe symptoms of MG benefited most from IVIG treatment. These findings are consistent with results from a previous unmasked study showing a comparable benefit of IVIG and plasma exchange at 1 and 4 weeks post treatment in patients with severe symptoms of MG requiring intensive care.7
This study supports therapeutic strategies for the treatment of patients with MG. One course of IVIG treatment given over 2 days produced a clinically meaningful benefit at least 4 weeks post treatment. In patients with more severe disease who cannot tolerate immunosuppressive therapy, IVIG treatments every 4 weeks may be a viable treatment option akin to patients with immune-mediated neuropathies who are maintained on IVIG alone. The low risk of major IVIG side effects observed in this study also supports this therapeutic strategy. Although not addressed in this study, IVIG treatment may be advantageous for patients initiated on steroid treatment to ameliorate the initial paradoxical worsening as the response to IVIG was rapid and effective in patients with moderate to severe disease. However, this steroid-protection hypothesis needs to be evaluated in an appropriately designed trial.
This study also provides data in the context of selecting appropriate patients for IVIG intervention. IVIG treatment did not produce a meaningful improvement in patients with milder symptoms or pure ocular disease, that is, those with abnormalities only on the ocular tests of the QMG Score. Patients with milder disease who do not respond to cholinesterase inhibitors are unlikely to benefit from IVIG treatment, and initiation of immunosuppressive medications should be considered. In this way, IVIG-related side effects and costs may be avoided in patients with milder disease. The results of this study suggest caution in how patients with MG are classified as 90% of patients diagnosed with ocular MG on clinical grounds had QMG Scores placing them in the generalized category. For these patients, denial of IVIG treatment or other therapeutic interventions such as thymectomy may not be the optimal management approach. This finding may also help explain the high sensitivity of SFEMG for patients with a clinical diagnosis of ocular MG.
Although the study was not powered to investigate the association between IVIG and a number of other variables, responsiveness appeared to be independent of patient age, sex, disease duration, and antibody status. The presence of thymoma and thymectomy did appear independently to predict responsiveness, but the number of patients is limited, and this finding needs to be interpreted cautiously. Future studies may further clarify which subgroups of patients with MG are most responsive to IVIG.
Acknowledgment
The authors thank David Liang for assistance in data management and preparation of figures for the manuscript, Bayer Health Care for an unrestricted educational grant, the Medical Day Unit and staff at the Toronto General Hospital for assistance with patient care and administration of infusions, the University Health Network pharmacy for preparation of masked infusion solutions, and C.Q. Deng for statistical analytical support.
Footnotes
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Editorial, see page 803
Disclosure: Talecris (formerly Bayer) provided an unrestricted education grant for this study. Bayer/Talecris was not involved in the study design, conduct of the study, collection and management of data, or interpretation of results. A Bayer statistician provided technical support and review of our own analyses of the data. Bayer/Telecric did not play a role in the preparation or approval of the manuscript..
Received July 14, 2006. Accepted in final form October 19, 2006.
References
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