Abstract
The authors report a prospective pilot trial of etanercept in corticosteroid-dependent autoimmune myasthenia gravis. Eleven patients were enrolled, with eight completing the 6-month trial. Two patients were withdrawn owing to disease worsening, and one patient was withdrawn because of an erythematous skin rash. Six of the eight patients who completed the trial improved, based on quantitative measures of muscle strength and lowering of corticosteroid requirement.
Autoimmune myasthenia gravis (MG) is a T-cell-dependent, antibody- and complement-mediated disease in which autoantibodies are directed against the nicotinic acetylcholine receptors (AChRs) at the skeletal muscle endplate.1 Tumor necrosis factor-α (TNFα) is a proinflammatory cytokine that has been implicated in the pathogenesis of a number of autoimmune diseases, including MG.2–4⇓⇓ Blockade of the actions of TNFα suppressed established experimental autoimmune MG.5 We conducted a pilot open-label clinical trial of soluble recombinant TNF receptor Fc (etanercept) in a group of corticosteroid-dependent patients with MG to assess its safety and potential efficacy.
Methods.
Patients.
We enrolled 11 patients with autoimmune generalized MG in the study. Diagnosis was based on signs and symptoms of facial, ocular, bulbar, or extremity weakness with fluctuating severity and improvement with rest and an elevated serum level of AChR binding antibodies. All subjects were corticosteroid dependent (dose ≥25 mg of prednisone every 48 hours for >6 months), with persistent symptoms of fatigable weakness, or a documented inability to adequately taper the steroid dose. Previous treatment with immunosuppressive agents was allowed, but patients were required to be off other immunosuppressive therapies for a minimum of 4 weeks prior to study enrollment.
Study design.
Etanercept (25 mg twice weekly) was given by subcutaneous injection with at least 72 hours between doses. Patients were seen 1 month after beginning treatment and again at 2, 4, and 6 months post treatment. At each visit, we evaluated the following: quantitative MG (QMG) score,6 manual muscle testing (MMT),7 prednisone dose, MG activities of daily living (ADL) score,8 complete blood cell count and chemistry panel, and adverse events. The QMG and MMT scores were each performed by a single examiner who did not have access to previous scores. The primary outcome measure was the change in the QMG score between baseline and 6 months. The range of achievable scores was 0 to 39, with a score of 0 indicating no myasthenic weakness. A change of ≥3 units on the QMG score was considered significant.9 Secondary outcome measures included changes in MMT, MG-ADL, and corticosteroid requirement. The range of achievable scores was 0 to 24 for the MG-ADL and 0 to 120 for the MMT. In both instances, the higher score indicates worsening myasthenic symptoms or signs. Prednisone taper was carried out using a standard protocol that allowed a maximum monthly decrease of 10 mg every 48 hours and required either improvement or stability in two of the three remaining outcome measures (QMG, MMT, MG-ADL). The final decision regarding whether to taper the prednisone and the magnitude of the taper was at the discretion of the clinical investigator as deemed clinically appropriate. Any clinical deterioration, based on history and clinical examination findings, subsequent to a prednisone dose decrease resulted in a mandatory reinstitution of the previous prednisone dose.
Plasma levels of circulating anti-AChR antibodies were measured by standard α-bungarotoxin radioimmunoassay and of TNFα by ELISA at baseline, 2 months post treatment, and 6 months post treatment.
The Rush Institutional Review Board approved the study, and approved informed consent procedures were followed.
Statistical analysis.
Summary statistics were computed of baseline values, changes from baseline, and percentage of baseline. The changes from baseline were tested via Wilcoxon (paired) signed rank tests; the percentages of baseline were compared with 100% via one-sample Wilcoxon signed rank tests. All tests were two tailed.
Results.
Of the 11 patients enrolled (table 1), 8 completed the study. One patient (Patient 9) was withdrawn owing to a diffuse erythematous skin rash, which resolved upon discontinuation of etanercept. Two patients were withdrawn because of disease worsening, which in one (Patient 11) was severe and occurred acutely after 3 weeks of treatment, necessitating urgent treatment with plasma exchange. In the other patient who worsened (Patient 8), the clinical deterioration was associated with a decrease in corticosteroid dose, and reinstitution of the previous dose resulted in improvement within 3 weeks. This patient requested to be withdrawn from the study medication at the time of symptom worsening. Of the remaining eight patients, five improved on the primary outcome measure. Six improved based on achievement of at least two of the following conditions: 1) improvement in QMG score of ≥3 points, 2) improvement in MMT score of ≥2 points, 3) decrease in prednisone dose by ≥50% (table 2). Patients who did not complete the study were not included in the QMG and MMT mean scores.
Table 1 Baseline characteristics
Table 2 Measures of efficacy
In patients who completed 6 months of treatment, the mean change in QMG score from baseline (baseline − 6 months) was 2.9 (p = 0.041, SD = 2.6). The time to significant improvement was 6 months. The mean change in MMT at 6 months was 8.4 (p = 0.020, SD = 8.0); improvement became significant at 2 months (p = 0.043). The mean percentage of baseline prednisone dose at study exit was 80.4% (p = 0.07, SD = 43.9%). Adverse events included diffuse skin rash, worsening of MG in two patients, and injection site reactions that were mild and self-limited. No other severe adverse events were observed.
Circulating levels of plasma TNFα (mean baseline level 1,173.18 pg/mL, mean exit level 1,723.18 pg/mL) and anti-AChR antibodies (mean baseline level 3.86 nM α-bungarotoxin binding sites, mean exit level 4.48 nM α-bungarotoxin binding sites) tended to slightly increase during treatment with etanercept, but this trend was not significant.
Discussion.
Six of 11 patients with MG enrolled in this pilot study improved after treatment with etanercept administered twice weekly, based on objective measures of muscle strength and the ability to successfully taper prednisone doses. Our patients had chronic (average disease duration 15.8 years) steroid-requiring disease and in most cases were previously treated unsuccessfully with one or more other immunosuppressive medications.
We included only patients who completed the 6-month study in the statistical analysis of changes in quantitative muscle testing to determine whether the improvement in patients who tolerated the drug was significant. We recognize that the small numbers and open-label design of the study prohibit definitive assessment of efficacy. In addition, a synergistic effect with previous immunotherapies, although unlikely, cannot be excluded. Despite these limitations, the clinical improvement observed in patients with largely refractory MG suggests that etanercept may be effective in certain patients with chronic steroid-dependent disease.
Treatment with etanercept did not significantly change plasma anti-AChR antibody levels or circulating levels of TNFα. Patient 11 had a severe acute clinical worsening likely related to etanercept treatment. This patient showed a pronounced rise in TNFα levels (baseline level 13.13 pg/mL, exit level 3,716.48 pg/mL). Up-regulation of the production of TNFα has been observed with etanercept treatment of other autoimmune diseases,10 possibly due to a counterregulatory mechanism or inability to distinguish plasma free TNFα from TNFα bound to administered soluble TNF receptor Fc. This suggests that in certain patients, etanercept treatment may up-regulate the cytokine response, and as some of these “proinflammatory” cytokines are crucial for MG pathogenesis, these patients may worsen during treatment.
Based on the findings of this study, a randomized controlled trial of etanercept in steroid-dependent MG should be considered. Further study of etanercept in MG should take into account the risk of symptom exacerbation, as was observed in our patient, and should include more detailed immunologic analyses to better characterize the mechanism of etanercept’s effect and to possibly identify patients who may be at risk for disease exacerbation.
Acknowledgments
Supported by Amgen, Inc., and the Myasthenia Foundation of Illinois.
- Received May 11, 2004.
- Accepted in final form August 2, 2004.
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