Agentes inmunosupresores para la miastenia grave
Referencias
References to studies included in this review
References to studies excluded from this review
References to ongoing studies
Additional references
Characteristics of studies
Characteristics of included studies [ordered by study ID]
| Methods | Randomised, double‐blind controlled trial of cyclophosphamide plus prednisolone versus prednisolone plus placebo. | |
| Participants | 23 participants, 12 in the cyclophosphamide plus corticosteroids group and 11 in the corticosteroids plus placebo group. | |
| Interventions | Intravenous cyclophosphamide pulses were given at an initial dose of 500 mg/m2 of body surface and titrated according to response or side effects. During the 12‐month study period, treatment pulses were given monthly during the first 6 months and then every other month. | |
| Outcomes | Primary endpoints were changes in the QMG, steroid and pyridostigmine requirements, and the number of treatment failures, the latter defined as ventilatory failure (forced vital capacity < 30% predicted) or the development of swallowing impairment requiring a feeding tube. Cyclophosphamide was reported to be not significantly better than placebo at 6 months as assessed by the QMG. Cyclophosphamide was reported to significantly improve the QMG at 12 months. At six months, cyclophosphamide treated participants were on significantly lower doses of prednisolone (mean 13.3 mg/day) than the placebo group (mean 24 mg/day) (P < 0.05). Data on anticholinesterase medication use were not comprehensively reported or evaluated statistically. There was no significant difference in treatment failures between the two groups. | |
| Notes | The QMG was used for muscle strength assessment. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
| Methods | Randomised, unblinded, controlled trial of azathioprine plus initial prednisolone versus prednisolone. | |
| Participants | 41 participants, 21 in the azathioprine plus initial prednisolone group and 20 in the prednisolone group. | |
| Interventions | Prednisolone (1 mg/kg daily for 1 month, subsequently reduced to 0.5 mg/kg daily by the fifth month, and to 0.25 mg/kg daily by the tenth month) versus azathioprine (3 mg/kg daily for one year and then 2 mg/kg daily). In the latter group, participants were also given prednisolone 1 mg/kg daily for 1 month, which was then gradually tapered and discontinued. | |
| Outcomes | Efficacy of azathioprine plus initial prednisolone versus prednisolone at 6 months was not evaluated. No differences in the myasthenia muscle score or the modified Rankin scale were observed between the prednisolone or azathioprine plus initial prednisolone groups at 12 months. Primary endpoints of the study were time to the first episode of clinical deterioration within the first 60 months, defined by the occurrence of either impaired swallowing or respiratory insufficiency, or a drop in the myasthenia muscle score of at least 20 points. Among the 21 deterioration events, 9 were observed in the azathioprine group and 12 in the prednisolone group, giving a relative risk of 0.71 (95% CI 0.39 to 1.31). | |
| Notes | A myasthenia muscle strength score and a five‐grade functional scale (modified Rankin scale) were used for muscle assessment. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
| Methods | Randomised double‐blind controlled pilot trial of mycophenolate mofetil plus either ciclosporin or prednisolone or no immunosuppressants versus placebo plus either ciclosporin or prednisolone or no immunosuppressants. | |
| Participants | 14 participants, 7 in the mycophenolate mofetil plus either ciclosporin or prednisolone or no immunosuppressants group, 7 in the placebo plus either ciclosporin or prednisolone or no immunosuppressants group. | |
| Interventions | Mycophenolate mofetil (1 g twice daily) in one group versus placebo in the other group. Five participants in each group were also on prednisolone. One participant in each group was also on ciclosporin. Two participants in each group were on mycophenolate mofetil monotherapy. | |
| Outcomes | The primary endpoint was the change in QMG score compared with baseline. The study only ran for 5 months. One of the five participants in the placebo group and one of the six participants in the mycophenolate mofetil group showed mild improvement in the QMG at the end of the study. There was no significant difference in the change of group medians of titre at the end of the study. The median change of antibody titre in the mycophenolate mofetil group was 1.1 nmol/L and in the placebo group 0.1 nmol/L (P = 0.52). | |
| Notes | The QMG and manual muscle testing were used for muscle strength assessment. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
| Methods | Randomized, unblinded, nonplacebo‐controlled pilot trial of tacrolimus plus corticosteroids with/without plasma exchange versus no tacrolimus plus corticosteroids with/without plasma exchange. | |
| Participants | 34 participants, 18 in the tacrolimus plus corticosteroids with/without plasma exchange group, 16 in the no tacrolimus plus corticosteroids with/without plasma exchange. | |
| Interventions | Tacrolimus was administered orally at a dose of 3 mg/day. For early‐phase therapy, participants received tacrolimus or prednisolone or both. Normal quality of life corresponding to the category 'Minimal Manifestations' (MM) of the MGFA Postintervention Status scale was achieved by administering, as required, early‐phase treatment which consisted of oral prednisolone (not exceeding a daily dose of 20 mg), and combined therapy with plasmapheresis and high‐dose intravenous methylprednisolone (1 mg/day for the first three days). The prednisolone dose was tapered and adjusted to the minimal dose needed to maintain MM. For the follow‐up phase, participants were treated to maintain MM for one year. In the follow‐up phase, plasma exchange plus high‐dose intravenous methylprednisolone, high‐dose intravenous methylprednisolone alone or pyridostigmine was administered as needed to maintain MM. | |
| Outcomes | None of the primary and secondary outcome measures for review were available. In the study, endpoints of early‐phase therapy were frequency of plasma exchange plus high‐dose intravenous methylprednisolone, and the duration of early‐phase treatment. The number of treatments with plasma exchange plus high‐dose intravenous methylprednisolone was significantly lower in participants treated with tacrolimus compared with those treated without tacrolimus during early‐phase treatment, with a mean difference of ‐1.80 (95% CI ‐3.12, ‐0.48). The period of early‐phase treatment was significantly shorter in the group treated with tacrolimus, with a mean difference of ‐2.10 (95% CI ‐3.63 to ‐0.57). Endpoints of follow‐up phase therapy were frequency of plasma exchange plus high‐dose intravenous methylprednisolone or high‐dose intravenous methylprednisolone alone during this phase, and the dose of oral predisolone required at the endpoint. In this follow‐up phase, the number of treatments with plasma exchange plus high‐dose intravenous methylprednisolone was significantly lower for the participants treated with tacrolimus compared with those without tacrolimus, with a mean difference of ‐0.90 (95% CI ‐1.72 to ‐0.08). In addition, the number of treatments with high‐dose intravenous methylprednisolone alone were significantly lower for the participants treated with tacrolimus compared with those without tacrolimus, with a mean difference of ‐1.40 (95% CI ‐2.79 to ‐0.01). At one year into treatment, the oral prednisolone dose was significantly lower for participants treated with tacrolimus compared with those without tacrolimus, with a mean difference of ‐3.50 (95% CI ‐5.78 to ‐1.22). | |
| Notes | The MGFA Postintervention Status scale and the QMG were used for muscle strength assessment. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | High risk | C ‐ Inadequate |
| Methods | Randomised double‐blind controlled trial of azathioprine plus prednisolone versus prednisolone plus placebo. | |
| Participants | 34 participants, 15 in the azathioprine plus prednisolone group and 19 in the prednisolone plus placebo group. | |
| Interventions | All participants received initial high‐dose prednisolone (1.5 mg/kg or 100 mg on alternate days). In addition, participants were randomised to receive either azathioprine (2.5 mg/kg daily) or the equivalent dose of a matching placebo. The initial prednisolone dose was maintained until remission and then tapered to the minimum required to maintain remission. | |
| Outcomes | There were no significant differences between the two treatment groups in objective or subjective measurement scores at 12 months. Primary endpoints of the study were the maintenance dose of prednisolone, number of participants experiencing treatment failure (defined as either no remission achieved in the three year follow‐up period or clinical relapse after initial remission necessitating an increase in prednisolone dose), and the duration of the initial remission. The median prednisolone dose did not differ significantly between the two treatment groups at 12 months (exact figures not given), but was significantly reduced at 36 months in the azathioprine plus prednisolone group (0 mg) compared with the prednisolone plus placebo group (40mg) (P = 0.02). There was no significant difference between the two treatment groups in terms of number of participants experiencing treatment failure. Analysis of those who completed the trial showed that the duration of remission was significantly longer in the azathioprine plus prednisolone group compared with the prednisolone plus placebo group, giving a relative risk of 0.28 (95% CI 0.08 to 0.94). If those who withdrew or died were included as treatment failures, the duration of remission was not significantly different between the azathioprine plus prednisolone versus prednisolone plus placebo groups, with a relative risk of 0.67 (95% CI 0.43 to 1.04). | |
| Notes | For muscle strength assessment, right‐sided strength of neck flexion, elbow extension, first finger abduction, shoulder abduction, hip flexion and hip abduction; walking time, swallowing time, forced vital capacity; and subjective scoring of strength, double vision and swallowing were used. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
| Methods | Randomised double‐blind controlled trial of ciclosporin monotherapy versus placebo. | |
| Participants | 20 participants, 10 in the ciclosporin group, 10 in the placebo group. | |
| Interventions | Ciclosporin was started at a dose of 6 mg/kg daily and then adjusted on the basis of assessments of blood drug levels, renal function, clinical response and adverse events. | |
| Outcomes | 7 of the 10 participants in the ciclosporin group and four of the 10 participants in the placebo group showed mild improvement at 6 months. Therefore, the relative rate of improvement was 1.75 (95% CI 0.74 to 4.14). The ciclosporin group demonstrated significantly greater increase in muscle strength (measured by change in the QMG score) than the placebo group. The mean difference in QMG score between the ciclosporin group and placebo group was ‐0.46 (95% CI ‐0.83 to ‐0.09). 6 of the 10 participants in the ciclosporin group improved at 12 months: 5 had mild improvement and 1 had marked improvement. 1 of the 10 participants in the placebo group had mild improvement. Therefore, the overall relative rate of improvement was 6.00 (95% CI 0.87 to 41.21). The ciclosporin group demonstrated significantly greater increase in muscle strength (measured by change in the QMG score) than the placebo group. The mean difference in QMG score between the ciclosporin group and placebo group was ‐0.72 (95% CI ‐1.10 to ‐0.34). There was no significant mean difference of AChR antibody titre between the two groups at 6 months. Six participants in the ciclosporin group and 5 participants in the placebo group experienced treatment failure, giving a relative risk of 1.20 (95% CI 0.54 to 2.67). | |
| Notes | The QMG was used for muscle strength assessment. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
| Methods | Randomised double‐blind controlled trial of ciclosporin plus prednisolone versus prednisolone plus placebo | |
| Participants | 39 participants, 20 in the ciclosporin plus prednisolone group and 19 in the prednisolone plus placebo group. | |
| Interventions | Ciclosporin was started at a dose of 5 mg/kg daily. The dose was adjusted on the basis of blood drug levels, renal function and adverse reactions. Corticosteroid withdrawal was begun at 2 months with a reduction of 10 mg if the dose was 60 mg every other day or lower, and 20 mg if the dose was 80 to 100 mg. From the third to the sixth months, the dose of corticosteroids was reduced by 10 mg/month. If weakness increased following reduction in corticosteroids, the dose was increased. Participants were withdrawn from the study if treatment failed. | |
| Outcomes | Primary endpoints, measured when participants reached 6 months of treatment or an earlier endpoint, were entry to exit change in QMG, AChR antibody titre and dose of steroids. 8 of the 20 participants in the ciclosporin plus prednisolone group improved. 2 of the 19 participants in the prednisolone plus placebo group improved. Therefore, the overall relative rate of improvement was 5.70 (95% CI 1.46 to 22.18). The ciclosporin group demonstrated significantly greater increase in muscle strength than the placebo group. The mean difference in QMG score between the ciclosporin group and placebo group was ‐0.31 (95% CI ‐0.51 to ‐0.11). The ciclosporin group had a statistically significant percentage reduction of antibody titre compared with placebo at six months, with a mean difference of 62.90 (95% CI 1.22 to 124.58). There was no significant difference in corticosteroid dose between the two groups. The mean difference was 13.60 (95% CI ‐5.64 to 32.84). | |
| Notes | The QMG was used for muscle strength assessment. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
QMG ‐ Quantitative MG Score for Disease Severity
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
| There were major violations of the trial protocol. Patients were initially randomised to either azathioprine or prednisolone with the intention to treat for one year before they crossed over to the other drug. Only four out of the five patients initially randomised to azathioprine were crossed over to prednisolone, two within four weeks of starting the trial ‐ because they did not tolerate azathioprine ‐ and two at the end of one year. The other patient on azathioprine was kept on the drug beyond one year. None of the patients on prednisolone at initial randomisation were crossed over to azathioprine. Therefore, the intended crossover design of the trial was not achieved. | |
| The trial set out to compare ciclosporin with azathioprine. However, it lacked key data. In particular, it is unclear which participants had prior immunosuppression (azathioprine alone, ciclosporin alone or azathioprine plus ciclosporin), and if a washout period was instituted before randomisation. These problems make it difficult to know which drug was actually being evaluated. |
Characteristics of ongoing studies [ordered by study ID]
| Trial name or title | Trial of mycophenolate mofetil in myasthenia gravis. |
| Methods | |
| Participants | Randomised double‐blind controlled trial of mycophenolate mofetil plus prednisolone versus prednisolone versus placebo. 80 participants with seropositive MG were randomized. |
| Interventions | Thirty six weeks of treatment with 2.5 g mycophenolate mofetil/day plus at least 20 mg prednisone/day versus at least 20 mg/day prednisone plus placebo. |
| Outcomes | The primary outcome measure was the change from baseline in QMG score at the end of 36 weeks. Secondary outcome measures included survival analysis for treatment failure, MG‐related impairment of daily activities, functional assessment, manual muscle testing, SF‐36 Health Status, and serum concentration of anti‐AChR antibody. The trial failed to meet both primary and secondary endpoints. The trial is awaiting publication. |
| Starting date | January 2003 |
| Contact information | Donald B Sanders, M.D., Principal Investigator, Duke University. |
| Notes | The QMG was used for muscle strength assessment. |
| Trial name or title | International, double‐blind, placebo‐controlled phase III trial of mycophenolate mofetil as a steroid‐sparing adjunct in the treatment of myasthenia gravis. |
| Methods | |
| Participants | Randomised double‐blind controlled trial of mycophenolate mofetil plus prednisolone versus prednisolone versus placebo. 176 participants with seropositive MG were randomized. |
| Interventions | Thirty six weeks of treatment with 2 g mycophenolate mofetil/day plus at least 20 mg prednisone/day versus at least 20 mg/day prednisone plus placebo. |
| Outcomes | The primary outcome measures were: (1) minimal manifestations (MM) or pharmacologic remission (PR) on the MGFA Postintervention Status scale of disease symptoms for weeks 32‐36, and (2) =7.5 mg/day prednisolone for weeks 32‐36, and (3) =120 mg/day pyridostigmine for weeks 33‐36. Secondary efficacy outcomes included: time to initial 'treatment response' ‐ the first visit week when a participant met all three primary efficacy criteria and maintained this status at the next visit; time to sustained 'treatment response' ‐ the first visit week when a participant met all three primary efficacy criteria and maintained this status until week 36; prednisone area under the time/dose curve; prednisone dose at study termination; cholinesterase inhibitor dose at study termination; number of intravenous immunoglobulin and plasma exchange treatments received during the study; change from baseline in QMG score; change from baseline in Quality of Life (QoL) assessed using the 36‐item Short Form (SF‐36) health survey and the MG Activities of Daily Living (MG ADL) scale; change from baseline in investigator and patient Global Assessment of disease severity; and AChR antibody titres. The study is awaiting publication. |
| Starting date | August 2004 |
| Contact information | Donald B Sanders, M.D., Principal Investigator, Duke University. |
| Notes | The QMG was used for muscle strength assessment. |
Data and analyses
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Six months Show forest plot | 2 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.44 [1.13, 5.27] |
| Analysis 1.1  Comparison 1 Ciclosporin versus placebo at six months, Outcome 1 Six months. | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Six months Show forest plot | 2 | 59 | Mean Difference (IV, Fixed, 95% CI) | ‐0.34 [‐0.52, ‐0.17] |
| Analysis 2.1  Comparison 2 Ciclosporin versus placebo ‐ change in QMG at six months, Outcome 1 Six months. | ||||
Comparison 1 Ciclosporin versus placebo at six months, Outcome 1 Six months.
Comparison 2 Ciclosporin versus placebo ‐ change in QMG at six months, Outcome 1 Six months.
| Items tested |
| Time to develop diplopia with prolonged lateral gaze |
| Time to develop ptosis with prolonged upgaze |
| Facial strength |
| Ability to swallow 4 oz (1/2 cup) of water |
| Speech after counting aloud from 1 to 50 |
| Time patient can outstretch either arm |
| Vital capacity |
| Right and left grip strength |
| Time patient can lift head 45° in a supine position |
| Time patient can outstretch either leg |
| Category | Clinical state |
| Complete Stable Remission (CSR) | No symptoms or signs of MG. Not received therapy for MG for at least one year. |
| Pharmacologic Remission (PR) | Same as above, but continues to take some form of therapy for MG. Patients on cholinesterase inhibitors are excluded as their use suggests the presence of weakness. |
| Minimal Manifestations (MM) | No symptoms of functional limitations, but has some weakness on examination. |
| Minimal Manifestations MM‐0 | Not received MG treatment for at least one year. |
| Minimal Manifestations MM‐1 | Continues to receive some form of immunosuppression, but no cholinesterase inhibitors or other symptomatic therapy. |
| Minimal Manifestations MM‐2 | Received only low‐dose cholinesterase inhibitors (<120 mg pyridostigmine/day) for at least one year. |
| Minimal Manifestations MM‐3 | Received cholinesterase inhibitors or other symptomatic therapy and some form of immunosuppression during the past year. |
| Change in status | |
| Improved (I) | A substantial decrease in pretreatment clinical manifestations, or a sustained substantial reduction in medications, or a specific decrease in QMG score, as defined in the protocol. |
| Unchanged (U) | No substantial change in pretreatment clinical manifestations or reduction in medications, or a change in QMG score, as defined in the protocol. |
| Worse (W) | A substantial increase in pretreatment clinical manifestations, or a substantial increase in medications, or a specific increase in QMG score, as defined in the protocol. |
| Exacerbation (E) | Fulfilled criteria of CSR, PR or MM, but subsequently developed clinical findings greater than permitted by these criteria. |
| Died of MG (D of MG) | Died of MG, of complications of therapy, or within |
| Class | Definition |
| Class I | Any ocular muscle weakness |
| Class II | Mild weakness affecting other than ocular muscles |
| Class IIa | Predominantly affecting limb, axial muscles, or both |
| Class IIb | Predominantly affecting oropharyngeal, respiratory muscles, or both |
| Class III | Moderate weakness affecting other than ocular muscles |
| Class IIIa | Predominantly affecting limb, axial muscles, or both |
| Class IIIb | Predominantly affecting oropharyngeal, respiratory muscles, or both |
| Class IV | Severe weakness affecting other than ocular muscles |
| Class IVa | Predominantly affecting limb and/or axial muscles |
| Class IVb | Predominantly affecting oropharyngeal, respiratory muscles, or both |
| Class V | Defined by intubation, with or without mechanical ventilation, except when employed during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVb |
| Study ID | Alloc concealment | Patient blinding | Observer blinding | Desc of clin status | Explicit outcomes | Baseline difference | Follow‐up | Statistical power |
| Bromberg 1997 | B | C | C | B | A | C | B | C |
| De Feo 2002 | A | A | A | B | A | A | A | B |
| Gajdos 1993 | A | C | C | A | A | B | A | B |
| Meriggioli 2003b | A | A | A | A | A | C | B | C |
| Nagane 2005 | C | C | C | A | A | A | A | B |
| Palace 1998 | A | A | A | A | A | A | A | B |
| Schalke 1990 | C | A | A | C | A | A | A | B |
| Tindall 1987 | A | A | A | A | A | A | A | B |
| Tindall 1993 | A | A | A | A | A | A | A | B |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Six months Show forest plot | 2 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.44 [1.13, 5.27] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Six months Show forest plot | 2 | 59 | Mean Difference (IV, Fixed, 95% CI) | ‐0.34 [‐0.52, ‐0.17] |
