Myasthenia Gravis Therapeutic Benefits Of Monotherapy With Tacrolimus
Overview
In the management of mild to moderate myasthenia gravis (MG), the utilization of tacrolimus is typically reserved for cases that do not respond to glucocorticoids. This study sought to assess the potential advantages of mono-tacrolimus over mono-glucocorticoids in treating MG patients.
The primary endpoint of effectiveness was the time to minimal manifestations status or better, while secondary endpoints encompassed various parameters such as time to relapse, changes in MG-ADL scores, adverse events, and drug withdrawal. The study, adhering to STROBE guidelines, gathered demographic and clinical variables from the MG database, providing valuable insights into the comparative effectiveness and safety of mono-tacrolimus and mono-glucocorticoid treatments in mild to moderate MG patients.
Mono-tacrolimus demonstrated superior tolerability with non-inferior efficacy compared to mono-glucocorticoids in mild to moderate myasthenia gravis patients who either refuse or have a contraindication to glucocorticoids.
Introduction
Myasthenia gravis (MG) imposes a substantial health burden, necessitating prolonged treatment and often susceptible to recurrence. Glucocorticoids, a primary immunosuppressant in MG, exhibit high efficacy in the majority of patients but encounter limitations in approximately 20%–30%, leading to symptom exacerbation, complications during drug tapering, and adverse events-related discontinuation. The growing prevalence of elderly patients raises concerns about exacerbating comorbidities. Additionally, a considerable number of young patients resist glucocorticoid use due to apprehensions about side effects.
Tacrolimus has emerged as a successful steroid-sparing agent, employed alongside glucocorticoids to mitigate dosage and side effects. It has also shown promise as a monotherapy, inducing rapid remission of diverse MG symptoms. While a prior noncontrolled study demonstrated favorable outcomes with mono-tacrolimus, a comprehensive comparison between mono-tacrolimus and mono-glucocorticoid regimens in MG is lacking.
This study aims to scrutinize and compare the clinical outcomes of mono-tacrolimus and mono-glucocorticoid treatments in mild to moderate MG patients. Additionally, the investigation seeks to identify potential factors predictive of clinical effectiveness with mono-tacrolimus as an initial immunotherapy.
Methods
The study, conducted at Xuanwu Hospital, Capital Medical University, retrospectively examined participants in the Myasthenia Gravis Trial Database from July 2017 to June 2021. Approved by the hospital’s Ethics Committee, the research focused on MG patients diagnosed with fluctuating muscle weakness and positive results in specific tests. Exclusions were made based on criteria such as unavailable data, undesired study population, and interference in effectiveness evaluation.
Patients receiving mono-tacrolimus (mono-TAC group) or mono-glucocorticoids (mono-GC group) as initial treatment were included. The study aimed to compare clinical outcomes, considering endpoints like time to minimal manifestations status or better, time to relapse, changes in MG-ADL scores, adverse events, and drug withdrawal. Treatment details included glucocorticoids therapy, oral prednisone, intravenous methylprednisolone, and tacrolimus therapy with adjustments based on clinical efficacy and concentration monitoring.
– Inclusion of mild to moderate MG patients treated with either mono-tacrolimus (mono-TAC) or mono-glucocorticoids (mono-GC).
– Examination of the correlation between immunotherapy options and treatment efficacy, as well as side effects, through 1:1 propensity-score matching.
– Main outcome measure: Time to achieving minimal manifestations status or better (MMS or better).
– Secondary outcomes include time to relapse, mean changes in Myasthenia Gravis-specific Activities of Daily Living (MG-ADL) scores, and the rate of adverse events.
– Baseline characteristics showed no significant differences between matched groups (49 matched pairs).
– No significant differences observed in median time to MMS or better between the mono-TAC and mono-GC groups (5.1 vs. 2.8 months; unadjusted hazard ratio [HR], 0.73; 95% CI, 0.46–1.16; p=0.180).
– No significant differences in median time to relapse, and changes in MG-ADL scores between the two groups were similar (mean differences, 0.3; 95% CI, -0.4 to 1.0; p=0.462).
– The rate of adverse events was lower in the mono-TAC group compared to the mono-GC group (24.5% vs. 55.1%; p=0.002).
Statistical Analysis
The study conducted a comprehensive analysis of baseline demographic and clinical features, employing statistical methods for group comparisons. Wilcoxon rank-sum test and chi-square test were utilized for continuous and categorical variables, respectively. Categorical variables were expressed as a percentage of patients, while continuous variables were presented as mean with standard deviation or median with interquartile range.
To enhance the balance of baseline characteristics, propensity score matching was employed, considering factors such as age, sex, MGFA classification, disease course, stage of disease at the beginning of immunotherapy, and MG-ADL score at baseline. Density plots illustrated the distribution of propensity scores before and after matching, with standardized mean differences calculated for pre- and post-matching groups.
Time-to-event differences were estimated using hazard ratios (HRs) and 95% confidence intervals through Kaplan-Meier survival curves and unadjusted Cox proportional hazard regression models. An adjusted Cox proportional hazard regression model was utilized to explore the association between events and multiple variables, with right-censored data for patients yet to experience events.
Paired t-tests were employed for within-group comparisons in the DMG-ADL, and between-group differences in the DMG-ADL were tested with analysis of covariance, adjusting for baseline MG-ADL scores. Missing MG-ADL scores at the end of the third month treatment were estimated using the last record within the initial 3 months.
Receiver-operating characteristics (ROC) curves were used to evaluate the optimal cut-off value, determined by Youden’s index. Statistical analyses and figures were executed using R statistical software (version 3.6.0) and SPSS (version 22.0), considering a significance level of p < 0.05.
Results
The study included 57 patients in the mono-TAC group and 116 patients in the mono-GC group. In the mono-TAC group, tacrolimus monotherapy was prescribed due to contraindications or patient refusal of glucocorticoids or other immunosuppressants. Baseline characteristics were initially similar between the unmatched groups but with differences in age, proportion of early-onset, and initiation of immunotherapy at an early stage. Propensity score matching created a balanced cohort of 49 patients in each group.
Treatment response comparison, using propensity score-matched analysis, showed no significant difference in median time to MMS or better between mono-TAC and mono-GC groups (5.1 vs. 2.8 months; unadjusted HR 0.73, 95% CI 0.46–1.16; p = 0.180). Similarly, no difference was observed in median time to relapse. Changes in MG-ADL scores at month 3 (DMG-ADL) were not significantly different between the groups. Subgroup analysis in generalized MG patients also indicated no significant differences.
Better tolerability was observed in the mono-TAC group compared to the unmatched mono-GC group and became more evident in the matched groups (24.5% vs. 55.1%, p = 0.002). Adverse events profile differed between the groups, with the mono-TAC group experiencing fewer incidents of blood glucose increases, no weight gain, and less osteoporosis. All adverse events were resolved after dose reduction or withdrawal, and no deaths occurred in either group.
Factors associated with treatment response to tacrolimus were explored using a Cox proportional hazard model. Disease stage at the beginning of immunotherapy, changes in MG-ADL at month 3, and MGFA class I were associated with the time to MMS or better in the adjusted model. Age, age of onset, sex, AChR-Ab, QMG scores at baseline, tacrolimus trough concentration, and thymectomy showed no significant association. Additionally, ROC analysis suggested that achieving MMS or better was associated with a DMG-ADL percentage, with an optimal cut-off value of 50%.
Conclusion
The study concludes that mono-tacrolimus exhibits equivalent effectiveness in treating mild to moderate myasthenia gravis (MG) compared to mono-glucocorticoids but with a lower incidence of adverse events. This suggests that mono-tacrolimus could be a promising option, especially for MG patients who refuse steroid treatment or when other immunosuppressants are contraindicated. The analysis further indicates that mono-tacrolimus, as initial immunotherapy, may be more effective in patients with MGFA class I, onset within 12 months from MG onset, or MG-ADL improvement of no less than 50% at month three.
Several non-steroidal immunosuppressants have shown efficacy for MG patients for whom steroids are contraindicated or refused. Tacrolimus, in particular, is highlighted for its fast action onset and minimal adverse events. The study’s results demonstrate that mono-tacrolimus has noninferior effectiveness and fewer adverse events compared to mono-glucocorticoids in MG. Adverse events, such as BUN/sCr elevation, tremor, and gastrointestinal symptoms, were mild and reversible.
The findings emphasize the potential benefits of mono-tacrolimus in elderly MG patients, considering the limitations associated with steroids in this demographic. While the cost-effectiveness of mono-tacrolimus is not explored in the study, the authors suggest it should be a crucial consideration in MG treatment.
Accurate prediction of outcomes and early modification of mono-tacrolimus regimens are crucial. Ocular MG, earlier initiation of tacrolimus treatment, and a sufficient response within the first three months are identified as important factors for a desirable outcome. The study also suggests that initiating mono-tacrolimus within 12 months from MG onset improves prognosis. A favorable response of at least 50% improvement in MG-ADL at month 3 serves as a predictor for desirable outcomes.
However, the study has limitations, including its observational nature, potential selection bias, and a relatively small sample size. The authors recommend further prospective studies or high-quality randomized controlled trials to clarify the safety and effectiveness of tacrolimus monotherapy in a larger MG population.
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