Long-Term Improvement in a Chinese Cohort of Glucocorticoid-Resistant Childhood-Onset Myasthenia Gravis Patients Treated With Tacrolimus

Abstract

Objectives: To evaluate the long-term outcome of tacrolimus for childhood-onset myasthenia gravis (CMG) with an inadequate response to glucocorticoids, and investigate factors associated with favorable outcomes following tacrolimus treatment.

Methods: A retrospective, observational cohort study was performed for CMG patients who had not improved satisfactorily after sufficient prednisone therapy for at least 8 weeks. All patients were given tacrolimus in doses of 2-3 mg for more than 6 months. The primary efficacy outcome was assessed using the prednisone dose, quantitative MG (QMG), and MG-activity of daily living (ADL) scores. The participants were divided into improved and unimproved groups based on changes in QMG scores to investigate the risk factors that affected tacrolimus efficacy.

Results: A total of 149 glucocorticoid resistant CMG patients were finally enrolled in our study, with 113 (75.8%) responding well to tacrolimus (defined as minimal manifestation status or better). One month after initiating tacrolimus, there was a noticeable improvement in prednisone dose, QMG, and ADL scores, which continued to improve throughout the study. More importantly, the prednisone was eventually stopped in 89 of the patients (78.8%). Thymus type [odds ratio (OR) = 3.156, 95% confidence interval (CI) 1.427-6.978; P = 0.005] and pre-intervention status (OR = 0.284, 95%CI 0.109-0.741; P = 0.010) were independent predictors of tacrolimus efficacy after controlling for confounding factors in multiple logistic regression.

Conclusion: The majority of glucocorticoid-resistant CMG patients have a good long-term prognosis after adding tacrolimus. Thymus type and pre-intervention status can serve as potential predictors affecting the efficacy of tacrolimus.

Keywords: children; myasthenia gravis; pre-intervention status; tacrolimus; thymus type.

Figure 1

Flowchart of participants' recruitment. *During the follow-up throughout our study, 12 out of 183 (<7.5%) patients discontinued tacrolimus due to severe adverse drug reactions after a median of 2.8 months (ranged from 0.25 to 10.00 months): renal insufficiency in three, hepatic dysfunction in two, stomachache in two, tremor in two, hyperglycemia in one, infection in one, and allergic to tacrolimus in one.

Figure 2

Profiles of study participants. (A) Distribution of onset age between male and female. (B) The most severe MGFA classification before tacrolimus administration. (C) MGFA-PIS on the last follow-up [median 12.9 years (IQR: 6.9, 19.2) from diagnosis]. Data are presented as the number or proportion of patients in each category. CSR, complete stable remission; E, exacerbation; MGFA, Myasthenia Gravis Foundation of America; MM, minimal manifestation; PIS, post-intervention state; PR, pharmacologic remission; U, unchanged; W, worse.

Figure 3

Changes of the prednisone dose, QMG score and MG-ADL score during treatment with tacrolimus. ^#Mean follow-up of 3.16 ± 1.33 years (range 1.24–7.18 years). ADL, activity of daily living; QMG, quantitative MG. (A) Dose of prednisone, (B) QMG score, (C) MG-ADL score decreased gradually after initiation of tacrolimus treatment during the 6-month following-up (Dose of prednisone were 17.47 ± 9.16, 13.83 ± 8.69, 10.97 ± 7.38, 8.74 ± 6.65, 7.87 ± 6.46, 7.08 ± 6.28, 6.42 ± 6.39, 3.17 ± 4.93; QMG scores were 6.22 ± 2.58, 4.50 ± 2.47, 3.50 ± 2.52, 2.91 ± 2.71, 2.47 ± 2.49, 2.22 ± 2.59, 2.01 ± 2.57, 1.68 ± 2.49; and ADL scores were 3.70 ± 1.63, 3.02 ± 1.77, 2.38 ± 1.62, 1.95 ± 1.62, 1.73 ± 1.65, 1.45 ± 1.61, 1.26 ± 1.63, 1.01 ± 1.46 at the start of acrolimus treatment, 1, 2, 3, 4, 5, 6 month and the end of follow-up; respectively) (Compared with the last follow-up time point, *P < 0.05, **p < 0.001; 2-tailed Wilcoxon signed-rank test). *p < 0.05. **p < 0.01.

Figure 4

The Kaplan-Meier curve for time to discontinued steroids in children with steroid-resistant MG.