Long-term efficacy and safety of leflunomide combined with low-dose prednisone in treatment of myasthenia gravis: a retrospective study.

BACKGROUND: Leflunomide and low-dose prednisone (0.25 mg/kg/day) (LEF + Pred) rapidly improved the clinical symptoms of myasthenia gravis (MG) patients. Here, we aimed to analyze the long-term efficacy and safety of LEF + Pred in MG patients. METHODS: This retrospective cohort study enrolled MG patients treated with LEF + Pred in our center between 2012 and 2020. We reviewed all the MG patients continuously treated with LEF + Pred for more than 1 year. MG activities of daily living (MG-ADL) profile score and quantitative MG scale (QMG) score in each clinical follow-up visits were collected for the efficacy analysis. The laboratory testing results of MG patients, the relevant chief complain and physical examination results in each follow-up visits were collected for the safety evaluation. RESULTS: In total, 103 patients were examined. Effective treatment was achieved in 58.3% of patients after 1 month and in 88.4% after 12 months. Overall, 63 patients (61.2%) exhibited only minimal manifestations after 12 months of treatment. The average MG-ADL score decreased from 6.0 to 1.0, while the average QMG score decreased from 10.0 to 4.0. The decrease in MG-ADL and QMG scores of patients with generalized MG was more pronounced than those of the ocular MG patients. Patients with MG who had a thymectomy had a smaller decrease in MG-ADL and QMG scores than those who did not have a thymectomy. Sixteen adverse effects associated with LEF + Pred were observed; none was severe. CONCLUSIONS: Long-term LEF + Pred therapy could considerably improve clinical symptoms in MG patients while being well tolerated with just few side effects.

Corrigendum: Leflunomide combined with low-dose prednisone inhibits proinflammatory T cells responses in myasthenia gravis patients.

[This corrects the article DOI: 10.3389/fneur.2022.961628.].

Clinical evaluation of efficacy of leflunomide combined with low-dose prednisone for treatment of myasthenia gravis.

This study evaluated the clinical efficacy of leflunomide combined with low-dose prednisone (0.25 mg/kg/day) for treatment of myasthenia gravis (MG). We enrolled 32 MG patients treated with leflunomide combined with low-dose prednisone. In the control group, 14 patients were treated with low-dose prednisone. Improvement in MG composite (MGC) score of ≥ 3 points from enrollment to 12-week follow-up indicated that the treatment was effective. In the leflunomide combined low-dose prednisone group, the median of MGC score at the time of enrollment was 8.5 points. After 12 weeks, the MGC score dropped to four points. There was statistically significant difference in MGC score before and after treatment (p < 0.001). In the low-dose prednisone group also followed up for 12 weeks, the median of MGC score of the patients decreased from 7 to 4 points, and the change was not statistically significant (p = 0.05). In the leflunomide combined low-dose prednisone group, the improvement of clinical symptoms occurred mainly in the first 4 weeks and the last 4 weeks. Relatively, the decline of the score was mostly seen during the first 8 weeks in the low-dose prednisone group. In leflunomide combined with low-dose prednisone group, the effective rate of generalized MG(gMG) was significantly higher than ocular MG(oMG) (χ2 test, p = 0.036). However, there is no significant difference in the effective rate between AChR-Ab-positive and -negative groups (Fisher's Exact Test, p = 0.625). No serious side effects were observed in any of the subjects. Leflunomide combined with low-dose prednisone rapidly improved the clinical symptoms of patients with MG. It may be a promising treatment for gMG.

Leflunomide combined with low-dose prednisone inhibits proinflammatory T cells responses in myasthenia gravis patients.

We previously found that leflunomide combined with low-dose prednisone rapidly improved the clinical symptoms of myasthenia gravis (MG), but we had not investigated the mechanism of this phenomenon. This study documents the effect of leflunomide combined with low-dose prednisone on pro-inflammatory T cells in MG patients. We compared 32 treated MG patients with 18 controls. We collected peripheral blood before treatment and 4, 8, and 12 weeks after treatment. We extracted peripheral blood mononuclear cells (PBMCs) and stimulated them with phorbol 12-myristate 13-acetate (PMA) + ionomycin and quantified IFN-γ, IL-4, IL-17, and IL-9 secretion through ELISA. We quantified T helper (Th) cells Th1 (CD3+CD4+IFN-γ+), Th2 (CD3+CD4+IL-4+), Th17 (CD3+CD4+IL-17A+) and Th9 (CD3+CD4+IL-9+) among PBMCs. The treatment significantly reduced IL-17 and IL-9 secretion in peripheral blood but did not affect IFN-γ levels. Significant decreases in IL-17 and IL-9 appeared at week 12, and the trend of change was similar to that of the MG composite score. Flow cytometry indicated that leflunomide combined with low-dose prednisone significantly reduced the frequency of Th1 and Th17 cells. These findings demonstrate the potential of this treatment as an alternative immunosuppressive therapy for MG.

Is myasthenia gravis a contraindication for botulinum toxin?

Botulinum toxin (BTX) is a neurotoxin that has been used to treat various disorders and has also become a popular choice for cosmetic indications, yet traditionally, myasthenia gravis (MG) is considered a contraindication for BTX. To determine whether BTX should be avoided in MG patients, clinical data from our MG and dystonia specialist clinic were analyzed retrospectively. In addition, a systematic literature review was conducted to identify all published cases associated with the co-existence of MG and BTX treatments. Here, we described one patient from our clinic, who received BTX injections before being given MG diagnosis. After the literature review, 8 cases with subclinical MG previously treated with BTX for dystonia or cosmetic reasons ("BTX injections before MG diagnosis") were identified. Markedly, 8 out of 8 (100%) patients developed obvious muscle weakness. In contrast, 10 patients presenting MG as comorbidity had received BTX for dystonia or overactive bladder ("BTX injection after MG diagnosis"), and 8 out of 10 (80%) experienced improved symptoms through appropriate dose modifications and adequate treatment for MG before receiving BTX injections. These findings support that, under proper management of co-existing MG, BTX could be used safely and successfully in patients presenting MG comorbidities in the future.

Leflunomide ameliorates experimental autoimmune myasthenia gravis by regulating humoral and cellular immune responses.

Leflunomide, an immunosuppressive disease-modifying anti-rheumatic drug (DMARD), is widely used in the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PA) as well as multiple sclerosis. However, its role in myasthenia gravis (MG) has not yet been clearly explored. Here, we investigated the effect of leflunomide on experimental autoimmune myasthenia gravis (EAMG) in vivo and in vitro. The results demonstrated that leflunomide alleviated the severity of EAMG associated with reduced serum total anti-acetylcholine receptor (AChR) IgG levels. During the development of EAMG, the increase of follicular helper T cells (Tfh) 1, Tfh 17 cells and decrease of follicular regulatory T cells (Tfr) were reversely altered after leflunomide administration. Our work further found that leflunomide might inhibit Tfh cells through the IL-21/STAT3 pathway to reduce the secretion of antibodies by B cells. In addition, leflunomide rebuilt the balance of Th1/Th2/Th17/Treg subsets. These results suggested that leflunomide ameliorated EAMG severity by regulating humoral immune responses and Th cell profiles thereby providing a novel effective treatment strategy for MG.

Circulating Th1/17 cells serve as a biomarker of disease severity and a target for early intervention in AChR-MG patients.

Interleukin-17-expressing CD4+ T helper 17 (Th17) cells are considered to be critical regulators of thymic inflammation in AChR-MG patients. However, Th17 cells are functionally heterogeneous and circulating Th17 subsets are incompletely understood in AChR-MG patients. Here, we studied characteristics of Th17 subsets in peripheral blood from treatment-naïve AChR-MG patients, patients treated with immunosuppressants, as well as healthy controls. We found increased frequencies of circulating Th1-like Th17 (Th1/17) (IFN-γ + IL-17 + CD4 + CD3+) cells, which declined earlier than conventional Th17 (IFN-γ - IL-17 + CD4 + CD3+) cells in patients who respond well to immunosuppression treatment. Additionally, circulating Th1/17 cell frequencies were found to correlate positively with disease severity. Further, compared to conventional Th17 cells, Th1/17 cells showed an elevated expression of IFNG, TBX21, IL23R, CSF2, and a reduced expression of AHR and IL10. Taken together, our results suggest circulating Th1/17 cells may serve as a biomarker of disease severity and provide a strong rationale for early intervention in AChR-MG patients.

Quantitative features and clinical significance of two subpopulations of AChR-specific CD4+ T cells in patients with myasthenia gravis.

Acetylcholine receptor (AChR)-specific CD4+ T cells play a driving role in myasthenia gravis (MG) by regulating the production of autoantibodies. However, the quantitative features of AChR-specific T cells and their clinical significance in MG are unclear. In this study, we adopted standard and cultured enzyme-linked immunosorbent spot (ELISPOT) assays to quantify subpopulations of AChR-specific CD4+ T cells in MG patients, and evaluate their correlation with clinical characteristics. The results showed that Th1- and Th17-AChR-specific CD4+ T cells were detectable by standard and cultured ELISPOT assay respectively, with higher levels observed in MG patients comparing with healthy controls. The number of Th17-AChR-specific CD4+ T cells was positively correlated with anti-AChR antibody titer and quantitative MG score and may have latent capacity to reflect responses to immunosuppressants. These results highlight the differences in quantitative features of AChR-specific CD4+ T cells and imply Th17-AChR-specific CD4+ T cells can serve as a biomarker in MG.

AChR myasthenia gravis switching to MuSK or double antibody positive myasthenia gravis in two children and literature review.

Muscle-specific tyrosine kinase antibody (MuSK-Ab) and acetylcholine receptor antibody (AChR-Ab) coexistence in myasthenia gravis (MG) is very rare. In this report, two children with AChR-Ab switching to double antibody positive MG (DP-MG) or MuSK-Ab positive MG (MuSK-MG) are described. Six similar cases were found in the literature via online database search. Therefore, this study describes eight patients in total, six female and two male. The average age of onset was 7.25 ± 5.95 years. Four AChR-MG patients switched to DP-MG with no known precipitating factor and four switched after thymectomy (two to MuSK-MG and two to DP-MG). After the serological switch, the patients transitioned to the phenotype of MuSK-MG and responded poorly to cholinesterase inhibitors and well to corticosteroids and plasma exchange.

Imbalance of the two main circulating dendritic cell subsets in patients with myasthenia gravis.

Although it is well documented that circulating dendritic cells (DCs) have specialized features during many kinds of physiological and pathological conditions, there are few reports about the features of DCs in the peripheral blood of myasthenia gravis (MG) patients. We investigated the quantitative and component features of DCs and their implications in MG. Peripheral blood samples from different kinds of MG patients were collected and their clinical characteristics were recorded. Using flow cytometry, we distinguished circulating DC subsets [plasmacytoid DCs (pDCs) and myeloid DCs (mDCs)] and enumerated their densities in peripheral blood. Absolute numbers of circulating pDCs were significantly decreased in naïve MG patients compared with healthy controls, resulting in a markedly lower ratio of the pDC to mDC percentage in total circulating DCs (pDCs/mDCs), suggesting an imbalance in the proportions of the two main circulating DC subsets. The clinical status of MG patients was improved after drug treatment, together with increased pDCs/mDCs. In a longitudinal follow-up, we observed that circulating mDCs were significantly reduced after 1 month of therapy with a corticosteroid and immunosuppressant, resulting in recovery of pDCs/mDCs. Although the exact meaning of the proportion change in circulating DC subsets is unknown, pDCs/mDCs might reflect the balance between the autoimmune response and immune tolerance of a patient. Moreover, changes in pDCs/mDCs during treatment might be a promising marker to predict the efficacy of a specific drug used for MG patients.

Tacrolimus in the treatment of myasthenia gravis in patients with an inadequate response to glucocorticoid therapy: randomized, double-blind, placebo-controlled study conducted in China.

BACKGROUND: To determine the efficacy of low-dose, immediate-release tacrolimus in patients with myasthenia gravis (MG) with inadequate response to glucocorticoid therapy in a randomized, double-blind, placebo-controlled study. METHODS: Eligible patients had inadequate response to glucocorticoids (GCs) after ⩾6 weeks of treatment with prednisone ⩾0.75 mg/kg/day or 60-100 mg/day. Patients were randomized to receive 3 mg tacrolimus or placebo daily (orally) for 24 weeks. Concomitant glucocorticoids and pyridostigmine were allowed. Patients continued GC therapy from weeks 1-4; from week 5, the dose was decreased at the discretion of the investigator. The primary efficacy outcome measure was a reduction, relative to baseline, in quantitative myasthenia gravis (QMG) score assessed using a generalized linear model; supportive analyses used alternative models. RESULTS: Of 138 patients screened, 83 [tacrolimus (n = 45); placebo (n = 38)] were enrolled and treated. The change in adjusted mean QMG score from baseline to week 24 was -4.9 for tacrolimus and -3.3 for placebo (least squares mean difference: -1.7, 95% confidence interval: -3.5, -0.1; p = 0.067). A post-hoc analysis demonstrated a statistically significant difference for QMG score reduction of ⩾4 points in the tacrolimus group (68.2%) versus the placebo group (44.7%; p = 0.044). Adverse event profiles were similar between treatment groups. CONCLUSIONS: Tacrolimus 3 mg treatment for patients with MG and inadequate response to GCs did not demonstrate a statistically significant improvement in the primary endpoint versus placebo over 24 weeks; however, a post-hoc analysis demonstrated a statistically significant difference for QMG score reduction of ⩾4 points in the tacrolimus group versus the placebo group. This study was limited by the low number of patients, the absence of testing for acetylcholine receptor antibody and the absence of stratification by disease duration (which led to a disparity between the two groups). ClinicalTrials.gov identifier: NCT01325571.

International clinimetric evaluation of the MG-QOL15, resulting in slight revision and subsequent validation of the MG-QOL15r.

INTRODUCTION: The MG-QOL15 is a validated, health-related quality of life (HRQOL) measure for myasthenia gravis (MG). Widespread use of the scale gave us the opportunity to further analyze its clinimetric properties. METHODS: We first performed Rasch analysis on >1,300 15-item Myasthenia Gravis Quality of Life scale (MG-QOL15) completed surveys. Results were discussed during a conference call with specialists and biostatisticians. We decided to revise 3 items and prospectively evaluate the revised scale (MG-QOL15r) using either 3, 4, or 5 responses. Rasch analysis was then performed on >1,300 MG-QOL15r scales. RESULTS: The MGQOL15r performed slightly better than the MG-QOL15. The 3-response option MG-QOL15r demonstrated better clinimetric properties than the 4- or 5-option scales. Relative distributions of item and person location estimates showed good coverage of disease severity. CONCLUSIONS: The MG-QOL15r is now the preferred HRQOL instrument for MG because of improved clinimetrics and ease of use. This revision does not negate previous studies or interpretations of results using the MG-QOL15. Muscle Nerve 54: 1015-1022, 2016.

Leflunomide treatment in corticosteroid-dependent myasthenia gravis: an open-label pilot study.

Leflunomide is an effective drug used in the treatment of rheumatoid arthritis. Here we report the findings of an open-label pilot study, which found that leflunomide is also an effective treatment for myasthenia gravis (MG). This study recruited 15 corticosteroid-dependent MG patients. For 6 months, leflunomide 20 mg was given to these patients daily along with prednisone. The quantitative myasthenia gravis (QMG) scores and MG activities of daily living (MG-ADL) profiles were measured in these MG patients. After 6 months of treatment, 9 of the 15 patients enrolled in this study showed improvements in both QMG and MG-ADL. The mean QMG scores (13.4 to 8.5) and MG-ADL profiles (5.8 to 2.8) were significantly decreased (P = 0.01, 0.006 respectively). Furthermore, we found that the mean corticosteroid doses were reduced after treatment with leflunomide (24.3 to 12.3 mg per day). Leflunomide is a well-tolerated and efficacious treatment for corticosteroid-dependent MG, which may also enable lower doses of corticosteroids to be administered.

[Study of incidence and correlation factors of depression, anxiety and insomnia in patients with myasthenia gravis].

OBJECTIVE: To investigate the incidence rate and correlation factors of depression, anxiety and insomnia in patients with myasthenia gravis (MG). METHODS: A total of 161 MG patients were assessed and graded with HAMD, HAMA, PSQI, QMG, ADL and a self-made scale chart. And the correlation factors were analyzed by Logistic stepwise regression. RESULTS: The prevalence of depression, anxiety and insomnia was 58.3%, 45.3% and 39.1% respectively. The correlation factors with significant influences on MG were as follows: depression with age, physical weakness, score of QMG, life scale grading; anxiety with experience-sharing; insomnia age, dyspnea, thymoma, physical status at 1 month post-operation, prednisone dose and score of QMG. CONCLUSION: Nearly one half of the MG patients suffer from affective disorders to different degrees. And an analysis of its correlation factors provides references to prevent and treat the affective disorders concurrently with MG.