Efgartigimod for generalized myasthenia gravis: A multicenter real-world cohort study in China.

OBJECTIVE: Efgartigimod, a neonatal Fc receptor antagonist, facilitates antibody degradation including pathogenic IgGs. The ADAPT study demonstrated the tolerability and efficacy of efgartigimod in the treatment of generalized myasthenia gravis (gMG). However, very limited evidence is available for the Chinese population, and it remains inconclusive about which kind of patients are selected to preferentially receive efgartigimod in real-world settings. METHODS: This multicenter cohort study included gMG patients treated at 14 neuromuscular reference centers in China. The Myasthenia Gravis Activities of Daily Living (MG-ADL) score, immunosuppressants, and the incidence of treatment-emergent adverse events (TEAEs) were prospectively collected. RESULTS: Of the 1640 gMG admitted between September and December 2023, 61 (3.7%) received efgartigimod for at least one treatment cycle. Among them, 56 cases (92%) were anti-AChR antibody-positive, 4 were anti-MuSK antibody-positive, and 1 was seronegative. Thymoma-associated myasthenia gravis accounted for most cases (44%, 27 out of 61). The principal causes of efgartigimod initiation included MG acute exacerbation (MGAE) (48%, 29 out of 61) and myasthenic crisis (MC) (15%, 9 out of 61). Clinically meaningful improvement was rapidly achieved in 97% (58 out of 61) of patients at 1.3 ± 0.7 weeks. By week 12, the MG-ADL score reduced to 3.8 ± 4.1 (baseline:10.5 ± 5.2) for all participants, while it reduced to 4.0 ± 4.7 for MGAE and 3.8 ± 4.2 for MC, respectively. All but one TMG patient required no additional rescue therapies after efgartigimod initiation. 11.5% (7 out of 61) reported ≥1 TEAEs. INTERPRETATION: This multicenter cohort study demonstrated the efficacy of efgartigimod in rapid control of gMG. Patients with MGAE or MC would benefit from efgartigimod treatment.

Association between environmental phthalates exposure and gut microbiota and metabolome in dementia with Lewy bodies.

BACKGROUND: Emerging evidence has shown the potential involvement of phthalates (PAEs) exposure in the development of dementia with Lewy bodies (DLB). Metabolomics can reflect endogenous metabolites variation in the progress of disease after chemicals exposure. However, little is known about the association between PAEs, gut microbiota and metabolome in DLB. OBJECTIVE: We aim to explore the intricate relationship among urinary PAEs metabolites (mPAEs), dysbiosis of gut bacteria, and metabolite profiles in DLB. METHODS: A total of 43 DLB patients and 45 normal subjects were included in this study. Liquid chromatography was used to analyze the levels of mPAEs in the urine of the two populations. High-throughput sequencing and liquid chromatography-mass spectrometry were used to analyze gut microbiota and the profile of gut metabolome, respectively. The fecal microbiota transplantation (FMT) experiment was performed to verify the potential role of mPAEs on gut dysbiosis contribute to aggravating cognitive dysfunction in α-synuclein tg DLB/PD mice. RESULTS: The DLB patients had higher DEHP metabolites (MEOHP, MEHHP and MEHP), MMP and MnBP, lower MBP and MBzP than the control group and different microbiota. A significantly higher abundance of Ruminococcus gnavus and lower Prevotella copri, Prevotella stercorea and Bifidobacterium were observed in DLB. Higher 3 DEHP metabolites, MMP, MnBP and lower MBP and MBzP were significantly negatively associated with Prevotella copri, Prevotella stercorea and Bifidobacterium. Additionally, using metabolomics, we found that altered bile acids, short-chain fatty acids and amino acids metabolism are linked to these mPAEs. We further found that FMT of fecal microbiota from highest DEHP metabolites donors significantly impaired cognitive function in the germ-free DLB/PD mice. CONCLUSION: Our study suggested that PAEs exposure may alter the microbiota-gut-brain axis and providing novel insights into the interactions among environmental perturbations and microbiome-host in pathogenesis of DLB.

Clinical Features of Myasthenia Gravis With Antibodies to MuSK Based on Age at Onset: A Multicenter Retrospective Study in China.

Introduction: Antibodies to MuSK identify a rare subtype of myasthenia gravis (MuSK-MG). In western countries, the onset age of MuSK-MG peaks in the late 30's while it is unknown in Chinese population. Methods: In this retrospective multicenter study, we screened 69 MuSK-MG patients from 2042 MG patients in five tertiary referral centers in China from October 2016 to October 2021 and summarized the clinical features and treatment outcomes. Then we subgrouped the patients into early-onset (<50 years old), late-onset (50-64 years old), and very-late-onset (≥65 years old) MG and compared the differences in weakness distribution, disease progression and treatment outcomes among three subgroups. Results: The patients with MuSK-MG were female-dominant (55/69) and their mean age at onset was 44.70 ± 15.84 years old, with a broad range of 17-81 years old. At disease onset, 29/69 patients were classified as MGFA Type IIb and the frequency of bulbar and extraocular involvement was 53.6 and 69.6%, respectively. There was no difference in weakness distribution. Compared with early-onset MuSK-MG, very-late-onset patients had a higher proportion of limb muscle involvement (12/15 vs.16/40, p = 0.022) 3 months after onset. Six months after onset, more patients with bulbar (14/15 vs. 26/39, p = 0.044) and respiratory involvement (6/15 vs. 0/13, p = 0.013) were seen in very-late-onset than in late-onset subgroup. The very-late-onset subgroup had the highest frequency of limb weakness (86.7%, p < 0.001). One year after onset, very-late-onset patients demonstrated a higher frequency of respiratory involvement than early-onset patients (4/12 vs. 2/35, p = 0.036). 39/64 patients reached MSE. Among 46 patients who received rituximab, very-late-onset patients started earlier than late-onset patients [6 (5.5-7.5) vs. 18 (12-65) months, p = 0.039], but no difference in the time and rate to achieving MSE was identified. Conclusion: MuSK-MG patients usually manifested as acute onset and predominant bulbar and respiratory involvement with female dominance. Very-late-onset patients displayed an early involvement of limb, bulbar and respiratory muscles in the disease course, which might prompt their earlier use of rituximab. The majority MuSK-MG patients can benefit from rituximab treatment regardless of age at onset.

Retrospective Observation of Low-Dose Rituximab Treatment in Chinese Patients With Neuromyelitis Optica Spectrum Disorders in a Real-World Setting.

Objective: This study aimed to investigate the efficacy and safety of low-dose rituximab (RTX) in the treatment of neuromyelitis optica spectrum disorders (NMOSD) patients. Methods: NMOSD patients were treated with RTX at ~25% of the standard dose. The annualized relapse rate (ARR), expanded disability status scale (EDSS) score, visual function system scale (VFSS) and length of spinal cord lesions before and after treatment were statistically compared. The dynamic changes in the proportion of CD19+ B lymphocytes after treatment were monitored, and adverse reactions were recorded. Results: In total, 36 NMOSD patients who received a low-dose RTX treatment (375-mg/m2 induction dose and 500 mg every 6 months) were recruited. The mean follow-up time after the RTX treatment was 19.83 ± 7.74 months. After the treatment, the ARR decreased from 1.97 ± 1.93 to 0.12 ± 0.32, the EDSS score decreased from 3.43 ± 1.49 to 3.10 ± 1.88, and the spinal cord lesion length decreased from 5.54 ± 3.96 to 4.31 ± 3.73. These differences were all statistically significant. The subgroup analysis of the patients who had previously received non-steroidal immunosuppressants (NSISs) (n = 20) showed that after the RTX treatment, the ARR decreased from 0.66 ± 0.51 to 0.08 ± 0.26, the EDSS score decreased from 3.65 ± 1.22 to 3.40 ± 1.99, and the spinal cord lesion length decreased from 5.68 ± 3.73 to 4.21 ± 3.58. These differences were all statistically significant. The VFSS scores did not show a significant change. The Kaplan-Meier analysis showed that low-dose RTX significantly delayed recurrence, which was also observed in the subgroup analysis of patients who previously received NSISs. Five relapses in 5 cases were noted after the low-dose RTX administration, and the percentage of CD19+ B cells remained < 1% in 3 cases during relapse. During the RTX treatment and subsequent follow-up, 8 (22.2%) patients reported adverse reactions, all of which were minor. Conclusion: Low-dose RTX is an effective and safe treatment method for NMOSDs. This method is worth popularizing in developing countries or regions, especially in areas where RTX is not covered by medical insurance.

Mutation in the caveolin-3 gene causes asymmetrical distal myopathy.

Mutations in the gene encoding caveolin-3 (CAV3) can cause a broad spectrum of clinical phenotypes, including limb girdle muscular dystrophy, rippling muscle disease, distal myopathy (MD), idiopathic persistent elevation of serum creatine kinase and cardiomyopathy. MD is a relatively rare subtype of caveolinopathy. Here, we report a sporadic case of a middle-aged female Chinese patient with MD in which a CAV3 mutation was identical to that previously reported in cases of rippling muscle disease. T1-weighted enhanced skeletal muscle MRI of the lower limbs showed an abnormal signal in the distal and proximal muscles. A muscle biopsy revealed moderate dystrophic changes, and immunohistochemical staining showed reduced CAV-3 expression in the plasmalemma. Genetic analysis revealed a heterozygous c.136G > A (p.Ala46Thr) CAV3 mutation that appeared to be de novo because it was absent from the patient's parents. This study suggested that the CAV3 c.136G > A (p.Ala46Thr) mutation can cause MD as well as different phenotypes in different individuals, suggesting that additional unknown loci must affect the disease phenotypes.

Job stress and carotid intima-media thickness in Chinese workers.

OBJECTIVES: Carotid intima-media thickness (CIMT) can be used as a surrogate marker for cardiovascular health, and job stress is a risk factor for cardiovascular disease. However, there have been a limited number of studies focusing on the association between job stress and CIMT. The goal of this study was to explore the association between job stress and CIMT in a Chinese working population. METHODS: The study included 734 participants (508 males and 226 females) without coronary heart disease. Job stress was evaluated using the effort-reward imbalance (ERI) questionnaire at work. ERI is the ratio between efforts and rewards (weighted by number of items). High resolution carotid ultrasonographic studies were performed using a Sequoia 512 ultrasound system with an 8-13 MHz linear array transducer to assess CIMT. RESULTS: This study detected gender-specific associations between the indictors of the ERI model and increased CIMT among the study participants in China. This study demonstrated a robust association in women between the key indicators of ERI, effort, overcommitment and ERI, and increased CIMT (adjusted r(2)=0.258, p=0.001; adjusted r(2)=0.261; p<0.001; adjusted r(2)=0.274; p<0.001, respectively). Reward was inversely correlated with CIMT (adjusted r(2)=0.282, p<0.001), controlling for age, hypertension, diabetes mellitus, hyperlipidaemia and body mass index. For men, a similar pattern of associations was observed, but the associations were lost after adjustment for confounders. CONCLUSIONS: Our results show that effort, overcommitment and ERI may be associated with early atherosclerosis predicted by CIMT in women, and reward is inversely related to CIMT.