The Effect of Immunosuppression on the Risk of Generalization in Ocular Myasthenia Gravis

Background

Ocular Myasthenia Gravis (OMG) is an early and localized manifestation of Myasthenia Gravis (MG), with many patients initially presenting with ocular symptoms such as fatigable ptosis and diplopia. Approximately 85% of MG patients initially exhibit ocular symptoms. However, studies indicate that MG is not a localized disease, with up to 50%-80% of patients generalizing to Generalized Myasthenia Gravis (GMG) within the first two years of the disease. Several factors, such as age of onset, gender, severity of symptoms, abnormal repetitive nerve stimulation, positive acetylcholine receptor antibodies (AChR Ab), and thymic hyperplasia, are associated with generalization. However, these associations are not consistent across different studies.

Previous small-scale prospective and retrospective studies suggest that early use of corticosteroids may prevent OMG generalization, but the general applicability of this view is questioned due to the lack of high-quality evidence. Two randomized controlled trials failed to provide sufficient evidence due to various limitations. Statistical methods such as Propensity Score (PS) matching can effectively reduce confounding factors and treatment bias in observational studies, filling this knowledge gap.

Source

This study was conducted by a team of medical doctors including Deepak Menon, Mohammed Alharbi, Hans D. Katzberg, Vera Bril, Meg G. Mendoza, and Carolina Barnett-Tapia. The authors are from the National Institute of Mental Health and Neuro Sciences, Bangalore, India, and the Prosserman Neuromuscular Disease Centre at the University Health Network, Toronto, Canada. The paper was published in the journal Neurology on August 27, 2024, with the paper number e209722.

Study Process

The study includes a series of procedures and methods detailed as follows:

Detailed Procedure

a) Study Subjects and Data Collection: This is a retrospective cohort study that included all OMG patients who visited the Prosserman Neuromuscular Disease Centre in Toronto between 2015 and 2020 and had at least six months of follow-up. Out of 186 patients, 154 met the criteria. The diagnosis of OMG included symptoms of fatigable ptosis and/or diplopia without other systemic muscle weakness and met any of the following conditions: abnormal repetitive nerve stimulation test, abnormal electrophysiological examination, or positive acetylcholine receptor antibodies. Data collected included age, gender, age at symptom onset, antibody status, thymus status, time to generalization, follow-up duration, and the severity of MG at the last follow-up.

b) Data Analysis and Matching: Data analysis was performed using SPSS version 2020 and R version 3.5.1. Multiple imputation using the “MICE” package created 20 imputed datasets to fill missing data. Propensity score models were used to match variables and eliminate treatment selection bias in observational studies. A Cox proportional hazards model estimated the risk of generalization.

c) Main Results: During an average follow-up period of 87.4±73 months, 43 of 154 patients (28%) experienced generalization. Patients not treated with corticosteroids had a higher proportion of positive acetylcholine receptor antibodies and were predominantly male. The matched dataset showed that patients using corticosteroids had a significantly reduced risk of generalization (HR 0.43, 95% CI 0.19-1.06). In the unmatched dataset, the HR was 0.46 (95% CI 0.21-0.89).

Data Support and Actual Results

1. Hazard Ratio for Time to Generalization: The matched dataset showed that patients receiving any immunosuppressive treatment had a lower risk of generalization, HR 0.30 (95% CI 0.11-0.77).
2. Unmatched Dataset and Time-Weighted Analysis: Results were similar, confirming the effectiveness of immunosuppressive treatment.

Conclusion

The study concludes that OMG patients using corticosteroids and non-corticosteroid immunosuppressants have a significantly reduced risk of generalization to GMG. The findings indicate that early intervention and timely use of immunosuppressive therapy have important clinical value.

Study Highlights

• Important Findings: Confirmed the effectiveness of immunosuppressive therapy in controlling OMG generalization, providing important references for clinical practice.
• Statistical Balancing Methods: Used PS matching to minimize study bias and improve result reliability.
• Time-Weighted Models: Used time-weighted and time-dependent models to more accurately assess treatment effects, enhancing the credibility of the results.

Significance of the Study

This study, using large-scale data and various statistical analysis methods, fills the evidence gap in OMG treatment, highlighting the importance of early immunosuppressive treatment in controlling the disease course and reducing symptom generalization. It provides important decision-making references for clinicians. Additionally, the use of variable matching and time-dependent models in the study design offers a reference model for future clinical research.