Objective:

This exploratory in-depth proteomics analysis examined the differences in the immunopathogenesis of acetylcholine receptor (AChR) autoantibody-positive early onset (symptom onset < 50 years of age) and late-onset myasthenia gravis (EOMG and LOMG) utilizing the well-characterized BeatMG study (B-Cell Targeted Treatment in MG; NCT02110706) cohort.

Background:

MG is a heterogeneous autoimmune disease with autoantibodies against postsynaptic antigens at the neuromuscular junction. About 80% of patients with MG have autoantibodies against AChR, and their clinical features and treatment response may vary based on clinical characteristics. This investigation aimed to assess whether there was a unique signature based on symptom onset.

Design/Methods:

We used the Proximity Extension Assay (PEA) from the Olink platform to examine 768 inflammatory proteins in the baseline serum samples collected for the BeatMG study. After identifying the differentially expressed proteins, we performed enrichment analysis to assess the pathways involved with those proteins.

Results:

Baseline samples from 47 patients [age: 54.9 ± 17.7, 22 women (47%)] out of 52 patients from the BeatMG study with all necessary data points were included. Twenty patients were categorized as EOMG [38.4 ± 12.4, 15 women (75%)], and 27 were in the LOMG [67.1 ± 8.7, 7 women (25.9%)] category. The EOMG group had a higher percentage of thymectomy patients (55% vs. 0%, p-value <0.001). Principal component analysis showed separation of the EOMG and LOMG groups, and several proteins were highly expressed in the LOMG group, including CXCL17, JCHAIN, CD83, and TNFRSF11A. These proteins are involved in regulating leucocyte differentiation, interleukin-10 production, and myeloid leukocyte differentiation and migration pathways. TNFRSF11A SNP has been previously reported to be associated with LOMG.

Conclusions:

LOMG is potentially mediated by a distinct immunopathogenic mechanism. Further validation of these findings and an effort to identify tools to tailor therapeutic approaches for LOMG are warranted.