#AANAM – Study Examines Seronegative Characteristics

Editor’s note: The Myasthenia Gravis News team is providing in-depth coverage of the 2021 Virtual AAN Annual Meeting, April 17–22. Go here to read stories from the conference.

Myasthenia gravis (MG) patients who test negative for the presence of the most common MG self-reactive antibodies (autoantibodies) more commonly have ocular disease and a milder disease course than those who test positive for such autoantibodies, according to a single-center study.

In addition, these autoantibody-negative patients take about six years longer to be diagnosed than those positive for autoantibodies targeting acetylcholine receptors (AChRs) or muscle-specific tyrosine kinase (MuSK) — two of the most common self-reactive antibodies in MG.

These findings highlight the need for further understanding of this subset of patients to prevent delayed diagnosis, the researchers noted.

This information was presented in the poster “Seronegative Myasthenia Gravis: A Retrospective Review of the Clinical Characteristics at a Large Academic Center,” at the 2021 American Academy of Neurology (AAN) Virtual Annual Meeting, held April 17–22.

In MG, the immune system produces self-reactive antibodies that wrongly attack proteins involved in the communication between nerve cells and muscle cells. Most patients (80%) have anti-AChRs autoantibodies, while 7–15% test positive for autoantibodies targeting MuSK. Among those testing negative for both AChR and MuSK autoantibodies, 2–50% have been reported to produce antibodies targeting the lipoprotein receptor-related protein 4 (LRP4).

The remaining patients are currently classified as triple seronegative (negative in a blood test), since no such autoantibodies are detected in their bloodstream. In these cases, MG diagnosis is largely based on tests that assess nerve-muscle communication, which are time-consuming, require specialized training, and can be impractical in centers that do not evaluate a large number of MG patients.

However, there is limited data on the characteristics of this subset of patients who are commonly more difficult to diagnose.

Now, researchers at the Ohio State University retrospectively analyzed the clinical characteristics of triple seronegative MG patients versus autoantibody-positive patients seen at their center from 2009 to 2019.

The study included 21 triple-seronegative patients, 210 patients positive for anti-AChR autoantibodies (AChR-positive), nine with autoantibodies against MuSK (MuSK-positive), six with anti-LRP4 autoantibodies (LRP4-positive), and nine double-seronegative patients.

Results showed that triple seronegative patients had a similar age of symptom onset and female-to-male ratio, compared with patients positive for either of the three most common autoantibodies. There were no significant differences between double- and triple-seronegative patients.

However, triple-seronegative patients showed a greater frequency of ocular disease relative to autoantibody-positive groups (33% vs. 13% of AChR-positive patients, 11% of MuSK-positive patients, and no patients in the LRP4-positive group). Notably, this difference was statistically significant only when compared with the AChR-positive group.

In addition, a trend for less-frequent history of MG-related hospitalization, MG crisis, and intubation was seen in triple-seronegative patients compared with the other three groups. Absence of such autoantibodies also was significantly associated with the use of fewer immunosuppressive treatments.

All these findings suggested that triple-seronegative patients have a milder form of MG.

Notably, the mean time from symptom onset to MG diagnosis among triple-seronegative patients was 7.8 years, which was significantly longer than the mean of 2.1 years for AChR-positive patients and 0.7 years for MuSK-positive patients.

As such, “it is important to better characterize and understand the [seronegative MG] population to prevent delay in diagnosis, misdiagnosis, and unnecessary testing,” the researchers wrote.

Moreover, one patient who lacked autoantibodies against both AChR and MuSK and one triple-seronegative patient had an enlarged thymus (often linked to MG) and they both showed a reduction in symptoms and MG medication use following thymus removal surgery (thymectomy).

“Although likely rare, investigation for thymic [abnormalities] should be a consideration even in SNMG, and thymectomy should be considered if there is thymic [abnormalities],” the team added.

Also, 11 of the 21 triple-seronegative patients underwent genetic testing for congenital MG — that caused by a genetic defect, rather than an abnormal immune response — despite having no characteristic features of the disorder.

These findings indicate “that if patients do not have concerning characteristics for [congenital MG], genetic testing is low yield,” and therefore “ancillary testing should be considered in carefully selected patients for cost-effective care,” the researchers wrote.

“Our results further elucidate the clinical characteristics of SNMG and the predominance for ocular disease and a less severe disease course,” the team concluded.