Double-seronegative myasthenia gravis (dSN-MG, without detectable AChR and MuSK antibodies) presents a serious gap in MG diagnosis and understanding. Recently, autoantibodies against the low-density lipoprotein receptor-related protein 4 (LRP4) have been identified in several dSN-MG sera, but with dramatic frequency variation (∼2-50%). We have developed a cell based assay (CBA) based on human LRP4 expressing HEK293 cells, for the reliable and efficient detection of LRP4 antibodies. We have screened about 800 MG patient sera from 10 countries for LRP4 antibodies. The overall frequency of LRP4-MG in the dSN-MG group (635 patients) was 18.7% but with variations among different populations (range 7-32.7%). Interestingly, we also identified double positive sera: 8/107 anti-AChR positive and 10/67 anti-MuSK positive sera also had detectable LRP4 antibodies, predominantly originating from only two of the participating groups. No LRP4 antibodies were identified in sera from 56 healthy controls tested, while 4/110 from patients with other neuroimmune diseases were positive. The clinical data, when available, for the LRP4-MG patients were then studied. At disease onset symptoms were mild (81% had MGFA grade I or II), with some identified thymic changes (32% hyperplasia, none with thymoma). On the other hand, double positive patients (AChR/LRP4-MG and MuSK/LRP4-MG) had more severe symptoms at onset compared with any single positive MG subgroup. Contrary to MuSK-MG, 27% of ocular dSN-MG patients were LRP4 antibody positive. Similarly, contrary to MuSK antibodies, which are predominantly of the IgG4 subtype, LRP4 antibodies were predominantly of the IgG1 and IgG2 subtypes. The prevalence was higher in women than in men (female/male ratio 2.5/1), with an average disease onset at ages 33.4 for females and 41.9 for males. Overall, the response of LRP4-MG patients to treatment was similar to published responses of AChR-MG rather than to MuSK-MG patients.

Seronegative myasthenia gravis (MG) presents a serious gap in MG diagnosis and understanding. We applied a cell based assay (CBA) for the detection of muscle specific kinase (MuSK) antibodies undetectable by radioimmunoassay. We tested 633 triple-seronegative MG patients' sera from 13 countries, detecting 13% as positive. MuSK antibodies were found, at significantly lower frequencies, in 1.9% of healthy controls and 5.1% of other neuroimmune disease patients, including multiple sclerosis and neuromyelitis optica. The clinical data of the newly diagnosed MuSK-MG patients are presented. 27% of ocular seronegative patients were MuSK antibody positive. Moreover, 23% had thymic hyperplasia suggesting that thymic abnormalities are more common than believed.

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Antititin antibodies have high PPV and NPV for thymoma in EOMG. In MG without thymoma, antititin antibodies can be considered as markers of LOMG, but not of a severe course in our MG cohort.

ObjectivesAutoimmune thyroid diseases (ATDs) frequently accompany myasthenia gravis (MG) and may influence its course. We aimed to determine the association and impact of ATD with early‐ (<50 years), late‐onset MG, or thymoma‐MG.Materials and MethodsPrevalence of ATD was measured in a cross‐sectional study of 343 consecutive patients with MG (236 F, 107 M) aged 4–89 years; 83.8% were seropositive, in 2.9%, anti‐MuSK antibodies were detected. Concentrations of antithyroid peroxidase antibodies, antithyroglobulin antibodies, antithyrotropin receptor antibodies, and TSH level were measured in all patients. MG clinical course, treatment received, and treatment results were evaluated.ResultsAutoimmune thyroid diseases were diagnosed in 92 (26.8%) of MG patients including 4.4% with Graves (GD), 9% with Hashimoto thyroiditis (HT), and 13.4% with antithyroid antibodies only. GD patients had ocular symptoms more often than patients with antithyroid antibodies or HT (p = .008). ATD prevalence was comparable in MG with early and late onset, while non‐ATDs were more frequent in thymoma‐MG (p = .049). Immunosuppressive therapy was less frequently needed in the patients with MG and ATD, indirectly indicating milder MG course (p = .005). Risk of myasthenic crisis and the results of treatment did not differ between patients with and without ATD.ConclusionsAutoimmune thyroid diseases are frequently accompanied by early‐and late‐onset MG, while thymoma‐MG is related to higher risk of non‐ATD. Myasthenia coexisting with ATD follows milder course than MG alone.