A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis

Abstract

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.

Outcomes of Preoperative and Postoperative Corticosteroid Therapies in Myasthenia Gravis

“…These anti-AChR abs-negative patients may have clustered AChR abs or anti-LRP4 abs [2] , because only 5% of the patients (2/40) without detectable anti-AChR abs tested positive for anti-MuSK abs. In the double-seronegative MG patients without anti-AChR abs or anti-MuSK abs, 16-50% of the patients tested positive for clustered AChR abs [2,31] , and 9.2-50% were positive for anti-LRP4 abs [32][33][34] . The majority of the double-seronegative MG patients resembled patients with ocular or mild generalized AChR-MG in clinical manifestation and treatment response [31,32] .…”

“…OMG is also involved with the presence of disease-specific antibodies [2,19,31,32,36] . The consistent production of anti-AChR abs has been found to be elevated in 50% of patients with OMG and 90% of patients with GMG [36] .…”

Precision medicine in myasthenia graves: begin from the data precision

“…The antibody negative subgroup is a heterogeneous group, patients are essentially indistinguishable from patients with AChR antibody positive MG in terms of clinical features, pharmacological treatment response, and even thymic abnormalities in some cases. Moreover, patients with pathogenic antibodies against more than one NMJ proteins (e.g., MuSK and LRP4) were found with improved testing methods, which makes some patients be allocated into more than one antibody associated subgroup (57)(58)(59). The present "standard" diagnostic testing might change in the future, making studies on subgroups with different testing methods incomparable.…”

Miastenia gravis de tipo bulbar en niños: un caso de difícil diagnóstico.

“…La Miastenia gravis (MG) cuya denominación proviene de: mio músculo, astenia debilidad y gravis intensa, es un trastorno neuromuscular autoinmune caracterizado por debilidad y fatigabilidad de los músculos esqueléticos (1). Fue descrita por primera vez por el médico inglés Sir Thomas Willis en 1672 (2).…”