LRP4 Antibody-Associated Myasthenia Gravis: Distinct Clinical Phenotype and Treatment Challenges in the German MG Registry

Highlight

• LRP4-Ab-single-positive myasthenia gravis (MG) patients display significantly higher disease burden and symptom severity compared to other MG antibody subgroups.
• These patients require more frequent escalation therapies such as rituximab and rescue treatments including intravenous immunoglobulin (IVIG).
• LRP4/AChR-Ab-double-positive MG patients exhibit clinical features and treatment responses similar to traditional MG subtypes, suggesting distinct immunopathogenic mechanisms in single versus double antibody positivity.

Study Background

Myasthenia gravis is an autoimmune disorder primarily targeting the neuromuscular junction, characterized by fatigable muscle weakness. The majority of cases are associated with antibodies against acetylcholine receptors (AChR) or muscle-specific tyrosine kinase (MuSK), which have been well characterized. However, a rare subgroup is defined by antibodies against lipoprotein receptor-related protein 4 (LRP4), a critical component in neuromuscular junction development and function. Despite its biological significance, the clinical phenotype, disease burden, and treatment responses of LRP4-Ab-positive MG remain poorly understood.

This study addresses an unmet clinical need by characterizing the LRP4-Ab-positive MG subgroup within a large, well-documented patient registry, comparing it against other antibody-defined MG populations in terms of demographics, disease severity, therapeutic interventions, and quality-of-life outcomes.

Study Design

This investigation utilized data from the prospective longitudinal German Myasthenia Gravis Registry, including 3,319 patients enrolled since 2019. Of these, 1,432 patients with complete antibody profiling for LRP4, AChR, and MuSK antibodies were identified and stratified into subgroups: LRP4-Ab-single-positive, LRP4/AChR-Ab-double-positive, AChR-Ab-positive, MuSK-Ab-positive, MuSK/AChR-Ab-double-positive, and triple seronegative.

Clinical characteristics were analyzed regarding symptom frequency, treatment modalities—including escalation (rituximab) and rescue therapies (IVIG)—and disease burden using validated instruments: the Myasthenia Gravis Activities of Daily Living (MG-ADL) score and the Myasthenia Gravis Quality-of-Life 15-item revised scale (MG-Qol15r). Linear mixed-effects models were employed to compare disease burden across subgroups adjusting for relevant confounders.

Key Findings

Prevalence and Demographics: Among patients with complete antibody testing, 4.8% were LRP4-Ab-positive: half single-positive and half double-positive with AChR antibodies. The median age of the tested population was 54 years with a slight female predominance (57.4%).

Symptom Burden: LRP4-Ab-single-positive patients reported notably higher symptom rates across various muscular domains. Comparative analysis revealed that their MG-ADL scores were worse by a mean of 2.5 points (95% CI: -3.9 to -1.2) and MG-Qol15r scores were 8.4 points lower (95% CI: -13.3 to -3.4) compared to the AChR-Ab-positive cohort, indicating substantially impaired daily function and quality of life.

Treatment Patterns: All LRP4-Ab-positive patients received more frequent and intensified therapeutic interventions than other antibody groups. Notably, escalation therapies such as rituximab and rescue treatments including intravenous immunoglobulin (IVIG) were employed at higher rates, underscoring treatment refractory aspects within this subgroup. In contrast, patients with LRP4/AChR-Ab-double positivity displayed disease severity and treatment requirements comparable to those with only AChR antibodies.

Clinical Implications: This evidence supports the concept that LRP4-Ab-single-positive MG represents a distinct clinical phenotype characterized by greater disease severity and increased treatment complexity. This contrasts with the double-positive group, which aligns more closely with classical MG phenotypes regarding both clinical expression and therapeutic response.

Expert Commentary

The study’s findings highlight the clinical heterogeneity within antibody-defined MG subgroups and reinforce the importance of comprehensive antibody testing in guiding diagnosis and management. The markedly higher burden in LRP4-Ab-single-positive patients raises critical questions about underlying immunopathogenic mechanisms that differ from AChR or MuSK antibody-mediated MG.

While the study leverages a robust registry with longitudinal follow-up, limitations include potential referral bias inherent to tertiary center-based registries and the relatively small proportion of LRP4-Ab-positive patients. Further mechanistic and interventional studies are warranted to elucidate optimal therapy and improve outcomes for this challenging subgroup.

Conclusion

LRP4 antibody-positive myasthenia gravis, particularly the single-positive form, constitutes a rare but clinically distinct subgroup with heightened symptom severity and treatment demands. Recognition of this phenotype is crucial for personalized therapeutic strategies aiming to ameliorate disease burden. Future research should explore targeted immunomodulatory approaches tailored to this unique pathogenic subset.

Funding and Clinical Trials

The study was registered with the German clinical trial registry (DRKS00024099), with first patient enrollment on February 4, 2019. Details on funding were not specified but can be accessed through the registry or corresponding publication.

References

• Preßler H, Stascheit F, Aigner A, et al. Phenotype, Severity, and Therapy of Patients With LRP4 Antibody-Associated Myasthenia Gravis in the German Myasthenia Gravis Registry. Neurology. 2026 Jul 6;107(3):e218308. PMID: 42407020.
• Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis. Lancet. 2001 Mar 24;357(9274):2122-8.
• Hübers A, Müller-Felber W, Schwab S. The Lipoprotein Receptor-Related Protein 4 in Myasthenia Gravis: Pathophysiology, Diagnosis, and Treatment. Curr Neuropharmacol. 2020;18(3):200-209.