Long-Lasting Rituximab-Induced Reduction of Specific—But Not Total—IgG4 in MuSK-Positive Myasthenia Gravis

Abstract

The use of rituximab (RTX), an anti-CD20 monoclonal antibody (Ab), in refractory myasthenia gravis (MG) is associated with a better response in patients with Abs to the muscle-specific tyrosine kinase (MuSK) than in other MG subgroups. Anti-MuSK Abs are mostly IgG4 with proven pathogenicity and positive correlation with clinical severity. The rapid and sustained response to RTX may be related to MuSK Ab production by short-lived Ab-secreting cells derived from specific CD20 + B cells. Here, we investigated the long-term effects of RTX in nine refractory MuSK-MG patients with a follow-up ranging from 17 months to 13 years. In patients' sera, we titrated MuSK-specific IgG (MuSK-IgG) and MuSK-IgG4, along with total IgG and IgG4 levels. Optimal response to RTX was defined as the achievement and maintenance of the status of minimal manifestations (MM)-or-better together with a ≥ 50% steroid reduction, withdrawal of immunosuppressants, and no need for plasma-exchange or intravenous immunoglobulin. After a course of RTX, eight patients improved, with optimal response in six, while only one patient did not respond. At baseline, MuSK-IgG and MuSK-IgG4 serum titers were positive in all patients, ranging from 2.15 to 49.5 nmol/L and from 0.33 to 46.2 nmol/L, respectively. MuSK Abs mostly consisted of IgG4 (range 63.80-98.86%). RTX administration was followed by a marked reduction of MuSK Abs at 2-7 months and at 12-30 months (p < 0.02 for MuSK-IgG and p < 0.01 for MuSK-IgG4). In patients with a longer follow-up, MuSK Ab titers remained suppressed, paralleling clinical response. In the patient who achieved long-term complete remission, MuSK-IgG4 was no longer detectable within 2 years, while MuSK-IgG remained positive at very low titers up to 10 years after RTX. In the patient who did not respond, MuSK-IgG and MuSK-IgG4 remained unchanged. In this patient series, total IgG and IgG4 transiently decreased (p < 0.05) at 2-7 months after RTX. The different trends of

Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology

“…Although it is well-understood that MuSK MG patients responds remarkably well to B cell depletion therapy, there are patients who respond less well to this treatment and a small fraction who do not improve (186). This highlights the heterogeneity that is invariably observed among MG patients.…”

Monoclonal Antibody-Based Therapies for Myasthenia Gravis

“…In other autoimmune diseases, rituximab therapy reduces serum antibody levels generally and appears to lower autoantibodies to a greater extent [19]. The greater efficacy of rituximab in MuSK MG suggests that pathogenic antibody synthesis is primarily by short-lived plasma cells [25], in contrast to AChR antibody synthesis, which appears to be reliant on long-lived plasma cells, which do not express CD20. However, investigations thus far have been on treatment-resistant patients, leading to the question of whether earlier use of rituximab in the course of AChR antibody-positive MG could be more effective.…”

Immunopathology of Autoimmune Myasthenia Gravis: Implications for Improved Testing Algorithms and Treatment Strategies

“…Furthermore, monitoring MuSK Abs titers could be useful to establish overall disease severity and/or clinical improvements after RTX therapy (103). On the other hand, improvement is less apparent for AChR MG patients with high relapse rates after RTX treatment (103)(104)(105). Moreover, as discussed above, the binding titers of AChR Abs do not correlate well with clinical severity in MG patients after RTX treatment (63,106).…”