Long-Lasting Rituximab-Induced Reduction of Specific—But Not Total—IgG4 in MuSK-Positive Myasthenia Gravis
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 posi...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00613/full |
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| author | Mariapaola Marino Mariapaola Marino Umberto Basile Gregorio Spagni Gregorio Spagni Cecilia Napodano Cecilia Napodano Raffaele Iorio Francesca Gulli Laura Todi Laura Todi Carlo Provenzano Carlo Provenzano Emanuela Bartoccioni Emanuela Bartoccioni Amelia Evoli Amelia Evoli |
| author_facet | Mariapaola Marino Mariapaola Marino Umberto Basile Gregorio Spagni Gregorio Spagni Cecilia Napodano Cecilia Napodano Raffaele Iorio Francesca Gulli Laura Todi Laura Todi Carlo Provenzano Carlo Provenzano Emanuela Bartoccioni Emanuela Bartoccioni Amelia Evoli Amelia Evoli |
| author_sort | Mariapaola Marino |
| collection | DOAJ |
| description | 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 reduction between MuSK-IgG4 and total IgG4 after RTX support the view that short-lived Ab-secreting cells are the main producers of MuSK Abs. The ratio between short-lived Ab-secreting cells and long-lived plasma cells may influence the response to RTX, and B-cell severe depletion may reduce self-maintaining autoimmune reactivity. |
| first_indexed | 2024-12-19T21:42:28Z |
| format | Article |
| id | doaj.art-0ad1969741b245079a5905aa99cc99ec |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T21:42:28Z |
| publishDate | 2020-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-0ad1969741b245079a5905aa99cc99ec2022-12-21T20:04:37ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-05-011110.3389/fimmu.2020.00613512137Long-Lasting Rituximab-Induced Reduction of Specific—But Not Total—IgG4 in MuSK-Positive Myasthenia GravisMariapaola Marino0Mariapaola Marino1Umberto Basile2Gregorio Spagni3Gregorio Spagni4Cecilia Napodano5Cecilia Napodano6Raffaele Iorio7Francesca Gulli8Laura Todi9Laura Todi10Carlo Provenzano11Carlo Provenzano12Emanuela Bartoccioni13Emanuela Bartoccioni14Amelia Evoli15Amelia Evoli16Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Rome, ItalyFondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, ItalyArea Diagnostica di Laboratorio, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, ItalyIstituto di Neurologia, Università Cattolica del Sacro Cuore, Rome, ItalyDipartimento di Neuroscienze, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, ItalyIstituto di Medicina Interna, Università Cattolica del Sacro Cuore, Rome, ItalyArea di Gastroenterologia e Oncologia Medica, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, ItalyDipartimento di Neuroscienze, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, ItalyDipartimento di Medicina di Laboratorio, Ospedale Madre Giuseppina Vannini, Rome, ItalyIstituto di Patologia Generale, Università Cattolica del Sacro Cuore, Rome, ItalyFondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, ItalyIstituto di Patologia Generale, Università Cattolica del Sacro Cuore, Rome, ItalyFondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, ItalyIstituto di Patologia Generale, Università Cattolica del Sacro Cuore, Rome, ItalyFondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, ItalyIstituto di Neurologia, Università Cattolica del Sacro Cuore, Rome, ItalyDipartimento di Neuroscienze, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, ItalyThe 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 reduction between MuSK-IgG4 and total IgG4 after RTX support the view that short-lived Ab-secreting cells are the main producers of MuSK Abs. The ratio between short-lived Ab-secreting cells and long-lived plasma cells may influence the response to RTX, and B-cell severe depletion may reduce self-maintaining autoimmune reactivity.https://www.frontiersin.org/article/10.3389/fimmu.2020.00613/fullrituximabantibodiesMuSKmyasthenia gravisIgG4short-lived antibody-secreting cells |
| spellingShingle | Mariapaola Marino Mariapaola Marino Umberto Basile Gregorio Spagni Gregorio Spagni Cecilia Napodano Cecilia Napodano Raffaele Iorio Francesca Gulli Laura Todi Laura Todi Carlo Provenzano Carlo Provenzano Emanuela Bartoccioni Emanuela Bartoccioni Amelia Evoli Amelia Evoli Long-Lasting Rituximab-Induced Reduction of Specific—But Not Total—IgG4 in MuSK-Positive Myasthenia Gravis Frontiers in Immunology rituximab antibodies MuSK myasthenia gravis IgG4 short-lived antibody-secreting cells |
| title | Long-Lasting Rituximab-Induced Reduction of Specific—But Not Total—IgG4 in MuSK-Positive Myasthenia Gravis |
| title_full | Long-Lasting Rituximab-Induced Reduction of Specific—But Not Total—IgG4 in MuSK-Positive Myasthenia Gravis |
| title_fullStr | Long-Lasting Rituximab-Induced Reduction of Specific—But Not Total—IgG4 in MuSK-Positive Myasthenia Gravis |
| title_full_unstemmed | Long-Lasting Rituximab-Induced Reduction of Specific—But Not Total—IgG4 in MuSK-Positive Myasthenia Gravis |
| title_short | Long-Lasting Rituximab-Induced Reduction of Specific—But Not Total—IgG4 in MuSK-Positive Myasthenia Gravis |
| title_sort | long lasting rituximab induced reduction of specific but not total igg4 in musk positive myasthenia gravis |
| topic | rituximab antibodies MuSK myasthenia gravis IgG4 short-lived antibody-secreting cells |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.00613/full |
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