Memory B cell resurgence requires repeated rituximab in myasthenia gravis

Muto, K; Matsui, Naoko; Unai, Yuki; Sakai, Waka; Haji, Shotaro; Udaka, Kengo; Miki, Hirokazu; Furukawa, Takahiro; Abe, Masahiro; Kaji, Ryuji

doi:10.1016/j.nmd.2017.06.012

Cited by 20 publications

(16 citation statements)

References 24 publications

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“…A small study with high doses (two infusions of 1000 mg each, given at 0 and 15 days) resulted in a sustained response, even years after rituximab treatment in MG patients. However, patients may still develop MG relapses if rituximab is not given repeatedly, related to the repopulation of memory B cells . Even after the initial elimination of CD20 + B cells, early pro–B cells can differentiate into new memory B cells and plasmablasts, which may lay the foundation for future MG relapses.…”

Section: Discussionmentioning

confidence: 99%

Low‐dose rituximab every 6 months for the treatment of acetylcholine receptor–positive refractory generalized myasthenia gravis

et al. 2020

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Introduction In this prospective, open‐label study we explore the effectiveness of low‐dose rituximab every 6 months in treating refractory generalized myasthenia gravis (GMG). Methods Twelve patients with acetylcholine receptor (AChR)‐positive refractory GMG were enrolled for the study. The primary endpoint was the change in quantitative myasthenia gravis (QMG) score from baseline to the study end. Secondary endpoints included changes in manual muscle testing (MMT), MG‐Related Activities of Daily Living (MG‐ADL), and 15‐item Quality‐of‐Life (MGQOL‐15) scores, as well as prednisolone reduction. Results MG decreased from 18.25 ± 4.03 to 8.42 ± 3.99 (P = .0001), MMT from 27.50 ± 17.78 to 4.58 ± 4.34 (P = .0001), ADL from 8.50 ± 2.84 to 1.17 ± 1.27 (P < .0001), MGQOL‐15 from 37.25 ± 13.78 to 17.50 ± 9.73 (P = .0015), and prednisolone dose from 29.38 ± 11.92 mg/day to 8.86 ± 1.88 mg/day (P ≤ .01). Discussion Low‐dose rituximab every 6 months is effective in treating refractory GMG patients.

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Section: Discussionmentioning

confidence: 99%

Low‐dose rituximab every 6 months for the treatment of acetylcholine receptor–positive refractory generalized myasthenia gravis

et al. 2020

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“…MBs are also involved in MG pathogenesis. In a recent case study of a patient with AChR-MG, relapse occurred after the discontinuation of rituximab and other drugs, with the repopulation of DNs and IgD − CD27 + MBs ( 141 ). The serum BAFF levels in patients with MG were significantly elevated, although the levels were not correlated with the clinical severity ( 140 ).…”

Section: Adaptive Immunitymentioning

confidence: 99%

“…Tfh cells interact with B cells to form GCs and promote B cell maturation and AChR antibody production with the help of BAFF and IL-6 ( 120 , 140 ). MBs, PBs, DNs, and PCs enter into the periphery from the thymus, MBs, and DNs then also differentiate into PBs to generate antibodies, and PCs migrate into the bone marrow to persistently produce antibodies ( 140 , 141 ). The antibodies destroy the AChR channel on the postsynaptic membrane by promoting antigen degradation, blocking functional sites, and inducing CDC ( 149 ).…”

Section: The Panorama Of Immunopathogenesismentioning

confidence: 99%

Immunopathogenesis in Myasthenia Gravis and Neuromyelitis Optica

Wang

Yan

2017

Front. Immunol.

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Myasthenia gravis (MG) and neuromyelitis optica (NMO) are autoimmune channelopathies of the peripheral neuromuscular junction (NMJ) and central nervous system (CNS) that are mainly mediated by humoral immunity against the acetylcholine receptor (AChR) and aquaporin-4 (AQP4), respectively. The diseases share some common features, including genetic predispositions, environmental factors, the breakdown of tolerance, the collaboration of T cells and B cells, imbalances in T helper 1 (Th1)/Th2/Th17/regulatory T cells, aberrant cytokine and antibody secretion, and complement system activation. However, some aspects of the immune mechanisms are unique. Both targets (AChR and AQP4) are expressed in the periphery and CNS, but MG mainly affects the NMJ in the periphery outside of CNS, whereas NMO preferentially involves the CNS. Inflammatory cells, including B cells and macrophages, often infiltrate the thymus but not the target—muscle in MG, whereas the infiltration of inflammatory cells, mainly polymorphonuclear leukocytes and macrophages, in NMO, is always observed in the target organ—the spinal cord. A review of the common and discrepant characteristics of these two autoimmune channelopathies may expand our understanding of the pathogenic mechanism of both disorders and assist in the development of proper treatments in the future.

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“…Current biological agents targeting B cells including rituximab have been trialed in autoimmune diseases, which to date have shown only limited success, failing to deplete and prevent the replenishment of aberrant ASCs. The reasons for the lack of therapeutic efficacy include memory B cellmediated relapse [12,13], some unaffected subsets in peripheral blood [13][14][15][16][17] and in tissue [18,19], unaffected factors such as BAFF and CD59 [18], and some autoantibodyproducing B cell clones protected from rituximab-mediated cytotoxicity [20,21]. Improving our knowledge of abnormally expanded autoimmune-associated subsets can enhance our understanding of ASC differentiation and explain therapeutic failures.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, a high frequency of memory B cells is also associated with poor clinical responses to RTX [13]. Muto and colleagues have reported that the repopulation of IgD -CD27and IgD -CD27 + memory B cells is associated with disease activity during relapse after anti-CD20 treatment [12]. Lazarus and colleagues suggested using therapies other than RTX in SLE patients with high levels of IgD − CD27 − memory B cells and low anti-dsDNA antibody levels [138].…”

mentioning

confidence: 99%

Peripheral B Cell Subsets in Autoimmune Diseases: Clinical Implications and Effects of B Cell-Targeted Therapies

Luo

Yang

2020

Journal of Immunology Research

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Antibody-secreting cells (ASCs) play a fundamental role in humoral immunity. The aberrant function of ASCs is related to a number of disease states, including autoimmune diseases and cancer. Recent insights into activated B cell subsets, including naïve B cell to ASC stages and their resultant cellular disturbances, suggest that aberrant ASC differentiation occurs during autoimmune diseases and is closely related to disease severity. However, the mechanisms underlying highly active ASC differentiation and the B cell subsets in autoimmune patients remain undefined. Here, we first review the processes of ASC generation. From the perspective of novel therapeutic target discovery, prediction of disease progression, and current clinical challenges, we further summarize the aberrant activity of B cell subsets including specialized memory CD11chiT-bet+ B cells that participate in the maintenance of autoreactive ASC populations. An improved understanding of subgroups may also enhance the knowledge of antigen-specific B cell differentiation. We further discuss the influence of current B cell therapies on B cell subsets, specifically focusing on systemic lupus erythematosus, rheumatoid arthritis, and myasthenia gravis.

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Memory B cell resurgence requires repeated rituximab in myasthenia gravis

Cited by 20 publications

References 24 publications

Low‐dose rituximab every 6 months for the treatment of acetylcholine receptor–positive refractory generalized myasthenia gravis

Low‐dose rituximab every 6 months for the treatment of acetylcholine receptor–positive refractory generalized myasthenia gravis

Immunopathogenesis in Myasthenia Gravis and Neuromyelitis Optica

Peripheral B Cell Subsets in Autoimmune Diseases: Clinical Implications and Effects of B Cell-Targeted Therapies

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