Review article
B cell-targeted therapy with rituximab and autoimmune neuromuscular disorders

https://doi.org/10.1016/j.jneuroim.2008.07.019Get rights and content

Abstract

B lymphocytes play a central role in the pathogenesis of autoimmunity, so that B cell suppression is considered a potential treatment option for immune-mediated diseases. Rituximab, a chimeric anti-human CD20 antibody, is the only anti-B cell biological agent presently under study for the treatment of autoimmune neuromuscular diseases. Isolated case histories and series, pilot and retrospective studies report on the experimental administration of rituximab as treatment of a variety of immune-mediated neuropathy syndromes, treatment-refractory myasthenia gravis and inflammatory myopathies. Rituximab was used as monotherapy or in combination with other types of immunomodulation, and was well tolerated. The mechanism whereby B cell depletion shows benefit is uncertain and may vary depending on the inherent differences in the pathogenesis of various autoimmune neuromuscular disorders.

Section snippets

B lymphocytes in autoimmunity

Improved understanding of the regulation of the immune system has elucidated a key role of B lymphocytes in the pathogenesis of many autoimmune diseases (Birnbaum et al., 2005, Dalakas, 2008). Based on the established immunobiological function of B cells in health, it is predicted that these cells support and perpetuate the autoimmune pathological process: (1) the presence of membrane-expressed immunoglobulin allows B cells to capture and concentrate proteins, including autoantigens, in an

Antibody-based therapeutics

In 1975, Kohler and Milstein employed a method of somatic hybridization that generated “hybridoma” cell lines capable of producing monoclonal antibodies of defined specificities. Therapeutic monoclonal antibodies are currently approved for use in organ transplantation, percutaneous coronary intervention, chronic lymphocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, breast cancer, colorectal cancer, rheumatoid arthritis, Crohn's disease, asthma, and prophylaxis of respiratory

B cell-directed biological therapy

Effective targeting of B cells may be a beneficial therapeutic goal in various autoimmune diseases (Arkfeld, 2008, Edwards and Cambridge, 2006, Looney, 2005, Silverman and Weisman, 2003). Different biological approaches aimed at the B cell compartment are under investigation, such as antibodies directed against cell surface markers (CD20 and CD22) and a B lymphocyte stimulator (BLyS), and a fusion protein that neutralizes BLyS and a proliferation ligand (APRIL). B cell depletion could induce

Neuropathy associated with IgM antibodies to myelin-associated glycoprotein

Myelin-associated glycoprotein (MAG) is a constituent of myelin membranes and is concentrated in the periaxonal region. IgM reactivity with MAG is specific for the light chain (usually kappa) of the M protein, and is always directed against closely related epitopes in the carbohydrate moiety in MAG (Nobile-Orazio, 1998, Nobile-Orazio et al., 2000). This epitope is also present in other glucoconjugates in nerve, including sulfated glucoronyl paragloboside (SGPG) so that IgM binding to SGPG is

Conclusion

The literature on the experimental use of rituximab in autoimmune neuromuscular disorders consists of case reports and series, pilot and retrospective studies so that positive reporting bias is likely. Therefore, until large-scale clinical trial data are available, it seems prudent to proceed with caution in the administration of rituximab outside approved indications. The results are awaited of randomized, controlled trials of rituximab for anti-MAG-associated neuropathy and inflammatory

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      The suggested mechanism includes immune-complex formation and deposition due to development of antibodies against omalizumab. Rituximab has been studied in a wide range of diseases, including different vasculitic disorders [258R, 259C, 260c, 261c], chronic immune thrombocytopenic purpura [262c], collapsing glomerulopathy with dominant C1q-containing mesangial immune deposits [263A], severe glucocorticoid- or ciclosporin-dependent nephrotic syndrome [264c, 265c], immune-mediated neuropathies [266C], treatment-refractory myasthenia gravis and inflammatory myopathies [267c, 268R], systemic lupus erythematosus [269c, 270c, 271R, 272M], Sjögren's syndrome [273c, 274M], autoimmune bullous diseases [275c, 276A], relapsing Graves’ disease [277c], chronic graft-versus-host disease [278M], primary gastric lymphoma [279c], autoimmune hemolytic anemia [280c], and thrombotic thrombocytopenic purpura [281cM]. Cases of interstitial lung disease, dyspnea, and pneumonitis associated with rituximab, some fatal, have been reported [282M, 283A, 284A, 285A, 286A, 287c].

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