Maintenance immunosuppression in myasthenia gravis, an update

Morren, John Anthony; Li, Yuebing

doi:10.1016/j.jns.2019.116648

Cited by 50 publications

(65 citation statements)

References 185 publications

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“…They are often combined with immunosuppressive drugs that reduce the overactivity of the immune system in production of antibodies against postsynaptic elements of neuromuscular junction. These drugs include glucocorticosteroids (GCS), AZT, cyclophosphamide and MTX [81], where GCS are the first-choice drugs applied for MG. In case of the absence of a response to the treatment, AZT may be applied or MTX as an alternative in AZT intolerance [82][83][84][85].…”

Section: Methotrexate-anti-inflammatory and Immunosuppressive Drugmentioning

confidence: 99%

Overview of Dual-Acting Drug Methotrexate in Different Neurological Diseases, Autoimmune Pathologies and Cancers

Koźmiński

Halik

Chesori

et al. 2020

IJMS

207

120

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Methotrexate, a structural analogue of folic acid, is one of the most effective and extensively used drugs for treating many kinds of cancer or severe and resistant forms of autoimmune diseases. In this paper, we take an overview of the present state of knowledge with regards to complex mechanisms of methotrexate action and its applications as immunosuppressive drug or chemotherapeutic agent in oncological combination therapy. In addition, the issue of the potential benefits of methotrexate in the development of neurological disorders in Alzheimer’s disease or myasthenia gravis will be discussed.

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Section: Methotrexate-anti-inflammatory and Immunosuppressive Drugmentioning

confidence: 99%

Overview of Dual-Acting Drug Methotrexate in Different Neurological Diseases, Autoimmune Pathologies and Cancers

Koźmiński

Halik

Chesori

et al. 2020

IJMS

207

120

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“…Some efficacy of an anti‐CD20 B‐cell depleting agent, rituximab, is demonstrated by sustained clinical improvement with prolonged time to relapse and reduce the need of other immunosuppressants 4‐7 . Treatments with these agents are commonly initiated in conjunction with steroids so that they may be gradually tapered to a lower maintenance dose, which varies among individual patients 8 . A previous network meta‐analysis showed the efficacy and tolerability of the immunosuppressants were heterogeneous 9 …”

Section: Introductionmentioning

confidence: 99%

Immunotherapy choice and maintenance for generalized myasthenia gravis in China

Zhang

Yang

et al. 2020

CNS Neurosci Ther

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Aims To compare long‐term efficacy and safety of immunotherapeutic strategies as maintenance to prevent disease relapses of generalized myasthenia gravis (MG) in real‐world settings. Methods This is a retrospective cohort study on generalized MG conducted in seven major neurological centers across China. Eligible participants were patients with generalized MG who were under minimal manifestation status or better. Main outcome measures were probability of patients free of relapses and causes of drug discontinuation. Results Among 1064 patients enrolled, the median (interquartile range) age was 50.3 (37.0‐62.5) years and 641 (60.2%) were women. Disease relapse was significantly lower for rituximab (6.1%) compared with all the other monotherapies (hazard ratio [HR] = 0.18, 95% confidence interval [CI] 0.06 to 0.56, P = .0030). As combination therapies, tacrolimus in combination with corticosteroids reduced risk of disease relapses compared with azathioprine with corticosteroids (HR = 0.45, 95% CI 0.25 to 0.81, P = .0077) or mycophenolate mofetil with corticosteroids (HR = 0.32, 95% CI 0.15 to 0.67, P = .0020). Otherwise, lower‐dose corticosteroids or azathioprine as monotherapy significantly increased risk of disease relapses (HR = 2.78, 95% CI 1.94 to 3.99, P < .0001; HR = 2.14, 95% CI 1.42 to 3.23, P = .0003, respectively). The proportion of discontinuation was lowest in patients with rituximab (20.4%) as monotherapy and tacrolimus with corticosteroids (23.6%). Overall, combination treatment of immunosuppressants with corticosteroids had a lower rate of discontinuation compared with corresponding monotherapy (HR = 0.51, 95% CI 0.36 to 0.71, P < .0001). Conclusions Rituximab as monotherapy and tacrolimus with corticosteroids displayed better clinical efficacy as well as drug maintenance to prevent disease relapses in patients with generalized MG.

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“…We emphasize: (1) the AChR cluster formation based on the Wnts-Lrp4-MuSK (CRD)-Dvl signaling (pre-innervated stage) which converges upon the agrin-Lrp4-MuSK (Ig1/2 domains) pathway (innervated stage); (2) the retrograde signaling (from muscle to the nerve) for presynaptic differentiation via MuSK CRD, Lrp4 and Laminins; (3) presynaptic Ca 2+ homeostasis by autoreceptors; and (4) the synaptic stability based on the lamininnetwork including the extracellular matrix and the cytoskeleton. The insight into the NMJ structural mechanisms discussed in this review will foster further immunological approaches to search for new antigenic targets (Li L. et al, 2018;Koneczny and Herbst, 2019) and to enhance antibody detection (Vincent et al, 2012(Vincent et al, , 2018Rodríguez Cruz et al, 2015a;Huda et al, 2017; in MG, and may thereby help to view clinical profiles in MG subtypes (Verschuuren et al, 2013;Gilhus et al, 2019) and to provide potential therapeutic approaches (Losen et al, 2005;Ghazanfari et al, 2014;Gomez et al, 2014;Dalakas, 2015Dalakas, , 2019Behin and Le Panse, 2018;Ito and Ohno, 2018;Morren and Li, 2020).…”

Section: Conclusion and Perspectivementioning

confidence: 99%

Myasthenia Gravis: From the Viewpoint of Pathogenicity Focusing on Acetylcholine Receptor Clustering, Trans-Synaptic Homeostasis and Synaptic Stability

Takamori

2020

Front. Mol. Neurosci.

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Myasthenia gravis (MG) is a disease of the postsynaptic neuromuscular junction (NMJ) where nicotinic acetylcholine (ACh) receptors (AChRs) are targeted by autoantibodies. Search for other pathogenic antigens has detected the antibodies against musclespecific tyrosine kinase (MuSK) and low-density lipoprotein-related protein 4 (Lrp4), both causing pre-and post-synaptic impairments. Agrin is also suspected as a fourth pathogen. In a complex NMJ organization centering on MuSK: (1) the Wnt non-canonical pathway through the Wnt-Lrp4-MuSK cysteine-rich domain (CRD)-Dishevelled (Dvl, scaffold protein) signaling acts to form AChR prepatterning with axonal guidance; (2) the neural agrin-Lrp4-MuSK (Ig1/2 domains) signaling acts to form rapsyn-anchored AChR clusters at the innervated stage of muscle; (3) adaptor protein Dok-7 acts on MuSK activation for AChR clustering from "inside" and also on cytoskeleton to stabilize AChR clusters by the downstream effector Sorbs1/2; (4) the trans-synaptic retrograde signaling contributes to the presynaptic organization via: (i) Wnt-MuSK CRD-Dvl-β catenin-Slit 2 pathway; (ii) Lrp4; and (iii) laminins. The presynaptic Ca 2+ homeostasis conditioning ACh release is modified by autoreceptors such as M1-type muscarinic AChR and A2A adenosine receptors. The post-synaptic structure is stabilized by: (i) lamininnetwork including the muscle-derived agrin; (ii) the extracellular matrix proteins (including collagen Q/perlecan and biglycan which link to MuSK Ig1 domain and CRD); and (iii) the dystrophin-associated glycoprotein complex. The study on MuSK ectodomains (Ig1/2 domains and CRD) recognized by antibodies suggested that the MuSK antibodies were pathologically heterogeneous due to their binding to multiple functional domains. Focussing one of the matrix proteins, biglycan which functions in the manner similar to collagen Q, our antibody assay showed the negative result in MG patients. However, the synaptic stability may be impaired by antibodies against MuSK ectodomains because of the linkage of biglycan with MuSK Ig1 domain and CRD. The pathogenic diversity of MG is discussed based on NMJ signaling molecules.

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Maintenance immunosuppression in myasthenia gravis, an update

Cited by 50 publications

References 185 publications

Overview of Dual-Acting Drug Methotrexate in Different Neurological Diseases, Autoimmune Pathologies and Cancers

Overview of Dual-Acting Drug Methotrexate in Different Neurological Diseases, Autoimmune Pathologies and Cancers

Immunotherapy choice and maintenance for generalized myasthenia gravis in China

Myasthenia Gravis: From the Viewpoint of Pathogenicity Focusing on Acetylcholine Receptor Clustering, Trans-Synaptic Homeostasis and Synaptic Stability

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