Changes in serum complements and their regulators in generalized myasthenia gravis

Ozawa, Yukiko; Uzawa, Akiyuki; Yasuda, Manato; Kojima, Yuta; Oda, Fumiko; Himuro, Keiichi; Kawaguchi, Naoki; Kuwabara, Satoshi

doi:10.1111/ene.14500

Cited by 12 publications

(11 citation statements)

References 32 publications

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“…Circulating levels of C3 and C4 have been investigated in MG with divergent results. Their levels were found to be the same as those found in HC [ 40 , 41 ] or conversely, the levels of C3 and C4 were reduced in MG patients [ 42 , 43 ]. Additionally, increased levels of soluble C5b-9 were found in MG patients in comparison to HCs [ 41 ] and C5a levels showed a positive correlation with disease severity [ 40 ].…”

Section: Discussionmentioning

confidence: 60%

“…Their levels were found to be the same as those found in HC [ 40 , 41 ] or conversely, the levels of C3 and C4 were reduced in MG patients [ 42 , 43 ]. Additionally, increased levels of soluble C5b-9 were found in MG patients in comparison to HCs [ 41 ] and C5a levels showed a positive correlation with disease severity [ 40 ]. While we identified six patients with diminished complement activity, determining which components were reduced was outside of the scope of the study.…”

Section: Discussionmentioning

confidence: 60%

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Myasthenia gravis complement activity is independent of autoantibody titer and disease severity

et al. 2022

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Acetylcholine receptor (AChR) autoantibodies, found in patients with autoimmune myasthenia gravis (MG), can directly contribute to disease pathology through activation of the classical complement pathway. Activation of the complement pathway in autoimmune diseases can lead to a secondary complement deficiency resulting in reduced complement activity, due to consumption, during episodes of disease activity. It is not clear whether complement activity in MG patients associates with measurements of disease activity or the titer of circulating pathogenic AChR autoantibodies. To explore such associations, as a means to identify a candidate biomarker, we measured complement activity in AChR MG samples (N = 51) using a CH50 hemolysis assay, then tested associations between these values and both clinical status and AChR autoantibody titer. The majority of the study subjects (88.2%) had complement activity within the range defined by healthy controls, while six patients (11.8%) showed reduced activity. No significant association between complement activity and disease status or AChR autoantibody titer was observed.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 60%

Myasthenia gravis complement activity is independent of autoantibody titer and disease severity

et al. 2022

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“…16 Later, in-vivo studies found that MG patients have higher serum levels of C5b-9 and that C5a levels are positively correlated with MG disease severity. 17 , 18 …”

Section: Complement and Its Role In Myasthenia Gravis ( Fig...mentioning

confidence: 99%

Practical Management for Use of Eculizumab in the Treatment of Severe, Refractory, Non-Thymomatous, AChR + Generalized Myasthenia Gravis: A Systematic Review

Waheed¹,

Newman²,

Aboukhatwa³

et al. 2022

TCRM

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Myasthenia gravis (MG) is a rare autoimmune disorder caused by specific autoantibodies at the neuromuscular junction. MG is classified by the antigen specificity of these antibodies. Acetylcholine receptor (AChR) antibodies are the most common type (74–88%), followed by anti-muscle specific kinase (MuSK) and other antibodies. While all these antibodies lead to neuromuscular transmission failure, the immuno-pathogenic mechanisms are distinct. Complement activation is a primary driver of AChR antibody-positive MG (AChR+ MG) pathogenesis. This leads to the formation of the membrane attack complex and destruction of AChR receptors and the postsynaptic membrane resulting in impaired neurotransmission and muscle weakness characteristic of MG. Broad-based immune-suppressants like corticosteroids are effective in controlling MG; however, their long-term use can be associated with significant adverse effects. Advances in translational research have led to the development of more directed therapeutic agents that are likely to alter the future of MG treatment. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of complement protein C5 and is approved for use in generalized MG. In this review, we discuss the pathophysiology of MG; the therapeutic efficacy and tolerability of eculizumab, as well as the practical guidelines for its use in MG; future studies exploring the role of eculizumab in different stages and subtypes of MG subtypes; the optimal duration of therapy and its discontinuation; the characterization of non-responder patients; and the use of biomarkers for monitoring therapy are highlighted. Based on the pathophysiologic mechanisms, emerging therapies and new therapeutic targets are also reviewed.

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“…Moreover, Ozawa et al reported higher serum levels of sC5b9 in AChR‐Ab positive patients with gMG than in healthy volunteers [16]. Conversely, Romi et al [17] and Liu et al [18] reported lower serum levels of the uncleaved C3 or C4 components in AChR‐Ab + MG patients than in healthy volunteers, again suggesting increased consumption due to activation.…”

Section: Discussionmentioning

confidence: 99%

Complement activation profiles in anti‐acetylcholine receptor positive myasthenia gravis

Stascheit

Chuquisana

Keller

et al. 2023

Euro J of Neurology

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Background and purpose: Complement component 5 (C5) targeting therapies are clinically beneficial in patients with acetylcholine receptor antibody + (AChR-Ab + ) generalized myasthenia gravis (MG). That clearly implicates antibody-mediated complement activation in MG pathogenesis. Here, classical and alternative complement pathways were profiled in patients from different MG subgroups. Methods: In a case-control study, concentrations of C3a, C5a and sC5b9 were simultaneously quantified, indicating general activation of the complement system, whether via the classical and lectin pathways (C4a) or the alternative pathway (factors Ba and Bb) in MG patients with AChR or muscle-specific kinase antibodies (MuSK-Abs) or seronegative MG compared to healthy donors. Results: Treatment-naïve patients with AChR-Ab + MG showed substantially increased plasma levels of cleaved complement components, indicating activation of the classical and alternative as well as the terminal complement pathways. These increases were still present in a validation cohort of AChR-Ab + patients under standard immunosuppressive therapies; notably, they were not evident in patients with MuSK-Abs or seronegative MG. Neither clinical severity parameters (at the time of sampling or 1 year later) nor anti-AChR titres correlated significantly with activated complement levels. Conclusions: Markers indicative of complement activation are prominently increased in patients with AChR-Ab MG despite standard immunosuppressive therapies. Complement inhibition proximal to C5 cleavage should be explored for its potential therapeutic benefits in AChR-Ab + MG.

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Changes in serum complements and their regulators in generalized myasthenia gravis

Cited by 12 publications

References 32 publications

Myasthenia gravis complement activity is independent of autoantibody titer and disease severity

Myasthenia gravis complement activity is independent of autoantibody titer and disease severity

Practical Management for Use of Eculizumab in the Treatment of Severe, Refractory, Non-Thymomatous, AChR + Generalized Myasthenia Gravis: A Systematic Review

Complement activation profiles in anti‐acetylcholine receptor positive myasthenia gravis

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