Diagnosis and Treatment of Myasthenia Gravis

Renato Mantegazza; Paola Cavalcante

Disclosures

Curr Opin Rheumatol. 2019;31(6):623-633. 

In This Article

Therapeutic Treatment

Current treatments for myasthenia gravis include symptomatic therapy with cholinesterase inhibitors, immunosuppression, thymectomy in selected patients and plasmapheresis or immunoglobulins for acute exacerbations.[3,4] New biological drugs are promising for refractory disease (approximately 10% of patients), and also to reduce/eliminate chronic immunosuppression and the associated side effects.[6] Myasthenia gravis is clinically heterogeneous and exhibits variable treatment response, hence its treatment should be, as much as possible, personalized and possibly falling into the precision medicine. Therapeutic algorithms for myasthenia gravis, including possible new flow-charts, are shown in Figure 3.

Figure 3.

Therapeutic algorithm for myasthenia gravis. The dashed lines represent future flow-chart of treatment not yet applied. Ab, antibodies; AChR, acetylcholine receptor; IVIG, intravenous immunoglobulin; MG, myasthenia gravis; TPE, therapeutic plasma exchange.

Current Therapies

Most myasthenic patients are chronically treated with immunosuppressive drugs, and prednisone remains essential though with a deleterious side-effect burden.[32] In a recent retrospective study, intravenous methylprednisolone (IVMP) therapy (1000 mg/day administered one to three times within 6 months) was found to provide faster improvements in ocular myasthenic patients compared with conventional oral prednisolone (5–10 mg/day), indicating that IVMP may be a well tolerated and efficient therapeutic option for ocular disease.[33]

Plasma exchange or intravenous immunoglobulin are recommended for severely affected patients. A recent study showed 96% complete response rate to plasma exchange irrespective of antibody status.[34]

Using a multivariate model, an increased dose of corticosteroid therapy, mycophenolate mofetil, and plasma exchange, was associated with infections (e.g. pneumonia, sepsis and opportunistic infections) in a 10-year retrospective study performed including myasthenic patients, thus highlighting the risk of infections with the current immunosuppression.[35]

The beneficial effect of thymectomy in non-thymomatous myasthenia gravis was demonstrated by the MGTX clinical trial[36] and its 2-year extension.[37] Such a benefit was also recently shown in non-thymomatous elderly (≥50 years) patients with generalized myasthenia gravis.[38]

Myasthenia Gravis in the era of 'Biologicals'

Therapies based on biologic drugs, or 'biologicals', targeting molecules involved in the specific immunopathological mechanisms, represent a novel care strategy for myasthenia gravis patients aimed at more specific and effective interventions. The most recent randomized clinical trials (RCT) of biologicals in myasthenia patients are listed in Table 1.

Retrospective studies and meta-analyses showed that rituximab (RTX), a B-cell-depleting monoclonal antibody (mAb) could be beneficial in myasthenia gravis, especially in MuSK-MG.[45,46] Hence, a phase 2 BeatMG (NCT02110706) RCT was performed but did not reach the primary end-point: it was decided not to proceed to a phase 3 study. A recent uncontrolled prospective study showed the beneficial effects of RTX at 12 months on muscle function in 55% of patients with severe, refractory generalized AChR-MG.[47] Furthermore, a low-dose RTX treatment over a 6-month period was able to reduce B cells and to increase regulatory T cells' percentage, thus improving symptoms in refractory generalized myasthenia gravis.[48]

Efficacy and safety of belimumab (BEL), a mAb against the B-cell activating factor (BAFF), was investigated in a phase 2 RCT (NCT01480596; BEL115123) in generalized myasthenia gravis patients, who remained symptomatic despite standard of care:[39] in this study the primary end-point, that is, a mean change from baseline for Quantitative Myasthenia Gravis (QMG) score at week 24, as well as the secondary end-points, were not reached, questioning BEL as possible treatment for myasthenia gravis; however, the small sample size and the mild clinical severity of patients recruited in the study may have jeopardized the final results.

The results of a RCT (NCT02565576) to evaluate safety, tolerability, pharmacokinetics and efficacy of CFZ533, an anti-CD40 mAb inhibiting B-cell activation, in myasthenic patients have not yet been published.

Eculizumab, a mAb preventing the formation of C5b-induced MAC at the NMJ, was used in a phase 3 RCT in refractory generalized AChR-MG without thymoma (REGAIN); its use was well tolerated and clinically relevant: whereas the primary end-point (a statistically significant change of at least points in the myasthenia gravis Activities of Daily Living (MG-ADL) score) was not reached, all the other end-points were reached.[40] Subsequently, both Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved Eculizumab for treatment of myasthenia gravis. Recently, Muppidi et al.[41] reported the results of the open-label extension study of REGAIN showing a long-term safety and a sustained efficacy of eculizumab in refractory generalized myasthenia gravis patients. Furthermore, Eculizumab treatment was associated with improvements in fatigue, strongly correlated with Quality of Life in Neurological Disorders (Neuro-QOL) Fatigue scores, and myasthenia gravis-specific outcome measures (MG-ADL, QMG, and MG-QOL15).[42]

Recently, the first phase 2, cross-over RCT using amifampridine phosphate, a blocker of presynaptic potassium channels, in MuSK-MG patients (MuSK-001) was concluded.[43] Despite the low number of patients, amifampridine phosphate was well tolerated and effective as both the primary and secondary endpoints were reached. A large multicenter phase 3 trial (NCT03579966) to confirm the efficacy of amifampridine phosphate in MuSK-MG is presently recruiting.

The results of a phase 2 exploratory, multicenter RCT in patients with generalized AChR-MG using efgartigimod (NCT02965573), a functional blocker of the neonatal Fc receptor targeting IgGs, have been recently published.[44] Efgartigimod was well tolerated and clinical efficacy was concomitant to a rapid decrease in total IgG and anti-AChR autoantibodies; 75% of patients had a rapid and long-lasting disease improvement using four different scales, suggesting that reducing pathogenic autoantibodies would offer an innovative approach to treat generalized myasthenia gravis.[44] A recent assessment of efgartigimod in a passive transfer mouse model for MuSK-MG revealed reduction of IgG4 titers (about eight-fold), improvement of muscle strength and reduced myasthenic CMAP decrement in treated mice, thus suggesting that this drug could offer a good candidate therapy also for patients with anti-MuSK antibodies.[49]

The new Frontier of Personalized Medicine

Variation in drug response and side effects highlight the importance to develop novel therapeutic strategies for myasthenia gravis, to improve clinical decisions, and hence, therapeutic success via a more targeted choice in individual patients. Thus, the identification of molecular factors able to modulate and predict patient-specific treatment response represents a crucial medical need. Among genetic factors, our previous studies identified an association between response to azathioprine and two haplotypes, the TPMT*3E haplotype in the thiopurine S-methyltransferase and a haplotype in the ATP-binding cassette sub-family C member 6 transporter.[50,51] Moreover, non-responsiveness to glucocorticoid therapy in myasthenic patients was recently associated with genetic variants in the secreted phosphoprotein 1 (SPP1) gene, encoding osteopontin.[52]

Serological levels of free immunoglobulin light chains (FLCs), indicative of B-cell activity, represent a useful predictor of RTX therapeutic efficacy in autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus.[53,54] Recently, Basile et al.[55] demonstrated a significant increase in free κ chains in both AChR-MG and MuSK-MG patients, and a significant reduction of both free κ and λ chains in a MuSK-MG patient after 2 months of RTX treatment, suggesting a potential role of FLC as biomarkers of RTX therapy response in myasthenia gravis patients.

Due to their well known function in modulating both immune response and drug metabolism,[56,57] microRNAs (miRNAs) are promising 'pharmacoepigenetics' markers for autoimmune conditions. Dysregulated miRNA expression has been described in serum, peripheral blood cells and thymus of myasthenic patients,[58,59,60] suggesting a significant contribution of these molecules to the disease pathogenesis, as well as their potential role as predictive biomarkers to improve stratification of patients within a personalized medicine framework. Among miRNAs, circulating miR-21-5p, miR-150-5p and miR-30e-5p were recently found to correlate with clinical improvement after initiation of immunosuppression in late-onset myasthenia gravis patients,[61] and mir-30e-5p was described as predictor of generalization in patients with ocular disease,[62] supporting a potential value of these molecules as disease biomarkers potentially associated with treatment response.

Personalized medicine is a big challenge in autoimmune conditions. Further investigations aimed at revealing serological, pharmacogenomics and pharmaco-miR biomarkers, able to predict patient-specific drug efficacy, promise to open new perspectives towards the development of novel and more efficient personalized therapeutic approaches.

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