Immunotherapy in myasthenia gravis in the era of biologics

• Published in: Nature reviews. Neurology Vol. 15; no. 2; pp. 113 - 124
• Main Author: Dalakas, Marinos C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2019; Nature Publishing Group
• Subjects: 631/61/51; 692/617/375/374; 692/700/565/251; Biological products; Biological Products - therapeutic use; Care and treatment; Forecasts and trends; Health aspects; Humans; Immunoglobulins; Immunologic Factors - immunology; Immunosuppressive Agents - therapeutic use; Immunotherapy; Immunotherapy - methods; Immunotherapy - trends; Medicine; Medicine & Public Health; Methods; Monoclonal antibodies; Myasthenia gravis; Myasthenia Gravis - diagnosis; Myasthenia Gravis - drug therapy; Myasthenia Gravis - immunology; Neurology; Review Article; United States
• ISSN: 1759-4758; 1759-4766
• DOI: 10.1038/s41582-018-0110-z

No consensus has been reached on the ideal therapeutic algorithm for myasthenia gravis (MG). Most patients with MG require induction therapy with high doses of corticosteroids and maintenance with an immunosuppressant. Severe cases and acute worsening require intravenous immunoglobulin or plasmapheresis before oral immunosuppressants start having an effect. However, biologics are emerging as important therapeutic tools that promise to provide better corticosteroid sparing effects than standard treatments and can even induce remission. In particular, eculizumab, a monoclonal antibody against complement C5, has been approved by the FDA for refractory MG on the basis of a phase III trial. Rituximab, an anti-CD20 monoclonal antibody that depletes peripheral B cells, has also been effective in many large uncontrolled series, although was not in a small phase III trial. Whether the newer anti-CD20 agents ocrelizumab, ofatumumab, obinutuzumab, ublituximab or inebilizumab will be more effective remains unclear. Belimumab, an antibody against the B cell trophic factor BAFF, was ineffective in phase III trials, and efgartigimod, which depletes antibodies, was effective in a phase II study. Some anti-cytokine agents relevant to MG immunopathogenesis also seem promising. Checkpoint inhibitors can trigger MG in some patients, necessitating early intervention. Increased availability of new biologics provides targeted immunotherapies and the opportunities to develop more specific therapies.
Biologics are emerging as important therapeutic tools in myasthenia gravis. In this Review, Marinos Dalakas considers the promise of these drugs and how they could overcome the limitations of current standard treatments.
Key points
In myasthenia gravis (MG), the clinical phenotype and the type of circulating antibodies that are present have the greatest influence on therapeutic decisions and outcomes.
Targeted immunotherapy seems to be the most promising therapeutic approach in MG because it can effectively overcome the limitations of current nonspecific immunotherapies and has the potential to induce remission.
Biologics that are relevant to treating MG target B cells, molecules associated with T cell activation, complement, the neonatal crystallizable fragment of immunglobulin G antibodies, and cytokines associated with antibody production.
The checkpoint inhibitors that are used for the treatment of advanced malignancies have a paradoxical effect that means they can trigger MG that requires early recognition and prompt immunotherapy.
In the era of biologics, more-effective therapies are creating a need for new criteria that define clinical responses and remission, and for better outcome measures and biomarkers to assess clinical benefits.
Several outdated or unverified views, including unsubstantiated concerns that exercise or administration of common drugs, such as antibiotics or statins, can worsen MG symptoms, need to be revisited.