Novel and Emerging Strategies
Rituximab (Rituxan®) is a drug that targets a protein expressed on the surface of B cells called CD20; it leads to destruction of B cells. Rituximab is approved by the Food and Drug Administration (FDA) for the treatment of certain variants of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis (Schuna 2007; Genentech 2013; Harrison 2014; Bryan 2010). Several small clinical trials have reported that rituximab may also be effective for the treatment of myasthenia gravis (Collongues 2012; Lebrun 2009; Sathasivam 2011). One study showed that rituximab worked better in patients who had MuSK antibodies than patients with acetylcholine receptor antibodies. All MuSK+ patients had improvements in symptoms and immunosuppressant drugs were reduced or withdrawn, whereas 6 of 11 patients with acetylcholine receptor antibodies needed further treatment (Diaz-Manera 2012). Side effects associated with rituximab include fever, chills, nausea, vomiting, flushing, and bronchospasms. Severe side effects include infection, low neutrophil count, and the risk of leukoencephalopathy, which affects the white matter of brain (Sathasivam 2011). Additional studies are needed to confirm the possible benefit of rituximab in myasthenia gravis, and results of clinical trials are pending as of the time of this writing (Olivier 2012; Rup 2013).
The complement cascade is a network of approximately 25 proteins in the immune system that helps to amplify an immune response to destroy bacteria. Under normal circumstances, complement proteins circulate in the blood and search for activated antibodies attached to bacteria. The first protein in the complement system recognizes the activated antibody and binds to it causing the activation of the complement cascade. Binding of the remaining complement proteins results in the insertion of a cylindrical complex – the membrane attack complex (MAC) – into the cell wall of a bacterium, causing its eventual destruction (NIAID 2008). Scientists have shown that the complement cascade also plays an important role in the development of myasthenia gravis. Self-antibodies against the acetylcholine receptor cause complement proteins to bind to sites at the nerve-muscle junction (Jayam Trouth 2012). Complement activation might be an important pathogenic mechanism in myasthenia gravis, even in patients without acetylcholine receptor antibodies (Vincent 2008). This leads to the destruction of the cell membrane of muscle cells. Components of the complement system and the MAC are often observed in the serum and at the nerve-muscle junction in patients with myasthenia gravis. Many experimental studies have shown that inhibition of the complement cascade improves symptoms of myasthenia gravis (Kusner 2012), and researchers are examining the effect of targeting the complement system in clinical trials. A small phase II study showed that a drug called eculizumab (Soliris®), which inhibits the complement system, reduced symptoms of myasthenia gravis more than a placebo after 16 weeks of treatment, and it was well tolerated (Howard 2013). Additional results are expected from a larger phase III study involving myasthenia gravis patients (ALXN 2014).
Granulocyte Macrophage Colony-Stimulating Factor
Granulocyte macrophage colony-stimulating factor (GM-CSF) is a protein that helps stimulate the immune system to fight infection. It is primarily used in patients following chemotherapy to prevent the decrease of certain immune cells called neutrophils. GM-CSF also plays an important role in enhancing the suppressive activity of regulatory T cells (Treg). Given that defects in regulatory T cells are known to mediate the development of myasthenia gravis (Thiruppathi, Rowin, Li Jiang 2012), agents that stimulate their activity may be effective treatment options. A case study reported on a 77 year old patient who had prolonged myasthenia crisis and was resistant to standard immunomodulating agents. The patient was treated with 750 mcg of GM-CSF daily for 2 days, followed by 250 mcg daily for an additional 3 days. GM-CSF treatment significantly improved the patient’s symptoms and the activity of regulatory T cells (Rowin 2012). A pilot study assessing the effect of GM-CSF in myasthenia gravis is pending enrollment as of the time of this writing (Meriggioli 2012b).
Many patients with myasthenia gravis have high serum levels of a protein called B cell activating factor (BAFF) (Thangarajh 2006). BAFF is a protein that helps B cells survive, and high levels of BAFF in patients with myasthenia gravis may allow B cells to produce self-antibodies. Belimumab (Benlysta®), a drug that inhibits BAFF, is FDA-approved for the treatment of systemic lupus erythematosus (Ragheb 2011). A phase II study is recruiting patients as of the time of this writing to determine if belimumab is effective in treating myasthenia gravis (GSK 2014).
Etanercept (Enbrel®) is a drug that inhibits a protein called tumor necrosis factor-alpha (TNF-α) (Shi 2013). TNF-α is involved in inflammation and contributes to the development of several autoimmune diseases, including rheumatoid arthritis (Kodama 2005; Feldmann 2001). Etanercept is FDA-approved for the treatment of rheumatoid arthritis and plaque psoriasis (Haraoui 2007; Nguyen 2009). TNF-α is believed to play a role in the development of myasthenia gravis through its pro-inflammatory effects. Furthermore, a certain variant of the TNF-α gene is associated with early onset myasthenia gravis in some women. This version also leads to increased production of TNF-α (Huang 1999). A small pilot trial of etanercept in myasthenia gravis patients found that six out of eight patients who completed the trial had significant improvements in symptoms, while two patients had worsening of symptoms (Rowin 2004). However, a recent case study reported that a patient developed myasthenia gravis while taking etanercept and the symptoms resolved after the patient stopped taking the drug (Fee 2009). Additional studies are needed to determine if etanercept is an effective treatment option for myasthenia gravis and which patients could benefit from it.