Pharmaceutical Treatment Options for Myasthenia Gravis - Research Paper Example

Recent advances in pharmacological management of Myasthenia Gravis (MG). Introduction Myasthenia gravis (MG) is an autoimmune disease characterized by a fluctuating pathological weakness with remissions and exacerbations involving one or several skeletal muscle groups, mainly caused by antibodies to the acetylcholine receptor (AChR) at the post-synaptic site of the neuromuscular junction (Keesey JC, 2004). This affects primarily the musculature, causing loss of facial expression, speech difficulties, and chewing and swallowing problems. Typically, the muscular weakness increases during exercise. When the respiratory muscles are affected, MG becomes life threatening and the patient may enter an MG crisis, requiring intensive care including mechanical ventilation (Bedlack and Sanders, 2000). The neuromuscular junction (NMJ) has the distinction of being the first site of a defined autoantibody mediated neurological disease, namely myasthenia gravis (MG), which is due to autoantibodies to the acetylcholine receptor (AChR) (Vincent, 2002). Other targets at the NMJ include muscle specific kinase (MuSK) in MG patients without AChR antibodies. About 20% of MG patients with generalized disease in Europe, North America and Japan do not have AChR antibodies. These so called 'seronegative' MG patients can be divided into two groups: those with antibodies to MuSK and those without [AChR/MuSK seronegative MG (SN-MG) (Hoch etal, 2001). Mechanism of MG (Osterhuis, 1989) In normal neuromuscular transmission depolarization of the presynaptic nerve terminal produces an influx of calcium through voltage-gated calcium channels. Vesicles containing acetylcholine (ACh) then fuse with the presynaptic nerve terminal membrane. After release, ACh interacts with the acetylcholine receptor (AChR) on the muscle endplate surface. This opens the AChR channel, resulting in an influx of cations, largely sodium. Depolarization of the muscle surface produces an excitatory endplate potential, and if the endplate potential is of sufficient amplitude, muscle surface voltage-gated sodium channels are opened. This generates an action potential that eventually results in excitation-contraction coupling and muscle movement. ACh binds transiently to its receptor and then either diffuses from the neuromuscular junction or is hydrolyzed by acetylcholinesterase (AChE), providing a self-limited response to nerve depolarization. In MG, antibodies are directed against the acetylcholine receptors (AChR antibodies). AChR antibodies interfere with neuromuscular transmission through one of three mechanisms- First, some bind to the AChR cholinergic binding site, blocking the binding of ACh. Second, some AChR antibodies cross-link muscle surface AChRs, increasing their rate of internalization into muscle and reducing the numbers of available AChRs. Third, and perhaps most importantly, AChR antibodies that bind complement result in destruction of the muscle endplate, and a more long-lasting loss of AChRs. Drugs like acetylcholinestrase inhibitors nhibits AChE, increasing the amount of ACh available to interact with available AChRs, thus prolonging the action of Ach, and allowing muscle contraction. Pharmacological treatment Acetylcholinesterase inhibitors are the first pharmacological choice in the treatment of MG. Acetylcholinesterase is an acetylcholine-hydrolyzing enzyme which binds the overflowing acetylcholine in the neuromuscular junction, keeping the junction clean from excessive transmitter. Acetylcholinesterase inhibitors bind to the acetylcholinesterase, inhibiting its action. Pyridostigmine is a more recent long-acting reversible acetylcholinesterase inhibitor. Acetylcholinesterase inhibitors increase the amount of available acetylcholine in the neuromuscular junction. This leads to enhanced binding of acetylcholine to the diminished number of AChRs on the myasthenic muscle cell membrane, causing contractility improvement (Millard and Broom field, 1995) When additional pharmacological treatment is needed, immunosuppressive drugs are the second choice. These are corticosteroids, azathioprine, cyclophosphamide, cyclosporine, and methotrexate. While the steroid effect appears rapidly, the clinical effect of other immunosuppressants may take a few weeks and up to several months to develop. Immunosuppressive drugs act at many levels of the immune system, inhibiting both cellular and humoral mechanisms and reducing the damage caused by autoimmunity in MG (Keesey, 2004). Recent advances in pharmacological management Azathioprine and Cyclophosphamide has been in use for may years, with proven benefit Mycophenolate mofetil (MMF) is a new immunosuppressant in the treatment of MG. It is the most recent advance in the management of MG selectively blocking B- and T-lymphocyte proliferation. It has shown promising results in the treatment of progressive MG (Meriggioli etal, 2003, Allison, 2005). Chaudhry etal, 2001 conducted a retrospective analysis of 38 patients with neuromuscular disorders (32 of whom had MG) treated with MMF for 1 year, and suggested that the drug was effective and well tolerated, with only mild gastrointestinal side effects. The mean delay until onset of improvement was around 10 weeks, with maximum improvement achieved after a mean of 27 weeks. This must be taken into account when treating patients with severe symptoms in whom other more rapidly acting treatment will be required in the short term, although it still compares favourably with azathioprine. As reviewed recently MMF improves 70-75% of MG patients, although it may not be as effective in refractory MG, and seems to be better tolerated and safer than many other immunosuppressive drugs (Ciafaloni, 2005) Tacrolimus (FK506) is a new macrolide immunosuppressant that acts through inhibition of the calcium-calcineurin pathway - a mechanism of action similar to that of cyclosporin. However, when used at a low dose as a corticosteroid sparing medication it seems to be at least as effective as cyclosporin and with fewer side effects, as demonstrated in open prospective or noncontrolled studies (Tsukaguchi etal, 2005, Konishi etal, 2005, Ponseti etal, 2005). The time to onset of action was similar to that for cyclosporin, with an improvement seen in all patients within a month in one study (Ponseti, 2005). Each of these studies confirmed the benefit and safety of tacrolimus in association with corticosteroid tapering in a number of MG patients Cyclosporin has been advocated as a second line agent. Again its use has been there for many years (Lavrnic etal, 2005) Two new biological drug treatments may be useful in therapy resistant cases. Rituximab is a human/mouse chimeric anti-CD20 monoclonal antibody. It induces complement-dependent cytotoxicity against CD20 positive plasma cells. In MG (Wylam etal, 2003), it was used with success in a child with severe refractory MG, and in a patient with a lymphoma, whose myasthenia improved ( Gajra etal, 2004) following the treatment Interestingly, despite substantial falls in AChR antibodies in both cases, there was reassuringly little change in total immunoglobulin G levels, probably because rituximab targets the short lived plasma cells rather than the long lived CD20-negative plasma cells. Etanercept is a recombinant human tumour necrosis factor receptor:Fc that inhibits tumour necrosis factor-[alpha], which is one of the cytokines that has been implicated in the pathogenesis of some autoimmune diseases. Etanercept was tested with success in patients with AChR-MG, but it acts to dysregulate cytokine networks . This treatment should probably only be used in specialized centres, which can perform cytokine evaluation (Rowin etal, 2004) Plasmapheresis removes circulating antibodies, resulting in an improvement of the MG severity within a few days. The concentration of AChR antibody may fall to 50% of its initial level. The intravenous infusion of immunoglobulin modulates the immune response and is almost as fast and effective as the plasmapheresis, but with lower rate of cardiovascular and pulmonary complications. Plasmapheresis and immunoglobulin treatment are indicated in severe cases of MG, such as MG crisis, and in severe MG cases with poor response to standard pharmacological treatment (Richman and Agius, 2003) Summary MG is a progressive autoimmune disease which leads to progressive voluntary muscle weakness. Though rarely life-threatening, it can cause severe physical limitations. The treatment of MG is divided into several categories. Symptomatic treatments improve neuromuscular transmission, but do not affect the underlying immunopathogenesis. The suppression or modulation of the immune system affects the underlying problem. The long-term outlook may be improved by thymectomy. Treatment with intravenous immunoglobulin (IVIg) or plasma exchange is useful when there is significant and progressive weakness of either bulbar or respiratory muscles. Symptomatic treatments in the form of acetylcholinestrase inhibitors are the mainstay of treatment. In cases which do not respond, today there is an increasing role of steroids, and immunosuppressive agents like cyclosporine, MMF and tacrolimus. Plasma pheresis and immunoglobulin are useful in a mysthenic crisis. Thus treatment is more in the form of palliation rather than cure in MG. References 1 Keesey JC. A history of treatments for myasthenia gravis. Semin Neurol 2004; 24:5-16. 2 Bedlack RS, Sanders DB. How to handle myasthenic crisis. Essential steps in patient care. 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