Long-term results of corticosteroid therapy in patients with myasthenia gravis.In chronic autoimmune conditions such as myasthenia gravis MGimmunosuppression--usually long-term--is often necessary. The mechanisms of action of immunosuppressant drugs in MG fall into three main categories: Data on immunosuppressant corticosteroid treatment myasthenia gravis in MG derive mainly from clinical experience, observational studies and expert opinion. The main drawbacks of the randomized evidence are the small size of most treatmebt trials, variations in study design, and a lack of head-to-head studies. It is therefore difficult to determine the relative efficacy of each immunosuppressant.
Long-term results of corticosteroid therapy in patients with myasthenia gravis. - PubMed - NCBI
Mar 26, Author: Edrophonium is primarily used as a diagnostic tool owing to its short half-life. Pyridostigmine is used for long-term maintenance. High doses of corticosteroids commonly are used to suppress autoimmunity. Patients with MG also may be taking other immunosuppressive drugs eg, azathioprine or cyclosporine.
Adverse effects of these medications must be considered in assessment of the clinical picture. Bronchodilators may be useful in overcoming the bronchospasm associated with a cholinergic crisis. Anticholinesterase inhibitors interfere with the degradation of acetylcholine ACh by AChE, thereby increasing the amount of ACh available at the neuromuscular junction NMJ and increasing the chance of activating the acetylcholine receptors AChRs.
AChE inhibitors continue to be used as first-line treatment of MG. The improvement is usually partial and frequently decreases after many weeks to months of treatment. Besides, these agents are not as beneficial for ocular MG as for generalized MG. Hence, they often are complemented and sometimes replaced with immunosuppressive therapy.
Pyridostigmine acts in smooth muscle, the central nervous system CNS , and secretory glands, where it blocks the action of ACh at parasympathetic sites. An intermediate-acting agent, it is preferred in clinical use to the shorter-acting neostigmine bromide and the longer-acting ambenonium chloride.
It starts working in minutes; effects last hours. Individualize the dose; MG does not affect all skeletal muscles similarly, and all symptoms may not be controllable without adverse effects.
In critically ill or postoperative patients, administer the drug intravenously IV. In the United States, pyridostigmine is available in 3 forms: Dosing half hour before meals may help in swallowing and reduce the risk of aspiration. The effects of the timespan tablet last 2. The timespan form is a useful adjunct to regular pyridostigmine for nighttime control of myasthenic symptoms.
The absorption and bioavailability of the timespan tablet vary among subjects. It should be used only at bedtime, and patients need close monitoring for cholinergic adverse effects. Patients can develop cholinergic side effects secondary to the accumulation of ACh at muscarinic and nicotinic receptors. Muscarinic side effects include nausea, vomiting, abdominal cramping, diarrhea, increased oral and bronchial secretions, bradycardia, and sometimes confusion or psychosis.
When patients develop significant side effects, pretreatment with anticholinergic medications is recommended eg, propantheline, glycopyrrolate, or diphenoxylate with atropine 30 minutes before taking pyridostigmine.
Its half-life is minutes. It is poorly absorbed from the gastrointestinal GI tract and should be used only if pyridostigmine is unavailable. Individualize the dose for all patients. Edrophonium is primarily used as diagnostic tool to predict the response to longer-acting cholinesterase inhibitors.
Like other cholinesterase inhibitors, it decreases the metabolism of ACh, increasing the cholinergic effect at the NMJ. It was used in the past to distinguish between cholinergic and myasthenic crisis. If IV edrophonium resultsed in worsening of symptoms, the increased weakness in patients is probably due to overdosing the anticholinesterase medication.
If weakness, on the other hand, improves following edrophonium, the weakness is due to the underlying MG.
Corticosteroids are anti-inflammatory and immunomodulating agents used to treat idiopathic and acquired autoimmune disorders. They were among the first immunomodulating agents used to treat MG and still are used frequently and effectively. They are typically used in moderate or severe cases that do not respond adequately to AChE inhibitors and thymectomy.
Long-term treatment with corticosteroids is effective and may induce remission or cause marked to moderate improvement in most patients. Transient worsening might occur initially; clinical improvement then shows after weeks with maximal effect in months.
These agents are usually given over 1 or 2 years before tapering is begun. Corticosteroids act in both ocular MG and generalized MG. They can be combined with other immunosuppressive medications for better effect with lesser dose and shorter duration of administration. Pulsed IV steroids might be beneficial in refractory patients. Prednisone is most commonly used corticosteroid in the United States. Some experts believe that the long-term administration of prednisone is beneficial, but others use the drug only during acute exacerbations to limit the adverse effects of chronic steroid use.
Prednisone is effective in decreasing the severity of MG exacerbations by suppressing the formation of autoantibodies. However, clinical effects often are not seen for several weeks.
Significant improvement, which may be associated with a decreased antibody titer, usually occurs in months. An alternate-day regimen may minimize adverse effects. A trial of steroid withdrawal may be attempted, but most patients on long-term corticosteroid therapy relapse and require re-institution of steroids. Chronic administration of corticosteroids is associated with numerous serious side effects. The risk of infection, diabetes mellitus, hypotension, glaucoma, osteoporosis, steroid myopathy, and aseptic necrosis of the joints are some examples.
It is prudent to obtain chest X-ray, PPD skin test, and a detailed history of exposure to tuberculosis, strongyloides, or other organisms that may grow as a result of the chronic administration of corticosteroids.
Measurement of DEXA at baseline and every months while the patient is on corticosteroids is recommended. Prophylactic treatment with histamine-H2 receptor blockers are usually not required. BP monitoring, periodic eye exam to check for glaucoma and cataracts is recommended.
Fasting blood glucose, serum potassium levels should be periodically checked. Potassium may be supplemented if the patient becomes hypokalemic. High dose steroids and lack of physical activity can lead to type 2 muscle fiber atrophy with proximal muscle weakness. Distinction from myasthenic weakness is important and is challenging.
Patients who become weaker during a prednisone taper, and show craniobulbar, and upper extremity muscle weakness, and demonstrate worsening of their decremental response on RNS are more likely to experience worsening of their myasthenia gravis symptoms. In contrast, patients who are continued on high doses of corticosteroids, normal RNS, and other evidence of steroid induced toxicity i.
Methylprednisolone may be used in place of prednisone in patients who are intubated and in those unable to tolerate oral intake. It decreases inflammation by suppressing the migration of polymorphonuclear PMN leukocytes and reversing increased capillary permeability. MG is an autoimmune disease, and immunomodulatory therapies have been used for these disorders since introduction of steroids.
Although no rigorous clinical trials have established the efficacy of immunomodulatory therapies in MG, several uncontrolled trials and retrospective studies support use of such therapies. Azathioprine is an imidazolyl derivative of 6-mercaptopurine 6-MP. Many of its biological effects are similar to those of its parent compound. Both compounds are eliminated rapidly from the blood and are oxidized or methylated in erythrocytes and liver.
No azathioprine or 6-MP is detectable in urine 8 hours after being taken. The mechanism whereby it affects autoimmune diseases is unknown. It works primarily on T cells, suppresses hypersensitivities of the cell-mediated type and causing variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity tests are suppressed to a greater degree than antibody responses.
Azathioprine is the second most commonly used immunosuppressive medication in MG. It is reserved for patients with either steroid failure or unacceptable effects from prolonged steroid use.
Furthermore, it can be used for steroid-sparing effects to lower steroid doses. One drawback is that it works very slowly; it may require months to exert its therapeutic effect. Azathioprine is available in tablet form for oral administration or in mg vials for IV injection. Maximal effect is years. Check TPMT thiopurine methyltransferase enzyme activity. Heterozygous individuals for TPMT are given azathioprine in smaller doses and monitored carefully. Not to be used with allopurinol as the combination can result in bone marrow suppression and liver toxicity.
Concurrent administration of allopurinol can increase azathioprine toxicity by interfering with its metabolism by xanthine oxidase, an important degradative pathway. Azathioprine is a useful and generally well-tolerated agent in MG. If the patient is not already receiving corticosteroids, obtain an anergy panel, including a PPD, and check that a recent x-ray film has been taken.
Patients who have been receiving a stable dose for greater than 2 years and who have shown no signs of toxicity can be monitored 2 to 3 times per year. Upward adjustment of dose or signs of toxicity require returning to weekly monitoring and going through the same cycle. Macrocytosis is not an indication of discontinuation of therapy.
Leukopenia can present within a week or as late as 2 years after intiating azathioprine. This measure cannot be used in patients receiving prednisone, because of the steroid-induced leukocytosis. If LFTs show transaminases trend upwards of times of normal values, the medication is held.
This can be typically seen within a month of starting the medication. Side effects that may respond to lowering of the dose or dividing the daily dose to twice or three times a day include epigastric distress, nausea and vomiting, stomatitis, oral thrush, increased susceptibility to infections, marrow suppression, or increase in hepatocellular or obstructive liver chemistries. The majority of patients benefit from the drug and tolerate it long term years. Generally, leucopenia reverses within 1 month and hepatotoxicity usually takes several months to resolve.
Very little evidence has shown an increased incidence of neoplasm from azathioprine in the doses generally used in MG. The major disadvantage of azathioprine is the delay in therapeutic effect; it takes months to see a clinical effect, and it may take more than 12 months for maximal effect.
An adequate therapeutic trial with azathioprine should last at least years, since the lag to onset of effect may range from months, and the point of maximum benefit may be delayed years. Cyclosporine A is an amino acid cyclic peptide that is a natural product of fungi.