Which medications in the drug class Immunomodulators are used in the treatment of Myasthenia Gravis?

Updated: Aug 27, 2018
  • Author: Abbas Jowkar, MD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Answer

Immunomodulators

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. The therapies used in MG include prednisone, azathioprine, IV immunoglobulin (IVIg), plasmapheresis, and cyclosporine.

Azathioprine (Imuran, Azasan)

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.

Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. 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 12-18 months to exert its therapeutic effect. Up to 10% of patients may have idiosyncratic reaction disallowing use. Do not allow the white blood cell (WBC) count to drop below 3000/µL or the lymphocyte count to drop below 1000/µL.

Azathioprine is available in tablet form for oral administration or in 100-mg vials for IV injection.

Administer 2-3 mg/kg PO daily or BID; begin with a low initial dose. Maximal effect is 1-2 years.

The disadvantage of using this product is that it increases the risk of eoplasia, immunosuppression, pancytopenia, pancreatitis, and hepatotoxicity.

It is not for use in pregnant patients.

The drug causes flu-like symptoms, bone marrow suppression, and LFTs abnormalities. About 10% of patients do not tolerate the drug.

Check TPMT (thiopurine methyltransferase) enzyme activity. If the individual is homozygous for TPMT (1:300), do not give azathioprine as these individuals are unable to metabolize azathioprine and may have myelosuppression. 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. Reduce azathioprine dose by as much as 75% in patients who take allopurinol.

Perform a CBC to check WBC for the first few months of starting treatment. Azathioprine is a useful and generally well-tolerated agent in MG. The usual dosage is 2-3 mg/kg/day. Approximately 5-10% of individuals have idiosyncratic reaction with fever, nausea, and vomiting, sometimes accompanied by eosinophilia or increased hepatocellular enzymes at the initiating dose. Obtain a baseline CBC and differential, platelet count, and LFTs (ALT, AST, and ALP). 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.

Therapy starts with 50 mg/day for 5 days, blood tests are checked, and the dosage is increased by 50 mg/day every 5 days, with blood tests checked before each increase. After reaching 150 mg/day, increase 25 mg/day every 5 days, checking the blood studies. At 2 to 2.5 mg/kg/day, observe the patient for 3-4 months. If the patient has not started to show clinical improvement and an increase in red blood cell (RBC) mean cell volume (MCV; increase in MCV of >100 fL is a useful indicator of a therapeutic dose, in the absence of concomitant iron deficiency), increase dose again by 25 mg/day to 3 mg/kg/day.

CBC and LFTs are monitored every 2 weeks  for several months, until a stable dose of azathioprine is achieved. 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. WBC 3-4K/mm3 is a safe endpoint. If WBC falls <2.5K/mm3 or the absolute neutrophil count is less than 1000/mm3, azathioprine should be briefly discontinued, then reintroduced at a lower dose. 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. In that situation, an absolute lymphocyte count of  5-10% is an appropriate target. If LFTs show transaminases trend upwards of 2-3 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 3-4 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 1-2 years, since the lag to onset of effect may range from 3-12 months, and the point of maximum benefit may be delayed 1-3 years.

Cyclosporine A (Neoral, Sandimmune, Gengraf)

Cyclosporine A is an 11-amino acid cyclic peptide that is a natural product of fungi. It acts on T-cell replication and activity. It is a specific modulator of T-cell function and an agent that depresses cell-mediated immune responses by inhibiting helper T-cell function. Preferential and reversible inhibition of T lymphocytes in the G0 or G1 phase of the cell cycle is suggested.

Cyclosporine binds to cyclophilin, an intracellular protein, which, in turn, prevents formation of interleukin (IL)–2 and subsequent recruitment of activated T cells. It has about 30% bioavailability, but there is marked individual variability. It specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that drug be present during first 24 h of antigenic exposure.

Cyclosporine A suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease) for a variety of organs.

Cyclosporine A is used as a second-line immunosuppressive agent and has been shown effective in patients with MG in prospective, double-blind, placebo-controlled clinical trial. This agent does have some significant adverse effects (more serious than those of azathioprine), which usually preclude its use as first-line immunosuppressive therapy. However, in patients who are at high risk for adverse steroid effects, it can be used as initial therapy. The onset of action is within a few weeks to months, similar to that of prednisone.

Administer 2.5-4 mg/kg/day divided BID with a fat-containing meal or snack.

The onset of action for this agent is 2-4 months with optimum effect to be observed in 7 months.

The advantage of this product is that it is a steroid-sparing immunosuppression; not cytotoxic but selectively immunomodulatory.

Disadvantages include increased risk of neoplasia, skin malignancy, HTN, renal failure, immunosuppression, hepatotoxicity, seizures, PRES (posterior reversible encephalopathy syndrome), increased ICP, and tremor. It also has a broad range of interactions with many drugs.

Metabolized in liver CYP450 system, and excreted in bile; potentiates risk of necrotizing myopathy or myoglobinuria due to lovastatin, which also depends on biliary excretion. It is lipid soluble.

Corticosteroids increase plasma cyclosporine levels.

MG improvement noted in about 2 weeks, with maximal improvement by 4 months, correlating with reduction in AChR antibody levels.

Monitor plasma cyclosporine trough levels every 3 weeks until stable, then monthly. Trough levels are measured in the morning 12 hours after last dose. Trough levels should be maintained between 100–200 ng/mL. Decrease dose if Cr rises above 1.4 times the baseline level.

Common side effects include HTN, PRES (posterior reversible encephalopathy syndrome), and nephrotoxic (especially elderly). Facial hirsutism, GI disturbances, headache, tremor, convulsions, and hepatotoxicity are related to drug levels and are reversible with dose reduction. When used concurrently, NSAIDs will potentiate cyclosporine nephrotoxicity.   

Cyclophosphamide

Cyclophosphamide is an alkylating agent that interferes with cell proliferation. It is more effective against B cells than against T cells, which makes it a good choice in an antibody-mediated disease such as MG. Because of potential for serious side effects (ie, gastrointestinal upset, bone marrow toxicity, alopecia, hemorrhagic cystitis, teratogenicity, sterilization, and increased risk of infections and secondary malignancies), it is usually reserved for more severe cases where more routinely used immunotherapy has failed because of lack of efficacy or intolerable adverse effects.

Mycophenolate mofetil (CellCept)

Mycophenolate mofetil, a derivative of mycophenolic acid (MPA), blocks the de novo pathway of guanosine nucleotide synthesis by inhibiting the activity of inosine monophosphate dehydrogenase and thus inhibiting de novo purine synthesis. Both T and B lymphocytes are highly dependent upon the de novo pathway, whereas other cells use the purine salvage pathway of nucleotide synthesis. As a result, MPA selectively inhibits lymphocyte activity.

Mycophenolate mofetil has been shown to be effective in MG and is recommended as a steroid-sparing immune modulator.

The starting dose is 250 mg PO BID for 5 days, then 500 mg PO BID for 5 days, then 1 g PO BID

Its onset of action is 2-4 months with maximal effect observed at 5-6 months.

The advantage to using this agent is that it acts through steroid-sparing immunosuppression.

The disadvantages include increased risk of lymphoma, immunosuppression, teratogenicity risk, pancytopenia, GIB, renal failure, acute ILD, and HTN. It may also cause nausea, diarrhea, abdominal pain, fever, leukopenia, and edema.

Mycophenolate mofetil is an immunosuppressive drug with a mode of action similar to azathioprine. Its major advantage is that its effect seems to be limited to lymphocytes. Thus, although lymphocytes may be reduced in function and number, there is no effect on liver function tests and no effect on either RBC or PMN counts. Several uncontrolled studies have reported efficacy, and some also suggest that mycophenolate mofetil has a quicker mode of onset than azathioprine, particularly at 1 g BID. 

Begin with 500 mg BID, and if the drug is tolerated, increase the dose to 1 g bid after 4 weeks. If diarrhea occurs, try 1 to 1.5 g/day. Other side effects include gastrointestinal hemorrhage and perforation; increased susceptibility to infections is a consideration with all of these agents, particularly in combination with corticosteroids. Neutropenia is generally associated with doses of 2 g/day or greater. Mycophenolate mofetil eventually may replace azathioprine as the first-line immunosuppressive drug in patients with MG, but further studies are required.

Monitor blood tests weekly for the first month of treatment, twice monthly for the second and third months, and then monthly thereafter.

It is used sometimes as an adjuvant drug in combination with cyclosporine and prednisone. It is the preferred drug for elderly myasthenics.

Methotrexate (Otrexup, Rasuvo, Trexall)

Methotrexate is not used frequently in myasthenia gravis, although it may be effective. It has an earlier onset of action compared to azathioprine. It may be initiated orally at 7.5 mg/week given in three divided doses 12 hours apart. It is gradually increased by 2.5 mg a week up to 25 mg/week as necessary. Major side effects include alopecia, stomatitis, interstitial lung disease, teratogenicity, oncogenicity, risk of infection, pulmonary fibrosis, renal, liver, and bone marrow toxicities. Doses of over 50 mg a week are rarely used for MG as this may require leukovorin rescue. Patients are given folate along with methotrexate.


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