Chronic inflammatory demyelinating polyradiculoneuropathy
Sep. 05, 2022
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Mycophenolate mofetil is the semisynthetic morpholinoethyl ester of mycophenolate acid, which has been developed as an immunosuppressive agent to prevent rejection of transplanted organs. It was commercialized as CellCept by Hoffmann-La Roche. Mycophenolic acid was originally used to treat psoriasis in the 1970s. More recently, this agent has been used to treat several inflammatory conditions, including systemic lupus erythematosus, particularly in lupus nephritis. Currently it is in clinical trials for autoimmune myasthenia gravis, which will be the focus of this article. However, the knowledge of clinical pharmacology and safety of this drug is based on use in transplant patients, the only approved use.
Pharmacodynamics. Mycophenolate is a suppressor of T-cell proliferation and adhesion. Its primary mode of action is inhibition of inosine monophosphate dehydrogenase, a purine salvage pathway required by T lymphocytes. Moreover, mycophenolic acid is a 5-fold more potent inhibitor of the type II isoform of inosine monophosphate dehydrogenase, which is expressed in activated lymphocytes, than of the type I isoform of inosine monophosphate dehydrogenase, which is expressed in most cell types. Therefore, mycophenolic acid has a more potent cytostatic effect on lymphocytes than on other cell types. As the use of mycophenolate for indications other than organ transplantation is being explored, additional effects of the drug have been observed. Mycophenolate improves neuromuscular junction function in myasthenia gravis as demonstrated by single fiber EMG and is considered a useful biomarker of early response in clinical trials.
Pharmacokinetics. Following oral administration, mycophenolate mofetil is rapidly and completely absorbed and is rapidly converted to its active form, mycophenolic acid, on reaching the systemic circulation. Systemic plasma clearance of intravenous mycophenolate mofetil is approximately 10 L/min in healthy individuals, and plasma mycophenolate mofetil concentrations fall below the measurable level within 10 minutes of the cessation of infusion. Mycophenolate is metabolized to its glucuronide metabolite, mycophenolic acid glucuronide, by glucuronyl transferases in the liver and possibly elsewhere, which is then excreted by the kidney. Mycophenolate is extensively and avidly bound to serum albumin.
Pharmacogenetics. Elimination of mycophenolate mofetil in patients varies according to UGT1A8 gene polymorphisms, which can affect the activity of UDP-glucuronosyltransferase, the key metabolic enzyme for this drug (32).
In an open-label study of 12 patients with refractory myasthenia gravis, 8 patients improved following treatment with mycophenolate without major side effects (04). A retrospective analysis of the use of mycophenolate in 85 patients with autoimmune myasthenia gravis has been carried out (16). Improvement was seen in 73% of patients as was assessed by the Myasthenia Gravis Foundation of America postintervention status. A subsequent double-blind, placebo-controlled study showed that mycophenolate treatment was effective in autoimmune myasthenia gravis (17). Limited evidence from Cochrane Database Systematic Review based on a few available randomized clinical trials showed no significant benefit from mycophenolate mofetil as monotherapy or with either corticosteroids or ciclosporin (10). Better designed trials of longer duration are needed.
Retrospective analysis of data from 102 patients with AChR-antibody-positive myasthenia gravis shows that mycophenolate starts to produce improvement after 6 months, both in combination with prednisone and as monotherapy (11).
An ongoing prospective, multicenter observational cohort study is comparing the effectiveness of azathioprine and mycophenolate mofetil as treatments for myasthenia gravis with a patient-centered primary outcome measure to guide clinicians, patients, and payers regarding the choice of treatment options (ClinicalTrials.gov identifier: NCT03490539). The study started in 2018 and expected completion date is November 2020.
An ongoing observational cohort trial in the real-world clinical setting is recruiting new-onset ocular myasthenia patients in different regions of China with treatment choice between steroids, azathioprine, tacrolimus, and mycophenolate mofetil (ClinicalTrials.gov identifier: NCT04182984). Patients are followed up prospectively on regular to assess the outcomes of treatments and monitor any side effects. The study started in December 2019 and estimated completion date is November 2024.
Mycophenolate is approved for prevention of rejection in patients receiving heart, kidney, and liver transplants.
• According to the Myasthenia Gravis Foundation of America patient registry, 24% of the patients have been treated with mycophenolate (05).
• A randomized study demonstrated no benefit of mycophenolate 20 mg/day with prednisone compared to 20 mg/day of prednisone alone after 12 weeks in patients with myasthenic weakness (20). A prospective, randomized, double-blind, placebo-controlled, phase III trial showed that mycophenolate treatment was not superior to placebo in maintaining myasthenia gravis control during a 36-week schedule of prednisone tapering (25).
• Mycophenolate is an effective adjunctive therapy for the treatment of severe, refractory, and steroid-dependent myasthenia gravis.
• Mycophenolate is used as a non-nephrotoxic alternative to cyclosporine in cyclosporine-dependent myasthenia gravis patients with renal impairment.
• Case reports show promising results of mycophenolate in juvenile myasthenia gravis and chronic inflammatory demyelinating polyradiculoneuropathy of childhood, diseases in which adverse effects of chronic steroid therapy are a concern (15). Studies to examine its relative efficacy, tolerability, and adverse effects in children are needed.
• Mycophenolate may have a role in treating ocular myasthenia gravis where steroids are contraindicated (09).
• Inflammatory myopathies
• Inflammatory neuropathies
• Multiple sclerosis. Results of a retrospective multicenter study suggest that mycophenolate can improve or stabilize multiple sclerosis patients and can be used as an alternative therapy (18). In a small study, the evidence for efficacy of mycophenolate as add-on to interferon beta-1a in new-onset relapsing-remitting multiple sclerosis was insufficient (30).
• Experimental allergic encephalomyelitis
• Systemic lupus erythematosus. Although both mycophenolate and cyclosporin showed a significant effect on disease activity and circulating B-cell subsets in systemic lupus erythematosus in a comparative study, only myophenolate reduced circulating plasmablasts and plasma cells as well as circulating free light chains within 3 months of induction therapy (08). A systematic review of clinical trials indicates that the efficacy of mycophenolate in neuropsychiatric manifestations of systemic lupus erythematosus is unproven and should be limited to those patients who are refractory or intolerant to cyclophosphamide (19).
• Mycophenolate mofetil, in combination with steroids, has been used successfully in a case of primary angiitis of the central nervous system (03).
• Mycophenolate is associated with reduction in relapse frequency and reduced disability in patients with neuromyelitis optica (13).
• Mycophenolate has been reported to produce improvement in one case of idiopathic hypertrophic pachymeningitis (02).
• Behçet disease involving the nervous system (27).
• Results of a comparative open clinical study on patients with systemic lupus erythematosus indicate that both cyclophosphamide and mycophenolate can regulate the lymphocyte subsets and consequent abnormal immunity, but mycophenolate produces fewer side-effects than cyclophosphamide (31).
• A patient with chronic inflammatory demyelinating polyneuropathy who continued to deteriorate despite treatment with high-dose glucocorticoids was later diagnosed with a combination of chronic inflammatory demyelinating polyneuropathy and myasthenia gravis (24). He improved after treatment with pyridostigmine bromide, prednisone, and mycophenolate mofetil, raising the possibility of a common immunological abnormality in this rare association.
• Mycophenolate does not affect disease progression but influences relapse rate in progressive multiple sclerosis (07).
Mycophenolate is contraindicated in patients who are allergic to it or any components of the pharmaceutical preparations.
The goal of treatment in myasthenia gravis patients is clinical improvement as assessed by any of the recognized measures. Another indication of improvement is the reduction of dose of concomitantly used immunosuppressants. The duration of treatment is usually 6 months. Tapering of mycophenolate appears safe after years of disease stability in myasthenia gravis patients; reducing the dose by 500 mg/day every year is recommended (12). A retrospective study (NCT00683969) provides evidence that mycophenolate mofetil is an effective and beneficial nonsteroidal immunosuppressive agent in the treatment of myasthenia gravis when used for at least 1 year, with greater improvement after 2 years (26).
Approved oral dose for prevention of rejection of transplanted organs is 1 to 1.5 g as capsules or tablets twice a day. Oral suspension and intravenous preparations are also available. The dose used in clinical trials is 1 g twice daily. Dosing to achieve a target 12-hour post-dose area-under-the-curve of greater than 35 mg·h/L of mycophenolic acid is likely to lead to better efficacy outcomes in patients with autoimmune disease rather than just giving a standard dose (01).
Complete blood counts should be done weekly during the first month of treatment, twice monthly during the second and third months, and monthly thereafter during the first year.
Pediatric. Pharmacokinetics and efficacy of treatment of mycophenolate, as studied in transplant patients between the ages of 1 to 18 years, are like those of adults.
Geriatric. Use of mycophenolate has not been studies in geriatric patients.
Pregnancy. All immunosuppressant agents have potential adverse effects during pregnancy. Animal studies with mycophenolate have shown teratogenic effect. A study from a group of different European teratogen information services has provided evidence of a specific mycophenolate embryopathy with patterns that include external ear anomalies ranging from hypoplastic pinna to complete absence of pinna, cleft lip, with or without cleft palate, and ocular anomalies as iris or chorioretinal coloboma and anophthalmia/microphthalmia (23). There are no adequate or well-controlled studies of the mycophenolate therapy during pregnancy, and its use is not recommended unless the benefits of treatment outweigh the risks. Contraception is used during mycophenolate treatment in women of child-bearing age. Women on mycophenolate therapy should be aware of the potential risk of this drug to cause a specific embryopathy and the need of interrupting the treatment at least 6 weeks before becoming pregnant.
Anesthesia. No interaction of mycophenolate has been reported with anesthetic agents.
Renal insufficiency decreases the protein binding of mycophenolate and increases free mycophenolic acid concentrations. The disposition of mycophenolic acid in patients with severe renal impairment may be significantly affected by this change in protein binding.
Mycophenolate is compatible with other immunosuppressant agents such as cyclosporine and corticosteroids but may interact with other drugs (see the Physicians’ Desk Reference for complete listing). It is not recommended for use concomitant with cholestyramine due to fear of impairment of enterohepatic circulation. Live attenuated vaccines may be less effective during treatment with mycophenolate.
Enteric-coated mycophenolate sodium was developed to reduce the upper-gastrointestinal adverse effects by releasing mycophenolate in the small intestine rather than the stomach, but this anticipated improvement of upper gastrointestinal side effects has not been achieved in practice.
Serious adverse effects with mycophenolate are fewer compared to the older immunosuppressive agents. Product warning states the risk of developing lymphoma and gastrointestinal infections. Neutropenia is also a major concern. Opportunistic infections may be associated with increased immune suppression.
There is a report of a patient who developed urticaria during treatment of systemic lupus erythematosus with mycophenolate, and the diagnosis was confirmed by recurrence of urticaria on rechallenge (28). A desensitization protocol successfully induced tolerance to mycophenolate.
A patient with myasthenia gravis was effectively managed with mycophenolate but developed CNS lymphoma after 3 years of treatment, but it regressed after withdrawal of mycophenolate (29). Another patient with myasthenia gravis on long-term mycophenolate mofetil and pyridostigmine presented with neurologic deterioration, and MRI showed appearance of multiple brain abscesses, but a stereotactic biopsy reported B-cell lymphoma (14).
Treatment with mycophenolate is recommended in centers equipped to care for transplant patients and the complications of this treatment.
Mycophenolate mofetil has been reported to induce progressive multifocal leukoencephalopathy in a kidney transplant patient who improved following discontinuation of the drug (06).
Results of a retrospective cohort study suggests that discontinuation/marked reduction of mycophenolate therapy may increase the risk of myasthenia gravis exacerbation many fold (21).
A patient with myasthenia gravis who developed cytomegaloviral retinitis due to immunosuppression as a result of mycophenolate treatment was treated successfully with intravitreal injection of ganciclovir and foscarnet as well as oral valganciclovir (22).
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.See Profile
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