Mycophenolate mofetil: What is its place in the treatment of autoimmune rheumatic diseases?
Introduction
Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA), a non-competitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme which plays a key role in de novo synthesis of guanosine nucleotides. The inhibition of IMPDH leads to a depletion of guanosine nucleotides and an increase of adenosine nucleotides with a consequent inhibition of DNA synthesis and cell proliferation. MPA exerts a specific cytostatic effect on activated lymphocytes due to their dependence on the de novo pathway [1].
MMF was initially used in the prevention of acute rejection in renal, heart and liver transplantation. Recently MMF has been introduced in the treatment of systemic lupus erythematosus (SLE) and seems to be effective in controlling global disease activity even when other therapeutic regimens have failed [2]. MMF has been used for the treatment of specific SLE manifestations; major evidence is available for the treatment of lupus glomerulonephritis (GLN), the most frequent severe manifestation of SLE leading to poor long term prognosis [3]. However, some encouraging results have also been obtained in the treatment of other lupus manifestations.
Over the last few years MMF has also emerged as an alternative therapeutic regimen for patients affected with other autoimmune rheumatic diseases (ARD), including inflammatory arthropathy, idiopathic inflammatory myopathies, systemic sclerosis and systemic vasculitis.
This review is focused on the use of MMF in the treatment of SLE and other ARD (Table 1).
Section snippets
Renal manifestations
The treatment of lupus GLN includes IV cyclophosphamide (CYF) plus prednisone as induction therapy followed by maintenance therapy with oral azathioprine (AZA) plus prednisone. It has been shown that CYF use reduces the rate of mortality and end stage renal failure, but is associated with a high frequency of adverse events including amenorrhea [4], malignancy and infections. For this reason researchers are looking to MMF as an alternative treatment for lupus GLN.
With the use of MMF uncontrolled
Inflammatory arthropathy
Data regarding the use of MMF in patients with RA and PsA are limited and inconclusive.
A number of reports, mostly published as abstracts, indicated that MMF at the dosage of 2 g/day is both effective and safe in the treatment of RA [18]. Unfortunately, all these studies evaluated only clinical and serological parameters and no data on the radiological damage progression are available, preventing any definite conclusion on the efficacy of MMF in RA.
The experience with PsA is very limited.
Tolerability
MMF seems to have a very good tolerability in patients with SLE and other autoimmune disorders.
In patients with SLE, the most frequent side effects of MMF were gastrointestinal (diarrhea, nausea) and infections, which occurred respectively in 29% and 23% of patients, as reported in a recent large series [2]. Most of these adverse events were mild and they required drug discontinuation and/or hospitalization in only a minority of cases. Moreover, in all the randomized controlled studies on lupus
Conclusions
MMF is a widely used immunosuppressive drug in transplantation. It has more recently been shown to be effective and well-tolerated also in patients with SLE and other autoimmune rheumatic diseases particularly polymyositis, dermatomyositis and, more recently, systemic sclerosis. However, further studies are needed in order to determine its real place in the treatment of these disease.
Take home messages
- •
Mycophenolate mofetil (MMF) exerts a specific immunosuppressive action on activated T and B lymphocytes.
- •
MMF is better tolerated than all other immunosuppressants used in autoimmune rheumatic diseases.
- •
MMF is effective in the induction and maintenance therapy of lupus glomerulonephritis.
- •
MMF has given encouraging results in the treatment of other SLE manifestations or other autoimmune rheumatic diseases (ARD).
- •
Further studies are needed in order to determine the real place of MMF in the treatment
References (40)
- et al.
Long-term prognosis and causes of death in systemic lupus erythematosus
Am J Med
(2006) - et al.
Prevention of gonadal toxicity and preservation of gonadal function and fertility in young women with systemic lupus erythematosus treated by cyclophosphamide: the PREGO-study
Autoimmun Rev
(2006) - et al.
1st International Conference on Cutaneous Lupus Erythematosus. Düssendolf, Germany, September 1–5, 2004
Autoimmun Rev
(2005) Clinical manifestation of cutaneous lupus erythematosus
Autoimmun Rev
(2005)- et al.
Treatment of chronic plaque-stage psoriasis and psoriatic arthritis with mycophenolate mofetil
J Am Acad Dermatol
(2000) - et al.
Mycophenolate (CellCept) treatment of myastenia gravis, chronic inflammatory polyneuropathy and inclusion body myositis
J Neurol Sci
(2001) Targeted therapy for systemic sclerosis
Autoimmun Rev
(2006)- et al.
Analysis of autoantibodies repertoires in small- and medium-sized vessels vasculitidies. Evidence for specific perturbations in polyartheritis nodosa, microscopic polyangiitis, Churg–Strauss syndrome and Wegener's granulomatosis
J Autoimmun
(2005) Mechanism of action of mycophenolate mofetil
Lupus
(2005)- et al.
Mycophenolate mofetil in systemic lupus erythematosus: efficacy and tolerability in 86 patients
J Rheumatol
(2005)
Mycophenolate mofetil combined with prednisone for diffuse proliferative lupus nephritis: a histopathological study
Lupus
Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group
N Engl J Med
Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis
Nephrology
Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis
N Engl J Med
Sequential therapies for proliferative lupus nephritis
N Engl J Med
Long term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis
J Am Soc Nephrol
Mycophenolate mofetil for refractory haemolytic anemia in systemic lupus erythematosus
Lupus
Skin manifestations of systemic lupus erythematosus refractory to multiple treatment modalities: poor results with mycophenolate mofetil
Clin Exp Rheumatol
Positive and negative effects of thalidomide on refractory cutaneous lupus erythematosus
Autoimmunity
Cited by (67)
Development and validation of an ultrafast chromatographic method for quantification of the immunosuppressant mycophenolic acid in canine, feline and human plasma
2016, Journal of Pharmaceutical and Biomedical AnalysisCitation Excerpt :Mycophenolic acid inhibits inosine monophosphate dehydrogenase, preventing synthesis of lymphocyte DNA resulting in decreased lymphocyte proliferation, antibody production, cellular adhesion, and migration of T and B lymphocytes [1]. The MMF is extensively used in human medicine to prevent organ rejection and in the treatment of other immune-mediated conditions [2]. Following oral administration, MMF is hydrolyzed to MPA, N-(2-carboxymethyl)- morpholine, N-(2-hydroxyethyl)-morpholine and the N-oxide of N-(2-hydroxyethyl)-morpholine by carboxylesterases (CES)- 2 within the intestine [3].
Severe pneumonia in mycophenolate mofetil combined with low-dose corticosteroids-treated patients with immunoglobulin A nephropathy
2015, Kaohsiung Journal of Medical SciencesExperience with the use of mycophenolate mofetil in juvenile idiopathic inflammatory myopathies
2023, Rheumatology (United Kingdom)Diagnosis and treatment-related issues of autoimmune epilepsy
2023, Epilepsy and Paroxysmal Conditions