Lupus

Mycophenolate mofetil (MMF, CellCept®) is a prodrug of mycophenolic acid (MPA), an inhibitor of inosine-5′-monophosphate dehydrogenase. MPA depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation. MPA also inhibits the glycosylation and expression of adhesion molecules, and the recruitment of lymphocytes and monocytes into sites of inflammation. MPA depletes tetrahydrobiopterin and decreases the production of nitric oxide by inducible NO synthase without affecting the activity of constitutive NO synthases. Activated macrophages produce NO and superoxide, which combine to generate tissue-damaging peroxynitrite. By these two mechanisms MMF exerts anti-inflammatory activity. Unlike calcineurin inhibitors, MMF is not nephrotoxic and does not induce the production of TGF΢, which is fibrogenic. MMF does not increase blood pressure, cholesterol levels or triglyceride levels in recipients. MMF reduces acute and chronic rejection in allograft recipients and is efficacious in some nephropathies. Evidence is accumulating that MMF may have clinical utility in some autoimmune disorders.

Mycophenolate mofetil (MMF) is an immunosuppressive agent used in transplantation, with evidence of superior protection against acute transplant rejection compared to azathioprine-containing regimens. Subsequently MMF has been used in a variety of autoimmune conditions. The major experience in systemic lupus erythematosus (SLE) has focused on proliferative lupus nephritis. Following its success in the treatment of lupus nephritis, MMF is now being used to control other SLE manifestations such as, lupus disease activity, haematological manifestations and resistant skin lupus. In this review, we discuss our own experience and the literature report about the use of MMF in SLE.

Mycofenolate mofetil (MMF-Cellcept) is an immunomodulatory drug utilized extensively in transplant medicine. The efficacy of regimes including Cellcept in preventing allograft rejection, and in the treatment of rejection, is now firmly established. The immunosuppressive actions of this drug enabled the investigation for the beneficial effects in autoimmune diseases. We review the evidence for the contribution of MMF in autoimmunity in animal models of systemic lupus erythematosus (SLE), mercury induced autoimmune glomerulonephritis, diabetes mellitus, experimental autoimmune uveoretinitis, and experimental allergic encephalitis. MMF has an influence on the T and B cell pathways. It is immunosuppressive and anti-inflammatory.

Mycophenolate mofetil (MMF) has been reproducibly shown to inhibit lymphocyte adhesion and penetration of endothelial cell surfaces. The mechanism is not yet elucidated. In vitro studies on the effects of MMF on cell adhesion molecules (CAM) using human umbilical vein endothelial cells (HUVEC) have shown conflicting results. Different studies have independently shown that MMF increased, decreased or had no effect on intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1). Several studies suggest MMF may reduce the endothelial expression of E-selectin. Recent studies have been unable to replicate initial work, which suggested that MMF impaired glycosylation of lymphocyte CAM. The same studies concluded that MMF had no effect on the surface expression of lymphocyte CAM, but altered the binding ability of these molecules. ICAM-1/LFA-1 (lymphocyte function-associated antigen-1), VCAM-1/VLA-4 (very late antigen-4) and P-selectin/PSGL-1 (P-selectin glycoprotein ligand-1) ligand pairs are most likely to be involved. Few in vivo and no conclusive human studies have been carried out. The literature relevant to cell adhesion molecules in systemic lupus erythematosus (SLE) is reviewed in detail.

Effective induction therapy is of pivotal importance in minimizing renal parenchymal damage by the active immune-mediated inflammatory processes in severe proliferative lupus nephritis. Preservation of nephron mass is prerequisite to long-term renal survival. Data from US-based studies have shown improved efficacy with induction treatment comprising corticosteroid and cyclophosphamide, compared with corticosteroid treatment alone. Data from European studies have shown similar efficacy with a modified treatment regimen, in which smaller doses of cyclophosphamide were given at weekly or fortnightly intervals over a shortened treatment duration, and the treatment related adverse effects appeared less frequent with the reduced-dose regimen. We have also reported that sequential immunosuppression with prednisolone and oral cyclophosphamide as induction followed by azathioprine maintenance was associated with a high incidence of remission and relatively favourable long-term renal outcome in Chinese patients. However, cyclophosphamide treatment is associated with considerable adverse effects, which could be potentially fatal. Mycophenolate mofetil selectively inhibits lymphocyte proliferation, and thus targets an instrumental step in the pathogenesis of systemic lupus erythematosus. There is accumulating evidence that the combined use of mycophenolate mofetil and corticosteroid presents an effective treatment for severe proliferative lupus nephritis in different ethnic groups, and is associated with much fewer adverse effects compared with cyclophosphamide-based regimens. Recent data from our group also demonstrate the long-term efficacy of mycophenolate mofetil in preserving renal survival, when used continuously as both induction and maintenance therapy.

For the treatment of proliferative lupus nephritis, long-term cyclophosphamide (CY) regimens are efficacious, however, at the expense of substantial toxicity. In the last decade, sequential regimens of short-term CY induction followed by either mycophenolate mofetil (MMF) or azathioprine (AZA) maintenance have shown to be efficacious and safe reducing the long-term exposure to CY. In a maintenance study including predominantly Hispanics and African-Americans, the patients who received MMF and AZA maintenance had a higher cumulative probability of remaining free of the composite of death or chronic renal failure (CRF) compared to quarterly intravenous CY (IVCY) maintenance (89% in MMF, 80%, in AZA and 45% in IVCY). Likewise, MMF and AZA maintenance were associated with significantly lower incidence of severe infections (2% in each MMF or AZA, and 25% in IVCY), sustained amenorrhea (6% in MMF, 8% in AZA, and 32% in IVCY), and hospitalizations (one hospital-days per patient-year in each MMF or AZA, and 10 in IVCY). In a European induction study including predominantly Caucasians, patients who received any of two sequential regimens, low dose versus high dose IVCY induction both followed by AZA maintenance, had a high cumulative probability of remaining free of treatment failure (84% in low dose IVCY and 80% in high dose IVCY; treatment failure defined as a composite of free of corticosteroid resistant flare, nephrotic syndrome, doubling creatinine, and persistent elevated creatinine). Low dose IVCY and high dose IVCY induction were associated with low incidence of sustained amenorrhea (4% in each group) and severe infections (11% in low dose and 22% in high dose IVCY induction). Of interest, most of the severe infection episodes occurred while patients were receiving IVCY induction. Finally an Asian study demonstrated that patients with proliferative lupus nephritis could be effectively treated with short-term oral CY induction followed by AZA maintenance. The cumulative probability of complete remission was 76%. The relapse rate was only 11%. The incidence of permanent amenorrhea and infection were 8% and 33%, respectively. None of the Asian patients had an increase in serum creatinine level to double the baseline value. Maintenance therapies with MMF or AZA following short-term CY induction in a sequential regimen are efficacious and safe for the treatment of high-risk patients with proliferative lupus nephritis.

Mycophenolate mofetil (MMF) initially found widespread use in the immunoprophylaxis of rejection in organ transplantation. It has subsequently been used in lupus glomerulonephritis, where early studies have shown it to be effective in induction and maintenance therapy. The randomized studies have mostly studied small groups of patients and their conclusions do need to be confirmed in larger studies. MMF has also been used in small numbers of patients in a variety of nonlupus glomerulopathies, which have different underlying immunopathology as well as clinical course, including IgA nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, hepatitis-C-associated glomerulonephritis and even Goodpasture's syndrome. In this article, we discuss its use in such nonlupus glomerular diseases.

We describe experience with the use of mycophenolate mofetil (MMF) in neurological diseases. Although only small series of patients or case reports were described, MMF is promising in immunemediated neuromuscular disorders. MMF has been used for the treatment of polymyositis, chronic inflammatory demyelinating polyradiculoneuropathy, and multifocal motor neuropathy. These studies showed that MMF is well tolerated and may be useful in some patients. MMF can be effective alone but mainly as an adjuvant therapy by reducing steroid requirements or the frequency of infusions of IVIg. MMF has also been tested alone as a single drug treatment or in combination with immunomodulatory drugs in multiple sclerosis in open surveillance trials or in phase II studies. None of these studies have been designed to demonstrate a clinical efficacy but preliminary results are very promising.

Myasthenia gravis (MG) represents the prototypic autoimmune disorder with well characterized immunopathology. Advances in the diagnosis and treatment of this neuromuscular transmission disorder have significantly improved the management of myasthenic patients. Unfortunately the currently available immunomodulating treatments have significant side effects and some patients do not tolerate them or adequately respond to them. Therefore the possibility of a new immunosuppressant agent that is safe, effective and has steroid-sparing effect is very appealing. Mycophenolate mofetil (MMF) has shown promising effects in MG patients in preliminary studies and is currently being studied in two prospective, randomized, double-blind, placebo controlled, multicenter trials to better establish its role in the treatment of MG.

Immunosuppressive treatment has shown to be effective in various ocular inflammatory disorders. Factors limiting their use are the individual response and the rate of side effects. This report summarizes our knowledge about the use of mycophenolate mofetil (MMF) in the treatment of ocular cicatricial pemphigoid (OCP), uveitis, atopic keratoconjunctivitis (AKC), prevention of graft rejection after penetrating keratoplasty (PK) and scleritis. Controlled studies have been performed for prevention of graft rejection after PK, showing MMF as effective in the prevention of graft rejection as cyclosporine A. In experimental uveitis, MMF has been demonstrated to be highly effective in prevention of retinal destruction. A number of studies have now shown that MMF also seems effective in uveitis. There are also studies with smaller patient groups which point out the effectiveness of MMF in OCP, AKC, and scleritis. In most of the studies, the spectrum of side effects was small, compared to other immunosuppressives.

The systemic vasculitides are a group of potentially life-threatening multi-system autoimmune connective tissue diseases characterized by vascular inflammation. The gold standard therapies include corticosteroids and cyclophosphamide as induction therapy and other agents such as azathioprine and methotrexate to maintain remission. Mycophenolate mofetil (MMF) is increasingly being used in autoimmune disorders and this article reviews the use of this agent in the systemic vasculitides.

Mycophenolate mofetil (MMF) is an immunosuppressive drug the efficiency of which has been established in renal transplantation. Recent studies suggest that it may also be effective in the treatment of variant skin diseases especially if the skin lesions are triggered by lymphocytes. Studies have shown efficacy in autoimmune bullous dermatoses, atopic dermatitis and psoriasis. However, there are no placebo-controlled trials that support the use of MMF as first line therapy in these skin diseases.

Diagnosis and treatment of hepatitis C virus (HCV) -related autoimmune features has become a clinical challenge in HCV-infected patients, in whom chronic liver disease associated with severe autoimmune features may contribute to a very poor prognosis. Both antiviral and immunosuppressive therapies, either alone or in combination, seem likely to have a key role. Based on the experience of mycophenolate mofetil (MMF) use in HCV patients receiving organ transplantation, this new immunosuppressive agent might represent a safe and effective therapeutic option to treat HCV-related extrahepatic features. Recent data are available for the use of MMF in HCV patients with autoimmune manifestations, mainly for autoimmune cytopenias and vasculitic features. MMF may be used as monotherapy or in association with other drugs for cases of HCV-related autoimmune diseases refractory or intolerant to common immunosuppressive treatments, allowing the reduction of the drug dosage and avoiding serious side effects.