Mycophenolate mofetil and tacrolimus: New therapeutic options in neuroimmunological diseases

Abstract

Mycophenolate mofetil (MMF) and tacrolimus are novel immunosuppressive drugs, both first established in transplantation medicine and now used increasingly in neuroimmunological diseases including myasthenia gravis, dysimmune polyneuropathies, and myositis. In myasthenia gravis, the efficacy and safety of MMF has been shown by one open-label trial; one small, double-blind, placebo-controlled trial; and a few retrospective analyses. Similarly, for tacrolimus the greatest experience and evidence for efficacy and safety have been gathered in myasthenia gravis. MMF and tacrolimus have both been used as an alternative treatment for various other autoimmune diseases in which azathioprine or cyclosporine were not sufficiently effective. However, experience with tacrolimus in dysimmune polyneuropathies and myositis is limited. At this time, the available data suggest that MMF and tacrolimus are well suited for long-term immunosuppression in patients with myasthenia gravis. The spectrum of neuroimmunological diseases in which these drugs may be used has not been finally delineated and will require further controlled studies.

Immunosuppression of experimental autoimmune myasthenia gravis by mycophenolate mofetil

“…This case report subsequently prompted investigators to study the effects of MMF in more detail in MG. Adverse events are thought to be absent during treatment, as MMF only interferes with proliferating antibody producing B-and T-lymphocytes, due to inhibition of inosine monophosphate dehydrogenase type II (IMPDH II), a key enzyme in the de novo pathway of purine synthesis (Allison and Eugui, 2000;Schneider-Gold et al, 2006). Furthermore, as IMPDH II is not involved in the hypoxantine guanine phosphoribosyl transferase salvage pathway of purine synthesis, MMF does not inhibit key enzymes of other cell tissues, which is different from other immunosuppressants that are nowadays used for treatment of MG patients (Patel et al, 2006;Schneider-Gold et al, 2006).…”

“…Adverse events are thought to be absent during treatment, as MMF only interferes with proliferating antibody producing B-and T-lymphocytes, due to inhibition of inosine monophosphate dehydrogenase type II (IMPDH II), a key enzyme in the de novo pathway of purine synthesis (Allison and Eugui, 2000;Schneider-Gold et al, 2006). Furthermore, as IMPDH II is not involved in the hypoxantine guanine phosphoribosyl transferase salvage pathway of purine synthesis, MMF does not inhibit key enzymes of other cell tissues, which is different from other immunosuppressants that are nowadays used for treatment of MG patients (Patel et al, 2006;Schneider-Gold et al, 2006). For example, azathioprine exerts its immunosuppressive effect on both the de novo pathway of purine synthesis and the hypoxantine guanine phosphoribosyl transferase salvage pathway; thereby causing not only inhibition of B-and T-lymphocytes proliferation but also inhibition of purine synthesis in other tissues leading among other side effects to bone marrow suppression (Derijks et al, 2004;Gunnarsdottir and Elfarra, 1999).…”

“…A dose of 30 mg/kg/day was chosen as this dose has already been proven to be efficient in other experimental diseases (Gibson and Hayden, 2007;Tran et al, 2001;Zandman-Goddard and Shoenfeld, 2005). Moreover, MG patients daily receive an oral dose of 1.0-2.0 g, which is in the range of the body weight related dose of MMF used in the present study (Schneider-Gold et al, 2006). The results showed that MMF was able to suppress anti-rat AChR antibody titers to values to 0.9 ± 1.3 nmol/L 8 weeks after immunization in both experimental regimes.…”

“…Moreover, MMF does not only augment apoptosis of lymphocytic and monocytic cell lines (Cohn et al, 1999) and reduces the levels of immunoglobulin isotypes M, G and A produced by polyclonal activated Blymphocytes (Eugui et al, 1991), it also inhibits glycosylation of adhesion molecules (Blaheta et al, 1998) and regulates the secretion of inflammatory and anti-inflammatory cytokines (Durez et al, 1999). Consequently, MMF acts as a pluripotent immunomodulator in numerous types of immunological diseases (Schneider-Gold et al, 2006).…”

Recent Advances in the Treatment of Neurological Autoimmune Disorders

“…The clinical significance of this drug was that, it was the first drug tried in a double-blind and placebo-controlled trial MG patient population (Tindall et al, 1987). Patients with refractory MG show better responses towards cyclophosphamide, methotrexate and mycophenolate mofetil (Schneider-Gold et al, 2006). The recent advancements included are the administration of intravenous IgG that has a potential blocking activity against auto antibodies.…”