*2.3.3 Mycophenolate mofetil*

*Lupus - Need to Know*

**2.3 Immunosuppressants**

*2.3.1 Azathioprine*

*2.3.2 Methotrexate*

and fewer adverse effects, in particular severe infections [32]. An intensive treatment schedule of rituximab, cyclophosphamide and intravenous pulses of methylprednisolone has been applied with excellent results in patients with SLE and severe organ manifestations including nephritis [33]. Patients improved significantly and long-term immunosuppression other than prednisone 5 mg/day was avoided. Corticosteroids in the form of prednisone daily as maintenance treatment for SLE patients has been applied for years. New data show that introducing lower initial doses of prednisone (<15 mg/day) and thereafter tapering to low doses of prednisone (5 mg/day or even lower) has been shown to be effective in SLE [34–36]. Mild flares can be managed with transient increases of prednisone up to 15 mg/day with rapid reduction. In moderate severe flares the use of pulse methylprednisolone 125 mg, 250 mg or 500 mg/day for three consecutive days is much more effective and less toxic than increasing oral prednisone to 0.5-1 mg/kg/day [32]. Rapid reduction from doses up to 30 mg/day prednisone should be performed to 5-2.5 mg/ day within few weeks. Immunosuppressive therapy should be started early in severe forms of the disease and when prednisone cannot be reduced to 5 mg/day or less.

Azathioprine is a purine analogue. It inhibits DNA synthesis by acting on proliferating cells [37]. It acts on the DNA [38]. Azathioprine is metabolized to 6-mercaptopurine through reduction by glutathione and other sulfhydryl-containing compounds and then enzymatically converted into 6-thiouric acid, 6-methyl-mercaptopurine, and 6-thioguanine [38]. Ultimately, azathioprine is incorporated into replicating DNA and can block the de novo pathway of purine synthesis. It is this action that is thought to contribute to its relative specificity to lymphocytes due to lack of a salvage pathway. The inhibition of purine synthesis, leads to less DNA and RNA available for the synthesis of white blood cells, including cells of the immune system. Actively replicating cells, such as T cells and B cells of the immune system, which actively synthesize purine to make new DNA are strongly affected [39, 40]. Thus, immunosuppression ensues. It has been used successfully in SLE as steroid sparing agent and in cases of lupus flares. It can be used safely during pregnancy

If the disease is not controlled with up to 5 mg prednisone methotrexate can be used as an immunosuppressant and steroid sparing agent [43, 44]. Methotrexate exerts anti-inflammatory actions through some well-known and other less wellknown mechanisms [45, 46]. It inhibits dihydrofolate reductase thus diminishing the de novo synthesis of purines and pyrimidines by preventing the regeneration from dihydrofolate of tetrahydrofolate. Tetrahydrofolate is essential for the generation of folate cofactors required for purine and pyrimidine synthesis [47]. The reduction in the levels of methyl donors, such as tetrahydrofolate and methyl tetrahydrofolate, by the inhibition of dihydrofolate reductase results in the inhibition of the generation of lymphotoxin polyamines through methionine and S-adenosylmethionine. The inhibition of amino-imidazole-carboxamido-ribonucleotide transformylase results in an increase in intracellular amino-imidazole-carboxamido-ribonucleotide levels. This increase has potent inhibitory effects on AMP deaminase and adenosine deaminase. Thus, adenosine is accumulated. Adenosine confers anti-inflammatory effects [48, 49]. Methotrexate has favorable effects on

[41]. It can be used as maintenance treatment in lupus nephritis [42].

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Mycophenolate mofetil (MMF) has been used for many years in the treatment of SLE. It is a potent immunosuppressing agent with efficacy in lupus nephritis [52] (**Figure 2**) and non-renal lupus [53]. It is particularly indicated in patients with lupus nephritis [54]. MMF is an inhibitor of purine synthesis and it acts to inhibit lymphocyte proliferation and nitric oxide production by activated macrophages [55]. MMF is a prodrug of mycophenolic acid. Mycophenolic acid is an inhibitor of inosine-5'-monophosphate dehydrogenase [55], it depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation, it inhibits the glycosylation and expression of adhesion molecules, and the recruitment of lymphocytes and monocytes into sites of inflammation, it depletes tetrahydrobiopterin and decreases the production of nitric oxide by inducible NO synthase without affecting the activity of constitutive NO synthases. By these mechanisms MMF exerts anti-inflammatory activity [55]. MMF quickly and persistently reduces numbers of activated B cells and levels of free immunoglobulin light chains [56]. Careful studies in lupus nephritis have established the equivalence of MMF to intravenous (I.V.) cyclophosphamide and its equivalence or superiority to azathioprine in the maintenance phase of treatment [Aspreva Lupus Management Study (ALMS), (MAINTAIN) trial] [57–61]. MMF is effective in non-renal lupus as well. In a systematic review of 20 case series and openlabel trials MMF was shown to benefit patients with hematological manifestations and refractory dermatological involvement [62]. It has also been shown to improve lupus arthritis. MMF has side effects including gastrointestinal symptoms, bone marrow suppression, infection risk and long-term risk of cancer from immunosuppression. It appears to be less toxic than cyclophosphamide. Cases of drug sensitivity to MMF have been reported among an Asian subgroup of patients when combined with high-dose corticosteroids [62–64]. By contrast, MMF appears to be more effective in preventing renal flares in high-risk populations such as African Americans [65].
