*2.3.2 Methotrexate*

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

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*Novel Therapeutic Interventions in Systemic Lupus Erythematosus*

the joints and the skin [50]. It is teratogenic, therefore if pregnancy is contemplated

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].

Cyclophosphamide is an alkylating agent. It crosslinks DNA and results in the death of activated lymphocytes and protects glomeruli [56, 66]. It modulates the expression of T and B cell activation markers [67]. It has been demonstrated in a meta-analysis that there is a decreased risk of end-stage renal disease when cyclophosphamide is applied as standard of care therapy for lupus nephritis [68]. Cyclophosphamide has potential side effects, which include leukopenia, infection risk, bladder toxicity and increased risk of malignancy [69]. Consequently, cyclophosphamide is used as an induction treatment for severe lupus [64, 70] and is replaced by other agents, such as MMF and azathioprine for long-term maintenance treatment.

The use of calcineurin inhibitors tacrolimus and cyclosporin A in SLE is derived from the experience of these drugs gained in organ transplantation. These drugs suppress the production of cytokines, inhibit T- and B cell activation and preserve the renal podocyte actin cytoskeleton, thus reducing proteinuria [71]. In non-renal SLE cyclosporin A exhibits steroid-sparing effects, reduces disease activity and flares [72]. Cyclosporin A acts by modulating lymphocyte function [73, 74]. It forms

*DOI: http://dx.doi.org/10.5772/intechopen.97168*

*2.3.3 Mycophenolate mofetil*

*2.3.4 Cyclophosphamide*

*2.3.5 Calcineurin inhibitors*

it should be withdrawn before conception [51].

the joints and the skin [50]. It is teratogenic, therefore if pregnancy is contemplated it should be withdrawn before conception [51].
