**2. Systemic lupus erythematosus treatment**

#### **2.1 Antimalarials**

Antimalarials have been used for many years in the treatment of rheumatic diseases [1, 2]. Historically, antimalarials had been observed to ameliorate rheumatic symptoms in soldiers taking these drugs during World War II for the prevention of malaria [3]. Clinical application of hydroxychloroquine and chloroquine in the treatment of rheumatic diseases has been widely reported. The use of hydroxychloroquine in the treatment of SLE has been well established [4, 5]. It has been used in both discoid lupus and SLE [6]. Chloroquine and hydroxychloroquine increase pH within intracellular vacuoles and modify processes such as protein degradation by acidic hydrolases in the lysosome, organization of macromolecules in the

**113**

*Novel Therapeutic Interventions in Systemic Lupus Erythematosus*

reduces glucose levels via multiple mechanisms [18].

Corticosteroids have been used at large bolus doses as induction treatment as well as at small doses as maintenance treatment in patients with SLE [19] (**Figure 1**). They reduce disease activity as well as disease burden accrual on different organ systems [20]. Corticosteroids have potent immunomodulatory properties [21]. They are known to modulate all aspects of immune response and have strong immunosuppressive and anti-inflammatory properties [22, 23]. Their effects on the immune system are known to be mediated mainly by their trans repression mode of action, namely by their ability to reduce the expression of inflammatory transcription factors [24]. As corticosteroids are characterized by many severe and less severe side effects such as propensity to infections [25, 26], blood glucose elevation [27] and osteoporosis [28], different immunomodulating agents have been applied in patients with SLE as

Methylprednisolone pulse therapy is used for the treatment of severe manifestations of SLE. Intravenous pulses of prednisolone rapidly immunosuppress patients with organ and/or life-threatening manifestations of SLE [29, 30]. The gold standard is 1 g/day for 3-5 days [31]. However, this treatment schedule may be associated with significant infectious complications and lower doses may be useful as well. In particular, it has been shown that a lower dose pulse methylprednisolone treatment schedule involving <1500 mg/3 days may have the same beneficial effects

**2.2 Corticosteroids**

corticosteroid sparing agents.

endosomes, and post-translation modification of proteins in the Golgi apparatus. The antirheumatic properties of antimalarials is a consequence of their interference with antigen processing in antigen-presenting cells. For the digestion of antigenic proteins and for the peptides to assemble with the chains of the MHC class II proteins it is necessary to have acidic cytoplasmic compartments. Antimalarials increase the pH thereby diminishing the formation of peptide-MHC protein complexes which are required to stimulate CD4+ T cells and down-regulating the immune response against autoantigenic peptides [7, 8]. It also blocks Toll-like receptors on dendritic cells [9]. A review of controlled trials on the clinical efficacy and safety of antimalarials showed that adequate evidence exist for these drugs, in particular hydroxychloroquine in preventing lupus flares, increasing long term survival of patients and lupus activity in pregnant women without proven teratogenicity [10]. Moderate evidence exists for the prevention of irreversible organ damage, prevention of bone destruction and prevention of thrombosis. Weaker evidence exists for the reduction in severe lupus activity, lipid levels and subclinical atherosclerosis [11]. Hydroxychloroquine has been shown to improve glucose metabolism [12]. The toxicity of antimalarials is mild, infrequent and it is usually reversible. When given attention to dosage hydroxychloroquine has a safer profile. Ruiz-Irastorza et al recommended that hydroxychloroquine should be given to all patients with lupus during the full course of the disease [13]. They have described hydroxychloroquine as being the cornerstone of lupus treatment [13]. There have been very few efforts on discontinuation of the drug due to its proven efficacy and the few and mild side effects. Hydroxychloroquine has multiple beneficial effects in SLE. It reduces lipid levels, thereby inhibiting atherosclerosis [14, 15]. Hydroxychloroquine has multiple effects on cholesterol metabolism, as it inhibits cholesterol biosynthesis, inihibits lysosomal hydrolysis of cholesteryl ester and stimulates the capacity of LDL receptor and the activity of HMG-CoA reductase [16]. Hydroxychloroquine protects lupus patients from thrombosis, as it has known antithrombotic action. It reduces red blood sludging, blood viscosity, platelet aggregation and protects the annexin V "shield" from disruption by antiphospholipid antibodies [17]. Additionally, it

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

#### *Novel Therapeutic Interventions in Systemic Lupus Erythematosus DOI: http://dx.doi.org/10.5772/intechopen.97168*

*Lupus - Need to Know*

**Figure 1.**

**Figure 2.**

applied in the treatment of severe SLE cases. Recently, the use of belimumab has been introduced in the treatment of SLE and is indicated in patients with nonrenal disease and renal disease not responsive to standard treatment. Although, recent advances in treatment have improved prognosis and life expectancy in lupus patients, much progress remains to be achieved. In the present chapter, the use of various treatment modalities for SLE will be discussed. Additionally, the use of

Antimalarials have been used for many years in the treatment of rheumatic diseases [1, 2]. Historically, antimalarials had been observed to ameliorate rheumatic symptoms in soldiers taking these drugs during World War II for the prevention of malaria [3]. Clinical application of hydroxychloroquine and chloroquine in the treatment of rheumatic diseases has been widely reported. The use of hydroxychloroquine in the treatment of SLE has been well established [4, 5]. It has been used in both discoid lupus and SLE [6]. Chloroquine and hydroxychloroquine increase pH within intracellular vacuoles and modify processes such as protein degradation by acidic hydrolases in the lysosome, organization of macromolecules in the

supplementary drugs will be reviewed.

*Agents contributing to the treatment of lupus nephritis.*

*Agents involved in systemic lupus erythematosus treatment.*

**2.1 Antimalarials**

**2. Systemic lupus erythematosus treatment**

**112**

endosomes, and post-translation modification of proteins in the Golgi apparatus. The antirheumatic properties of antimalarials is a consequence of their interference with antigen processing in antigen-presenting cells. For the digestion of antigenic proteins and for the peptides to assemble with the chains of the MHC class II proteins it is necessary to have acidic cytoplasmic compartments. Antimalarials increase the pH thereby diminishing the formation of peptide-MHC protein complexes which are required to stimulate CD4+ T cells and down-regulating the immune response against autoantigenic peptides [7, 8]. It also blocks Toll-like receptors on dendritic cells [9]. A review of controlled trials on the clinical efficacy and safety of antimalarials showed that adequate evidence exist for these drugs, in particular hydroxychloroquine in preventing lupus flares, increasing long term survival of patients and lupus activity in pregnant women without proven teratogenicity [10]. Moderate evidence exists for the prevention of irreversible organ damage, prevention of bone destruction and prevention of thrombosis. Weaker evidence exists for the reduction in severe lupus activity, lipid levels and subclinical atherosclerosis [11]. Hydroxychloroquine has been shown to improve glucose metabolism [12]. The toxicity of antimalarials is mild, infrequent and it is usually reversible. When given attention to dosage hydroxychloroquine has a safer profile. Ruiz-Irastorza et al recommended that hydroxychloroquine should be given to all patients with lupus during the full course of the disease [13]. They have described hydroxychloroquine as being the cornerstone of lupus treatment [13]. There have been very few efforts on discontinuation of the drug due to its proven efficacy and the few and mild side effects. Hydroxychloroquine has multiple beneficial effects in SLE. It reduces lipid levels, thereby inhibiting atherosclerosis [14, 15]. Hydroxychloroquine has multiple effects on cholesterol metabolism, as it inhibits cholesterol biosynthesis, inihibits lysosomal hydrolysis of cholesteryl ester and stimulates the capacity of LDL receptor and the activity of HMG-CoA reductase [16]. Hydroxychloroquine protects lupus patients from thrombosis, as it has known antithrombotic action. It reduces red blood sludging, blood viscosity, platelet aggregation and protects the annexin V "shield" from disruption by antiphospholipid antibodies [17]. Additionally, it reduces glucose levels via multiple mechanisms [18].

### **2.2 Corticosteroids**

Corticosteroids have been used at large bolus doses as induction treatment as well as at small doses as maintenance treatment in patients with SLE [19] (**Figure 1**). They reduce disease activity as well as disease burden accrual on different organ systems [20]. Corticosteroids have potent immunomodulatory properties [21]. They are known to modulate all aspects of immune response and have strong immunosuppressive and anti-inflammatory properties [22, 23]. Their effects on the immune system are known to be mediated mainly by their trans repression mode of action, namely by their ability to reduce the expression of inflammatory transcription factors [24]. As corticosteroids are characterized by many severe and less severe side effects such as propensity to infections [25, 26], blood glucose elevation [27] and osteoporosis [28], different immunomodulating agents have been applied in patients with SLE as corticosteroid sparing agents.

Methylprednisolone pulse therapy is used for the treatment of severe manifestations of SLE. Intravenous pulses of prednisolone rapidly immunosuppress patients with organ and/or life-threatening manifestations of SLE [29, 30]. The gold standard is 1 g/day for 3-5 days [31]. However, this treatment schedule may be associated with significant infectious complications and lower doses may be useful as well. In particular, it has been shown that a lower dose pulse methylprednisolone treatment schedule involving <1500 mg/3 days may have the same beneficial effects 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.
